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Neurologic and Psychiatric Effects of SARS-CoV-2 Meeting: Day 2

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Neurologic and Psychiatric Effects of SARS-CoV-2 Meeting: Day 2

Transcript

DR. MASLIAH: Welcome.  Yesterday, we really had a very fantastic meeting, and focusing on the acute aspects of SARS-CoV-2 infection, and today we are going to focus more on the post-acute effects.

It's really my pleasure to introduce the session this morning.  I just have a few reminders.  Please, for all the participants, maintain the muted and listen-only mode and cameras will be turned off.  Please, put your questions via Q&A box any time during the presentation, and if you have any technical difficulties hearing or viewing the webinar, please note that in the Q&A box and our technicians will work to fix those problems.  You can send your emails of questions to the email that you find in the screen.

With that, it's really my great pleasure to introduce our plenary speaker this morning, Dr. Avi Nath, who is a clinical director at the NINDS and he will be speaking today about what we have learned from prior viral pandemics that might be relevant to the long-term neurologic effects of COVID-19, and with that, Avi.  Please, go ahead.  Thank you.

Have a great meeting, everybody.

Plenary Talk: What We Have Learned From Prior Viral Pandemics That May Be Relevant to Long Term Neurologic Effects of COVID-19?

DR. NATH: I want to start with this quote first from Sir William Osler.  In 1896 he gave a keynote address to the American Medical Association, and there he said that humanity has but three great enemies, fever, famine, and war.  Of these by far the greatest, by far the most terrible, is fever.  And that holds true even today, because infections have the potential of wiping out huge populations in a short period of time, and the number of people who die from it far exceeds that put together with famine as well as war.  And that holds true with the current pandemic.

But there are a lot of pandemics that we faced in the recent past and almost all of them have chronic neurological syndromes associated with them.  I'm going to go through each one of these pandemics and comment upon the possible pathophysiological mechanisms of each of these chronic neurological syndromes associated with them.  And at the end I'm going to end with Gulf War Syndrome and Chronic Fatigue Syndrome, which overlap with the long COVID associated with SARS-CoV-2.

First, Zika virus.  As many of you will remember, this devastated South America, and it resulted in a lot of congenital malformations in children, leading to anencephaly, microcephaly, and even in children who were thought to be born normal had all kinds of developmental abnormalities that were realized only after they were born. 

Autopsy cases that have been available in some of these children show that there's persistent virus within the brain, and there are areas of calcification, and within that you can find virus.  It infects the glial cells as well as the neurons.  Here you can see viral antigen in some glial cells.  The virus infects the progenitor cells, and that's why you get all these developmental abnormalities of the brain, because it then prevents them from differentiating into neurons. 

And there's another syndrome associated with Zika, and that is the Guillain-Barre syndrome, and as shown here from data from Colombia where they had the incidence of cases of Zika virus infection parallels the increase in Guillain Barre syndrome.  So there's a direct relationship between the two, and however, Guillain Barre syndrome is thought to be all immune-mediated.  So here there is no direct viral infection of the nerves, but rather it stimulates the immune system in a way that leads to the development of Guillain Barre syndrome.  So you have both types of syndrome, viral persistence and immune-mediated syndrome, but totally different clinical presentations. 

What about poliomyelitis?  As you know, polio devastated the world until the vaccine was available and became widely available.  And now it's been almost wiped out from the planet.  However, there are still a few cases that do emerge in Afghanistan and some other remote places. 

It's been associated with post-polio syndrome, and there are very few autopsy cases available of post-polio syndrome, but whatever they are show that you can find infiltrates within the spinal cord, around the areas where the anterior horn cells are present.  These patients usually present with a progressive leg weakness, with atrophy, paresthesias, in areas that were previously affected by polio, and it can occur several years after polio first developed.  But there's active inflammation, and this study here from several years ago shows that they were able to detect enterovirus RNA in the postmortem tissues from these patients, and it was present in the spinal cord but not in the cerebral cortex, so indicating that the virus was probably dormant for many years, and then with active inflammation, somehow how gets reactivated and that's probably leading to this progressive neurological syndrome.  But it occurs in that focal area where polio first had occurred.  So there's no spread, it's just in that same area or generalized area there. 

What about measles?  Measles causes a rash, it's highly infectious, and again, because of the availability of vaccine, we now have control on measles, but yet, in a number of developing countries, people are not fully vaccinated for measles, and there are recurrent cases of infection that occur every year.  In children, unfortunately, some of them can develop this condition called subacute sclerosing panencephalitis, and this occurs several years after the acute infection.  It causes a progressive mental deterioration with myoclonus, and the interesting thing is that if you look at the spinal fluid, you cannot detect the virus, however, there are oligoclonal bands, and the way you diagnose the disease is that the antibody levels to measles are much greater in the spinal fluid compared to the blood, suggesting that there's intrathecal synthesis of the antibodies.  These patients often have very classical EEG pattern, which is periodic spikes and sharp waves, as you can see over here. 

The MRI can show abnormalities, as you can see here, both gray and white matter abnormalities can be seen on the MRI scan in these patients.  And even though the virus cannot be found in the spinal fluid, you can certainly find it in the brain.  So if you immunostain for viral antigen, you'll find it in neurons.  All this beading that you see here in this neuronal axon is viral antigen here.  And in this insert, you can see measles antigen is also found in the oligodendrocyte.

The rest of the brain shows lymphocytic infiltrates here, in the meninges.  You can see neuronal loss, white matter pallor, and look at these astrocytes, very large astrocytes.  As I mentioned, you can find viral antigen, oligodendrocytes, as well as neurons.  It is thought that maybe by cell-to-cell contact there's transmission of the virus from neuron to neuron and from oligos to neurons. 

However, one would wonder why the virus doesn't leak into the spinal fluid.  And the reason it doesn't is that if you sequence the virus from the brain, what you will find is that there are mutations, one, in the matrix protein, which is called the M protein, and because of these mutations the virus is unable to form a viral particle.  And there are also mutations in the F protein, which is called the fusion protein, and that makes it hyperfusogenic.  So it allows the virus to transmit from cell to cell. 

Here, how it works.  Traditionally, if you look at, for example, rabies or herpes viruses, they transmit from neuron to neuron but they bud into the synaptic vesicle, into the synaptic space here between the neurons, and then are taken up by the other neuron that is in proximity to the first one.  However, in the case of measles, because you have this hyperfusogenic protein, what it does is it fuses the cell membranes here, and once this fusion is formed, the viral RNA and the nuclear protein complex -- so it's just an RNA protein complex -- now that will transmit from cell to cell.  So the complete virus is not formed, it doesn't shed outside, but yet it has the ability to transmit from cell to cell.  This evades the neutralizing antibodies. 

What about the Spanish flu?  Much has been said about that and parallels have been drawn between that as well as COVID.  This occurred in the early 1900s and devastated Europe and North America.  We had an acute phase, during which there were three different types of clinical syndromes that have been described, and probably more so.  But at least they could be put into these three buckets. 

First phase is called the somnolent-ophthalmoplegic phase, where the patients were hypersomnic and had all kinds of eye movement abnormalities.  And another subtype was hyperkinetic type, so they get all kinds of movement abnormalities.  And then you have the amyostatic or akinetic type, which is loss of movement.  One to five years later, in some individuals maybe 40 years later, you can develop a constellation of syndromes that includes Parkinsonism, it includes sleep disturbances, oculomotor abnormalities, and involuntary movements, speech and respiratory abnormalities, and also psychiatric dysfunction. 

If you try to localize these symptoms, they are referable to the brainstem.  So von Economo drew this diagram in 1926, and he said that a lot of these disturbances can be accounted for, lesions that are between the brainstem and the diencephalon.  And actually that makes a lot of sense, because the midbrain and all these areas are where sleep and wakefulness is controlled over here.  Certainly, some of these others may involve other areas of the brain.  But it is important to think about that these are still localizable lesions within the brain. 

Now, it's also claimed that there were a number of epidemics prior to encephalitis lethargica that resemble that same syndrome.  So Crookshank dug through the historical literature and claimed that they were called by various types of names that occurred in various parts of Europe, but the clinical presentation was very similar to encephalitis lethargica.  Interestingly, however, since the early 1900s, we have never seen another pandemic of this nature.

What about dengue?  Dengue, as you know, has devastated Africa and Asia, and still continues to this day in pandemic proportions.  It can cause encephalitis, usually an acute encephalitis, and here this is a case report, so it's fairly rare, but this is a patient that we saw, and this patient turned out to have chronic dengue encephalitis, but it presented as a progressive dementia.  So over a period of 15 years, he developed neurological symptoms that were gradually progressive, and ultimately died a neurological death. 

Here you can see his MRI scans, this is a thirty-year-old man, and this massive atrophy of the brain, both cortical and subcortical.  When we looked at the brain, you can find that there's viral antigen here spread throughout the -- you can see it at neurons, you can see it at endothelial cells here.  They are also present in some glial cells.  This is by immunostaining and then by in situ hybridization, for dengue virus, you can see here the neurons and endothelial cells that are positive for the RNA strand, and by PCR we could detect it at autopsy as well as in prior biopsy material.  This was caused by dengue 1.

Again, you can see that if you have persistent virus, it leads to a chronic neurodegenerative process in the brain.

What about HIV infection?  As you know, AIDS is a huge pandemic, and although we've done really well in being able to treat the infection, we still don't have a vaccine and we don't have a cure for it.  Early in the pandemic, there was a huge unrest because it affected the entire globe, and we really, there was a lot of stigma over the infection, and really very little scientific progress was being made in those times.

This is what it looked like in the pre-antiretroviral era.  You can see, this is a 30-year-old patient who has a massive atrophy affecting the basal ganglia and the frontal and temporal lobes over here, while the posterior parts of the brain are relatively preserved.  If you look at the brain at autopsy, we found a lot of perivascular infiltrates and macrophages, multinucleated giant cells, and here they're immunostaining brown for HIV antigens.  And the patients presented with a subcortical dementia.

In the antiretroviral era, now that we have antiretroviral drugs that prevent viral replication, in those patients where you cannot detect any replicating virus any longer in the blood or CSF, about a third of them still continue to have viral proteins that are present in the spinal fluid.  So here, we detected Tat protein, and you can see there's a cohort at NIH, and we found that about a third of them still have large amounts of Tat that are present there. 

We also found it in exosomes of these patients.  You can see this band on top, there's immunostaining for Tat, and in those individuals who had presence of Tat, you could see that there is a neurocognitive impairment, again, suggestive of subcortical impairment.  So there's processing speed was decreased, and you can see the psychomotor domain was also decreased, suggesting subcortical involvement, and that's where the maximal viral load is present.  Again, localizable lesions that are progressive in these patients. 

The other interesting thing about these patients who still have detectable Tat, if you look at autopsy here, you can find it's present in macrophages here.  We cannot find replicating virus, no p24 antigen.  However, you can find T-cell infiltrates within the brain, and that makes sense, because you have viral antigen being recognized by T cells, and now these patients are not immune-suppressed, so they have the ability to have T cells infiltrating there.

The other interesting thing is that if you take Tat and you put it in the hilum of the dentate gyrus, what it does is, it translocates all the way to the CA3 and CA4 regions, so it's gone along neuronal pathways.  As I showed you previously with measles, you have the viral protein and RNA complex goes across neurons. Here the viral protein alone can go along neuronal pathways and then at distant sites cause inflammation.

Now I'm going to transition to these other syndromes for which we don't really have a clear understanding of the pathophysiological basis.  Ebola, as you know, devastated West Africa, and there people tried to look for persistent virus, and you could find at least in one individual, there was some virus that was present in the aqueous humor of the eye for at least 14 weeks post-recovery from infection, and it was found in seminal plasma of some patients, as long as 13 months.  But none of this is infectious virus, and certainly evidence of sexual transmission of Ebola is very low, but bits and pieces of virus could still be found.  But long term, it's not present there, and it's present in a small subset of individuals. 

However, 30 percent of these individuals who recover from Ebola still complain of post-Ebola disease syndrome.  This is a constellation of joint pain, fatigue, anorexia, blurred vision, headaches, mood disorders, and the etiology remains unknown. 

There's another syndrome called Gulf War Syndrome.  We don't know what the underlying cause is, but it has similar kinds of clinical manifestations with mood and cognitive changes, headache, fatigue, sleep disturbance and joint pain. 

And then there is a syndrome called myalgic encephalomyelitis, or chronic fatigue syndrome, and these patients also have very similar symptoms, post-exertional malaise, exercise intolerance, dysautonomia, pain syndromes, cognitive and sleep disruption.  This is most often postinfectious, but what infection causes it, what the underlying pathophysiology is, is still not clearly understood, but these are not neurodegenerative or progressive types of syndromes, like I showed you where you have persistent viral infection.  So one possibility is that these things are largely immune-mediated.

What I'd like to divide these syndromes into two, and one is where it has clear evidence of persistent viral infection, that usually have focal neurological signs, they have progressive neurodegeneration, and neuroinflammation is confined to the areas where virus and viral protein has spread.

And then you have these other more nonspecific generalized symptoms.  These patients have persistent immune activation.  They're nonprogressive or very slowly progressive.  There's no evidence of neurodegeneration, and this predominantly innate immune activation that occurs in these individuals. 

So what about SARS-CoV-2, then?  What kind of a syndrome would this be?  These patients are now developing what we call as long haul COVID after recovering.  Almost 10 to 30 percent of individuals at six months post-infection are complaining of long-term symptoms.  It's more so in women compared to men, and the average age is about 40 years.

Again, you can divide them into three large buckets.  One, that have predominantly fatigue, insomnia, and headaches.  The others that complain of cognitive dysfunction, some have psychiatric manifestations.  The third have predominantly dysautonomia. 

What are the possibilities here?  And if you look at them pathologically, what we found was that there is evidence of fibrinogen leakage from the blood vessels.  You can see all this brown staining is fibrinogen leakage here in the pons.  This is in the optic bulb over here.   So the endothelial cells obviously are abnormal, and they're leaking a lot of blood products into the parenchyma.  And if you look at the inflammatory infiltrate, it's largely macrophages, and you can see some glial cell activation around the blood vessels, and you can find some T cells, but there are very few T cells.  It's largely a macrophage-mediated disease.  And we didn't find any virus by immunostaining, RNA seq, in situ hybridization, or PCR.

So the proposed pathophysiology of long COVID is then either the virus or the viral protein alone may have mediated damage to the endothelial cells, resulting in leakage of blood products.  This leads to a chronic innate immune activation, and it's possible that there may be other autoimmune phenomenon occurring.  At least if we look at all the previous pandemics, that suggest that maybe this is the pathophysiology of long COVID, but that remains to be conclusively determined. 

I'll stop here.  Thank you. 

DR. NATH: So, now we will move to the first session of this morning, and I have the pleasure of introducing our speakers.  So we have three wonderful speakers here in this panel.  They're all neurologists who have a lot of expertise in neuroinfectious diseases, and each one of them has been involved in actively taking care of patients with COVID.

So they are going to talk about post-acute sequelae of SARS-CoV-2.  Dr. Kiran Thakur is the Winifred Mercer Pitkin Assistant Professor of Neurology and director of the program of neuroinfectious diseases at Columbia University in New York.  Dr. Igor Koralnik is the Archibald Church Professor of Neurology and chief of the Division of Neuroinfectious Diseases and Global Neurology at Northwestern University in Chicago, and Dr. Spudich, she's already been introduced previously, and is a co-organizer of this meeting.  She is the Gilbert H. Glaser Professor of Neurology and the chief of the Division of Neuroinfectious Diseases and Global Neurology at Yale University.

Agenda Item: SESSION I: Post-Acute Sequelae of SARS-CoV-2

DR. THAKUR: Good morning.  My name is Dr. Kiran Thakur.  I'm the Winifred Mercer Pitkin Assistant Professor of Neurology and the director of the program in neuroinfectious diseases at Columbia University Irving Medical Center and New York Presbyterian Hospital.  I would like to thank the National Institute of Health and organizers of this important symposium for giving me the opportunity to speak today on the clinical characterization of neuropsychiatric syndromes persisting in individuals post-COVID-19.  The following are my disclosures of relevance.  I receive funding support from the U.S. CDC on COVID-19 related research.

I want to first and foremost thank those individuals who have educated us on persisting symptoms, and emphasize that we will continue to advocate to better understand post-COVID-19 effects through our scientific undertakings, though we must address the many unheard voices in the post-COVID-19 setting. 

Our discussions of early research today on post-COVID-19 effects will identify some of the important issues around equity in post-COVID-19 care, and while there are over 80 post-COVID-19 clinics which have rapidly arisen in the United States in the last several months, we need to ask whether these clinics are accessible to uninsured populations, what are the proportion of Black and Hispanic Latinx survivors being treated and followed in research efforts, and how are we reaching hardest-hit communities.

Thus, in order to understand neuropsychiatric syndromes after COVID-19 infection, it's fundamental to design research and care models which are accessible to all individuals as has been done effectively during the HIV pandemic.  Identifying the social determinants of health factors are strongly associated with the development of COVID-19, disease severity, and likely play a huge role in the post-COVID-19 period.  We need to contextualize findings across the spectrum of COVID-19 disease severities that.

Thus, I will discuss neuropsychiatric conditions in those with asymptomatic and mild disease and those with severe illness requiring hospitalization separately.  One of the biggest challenges we face is around defining clinical phenotypes.  Recognizing the complexity of post-COVID-19 symptoms and their associated risk factors, such a framework should encompass primary psychiatric conditions, neurocognitive domains, and primary neurological syndromes, as illustrated here by the DSM-5 categorization of neuropsychiatric syndromes.  Clustering of these with other systemic effects, recognizing again the complex interplay amongst these syndromes, will help to identify phenotypic patterns among heterogenous clinical pictures.

I'll start by highlighting early research in asymptomatic and mild acute infections, touching upon a few studies, recognizing that the field is rapidly evolving.  The first author of this study, Hannah Davis, will be speaking today on the work she led of an expansive collection of subjective symptoms from on online survey.  While the survey was distributed globally and translated into multiple languages, the majority of the 3,762 respondents were white, 41 percent resided in the United States, and 92 percent completed the survey in English.

As shown here in these bar graphs, there was a significant amount of cognitive symptoms reported during the post-COVID-19 period, which was reported to have significant impact on daily life, most importantly the ability to return and perform at work.  Major limitations of this study included subjective symptom reporting without objective measures, the need for a high degree of health literacy and access to technology to respond to this extensive online survey, and a degree of selection bias, and I think despite the best efforts of this study, really truly did not represent the complete global cohort.

We will also be hearing about other study populations, including the post-COVID-19 neurological clinic by Dr. Igor Koralnik, after this talk.

Psychiatric symptoms and syndromes are also common, with almost 90 percent of survey respondents in the Davis et al study reporting mood and emotion symptoms at any point in the post-COVID-19 setting.  In a meta-analysis of studies in Chinese COVID-19 survivors, acute COVID-19 patients presented with a variety of acute symptoms as is shown here in this radar graph, which improved but persisted in their kind of mild to moderate degree in the post-COVID-19 setting.

In another study of 284 patients who completed a web-based or paper survey, symptom questionnaires were distributed up to 50 days after COVID-19 infection, with 35 percent reporting clinically significant PTSD, anxiety, and/or depression.  Predictors of PTSD were shown in this table which was the most common psychiatric symptom in the post-COVID-19 setting.

Neurological symptoms and syndromes are commonly reported and some of the categories are shown here, including headache syndromes, sleep disorders, sensorimotor symptoms, movement and vestibular disorders, a persistent loss of smell and taste, as well as functional neurological conditions.

Importantly, the pediatric and adolescent population have not only been impacted directed by COVID-19, but by the indirect effects of the pandemic, including a lack of socialization and isolation due to remote schooling, food and economic insecurity, amongst other challenges.  A recent report describes two interesting cases meeting criteria for pediatric acute onset neuropsychiatric syndrome, which has been described in those with a history of strep infections.  Further studies are required to identify the true neuropsychiatric impact across a variety of domains as shown in this table in this vulnerable population.

I will now speak on post-acute COVID-19 in those who are hospitalized with severe COVID-19 infection.  As shown here in this image, multiple systemic factors contribute to the neuropsychiatric syndromes in the post-COVID-19 period in this patient population.

In this large retrospective cohort study that predominantly captured hospitalized participants, and time to event analysis, data was obtained from a large electronic health records network.  ICD-based data was used with the primary cohort being those who had COVID-19 diagnosis and two control cohorts of influenza and upper respiratory tract infections.  Although one third of patients had a new ICD diagnosis for a neuropsychiatric condition after COVID-19, most diagnostic categories were more common in patients who had COVID-19 than in those who had other respiratory tract infections.

The major limitations of this study was it was really reliant on ICD-based data with a temporal association to COVID-19 diagnosis and subsequent ICD-based codes, rather verification of a possible causal linkage.

This article by Frontera and colleagues, six-month follow-up after hospitalization for COVID-19 was assessed.  Patients with new neurological complications during hospitalization who survived were propensity score matched to COVID-19 survivors without neurological complications, hospitalized during the same time period.  The study utilized telephone-based questionnaires and assessments and found that over half could not independently perform some of their basic activities of daily living, and over 50 percent had cognitive impairment.  Poor functional outcomes were associated with neurological complications while hospitalized.

The data emerging on poor neuropsychiatric outcomes after severe COVID-19 is not surprising, given evidence that we know on post-intensive care syndrome or PICS for short, and the prevalence of neuropsychiatric syndromes after acute respiratory distress syndrome.  PICS comprises impairment and cognition, psychological health, and physical function of the ICU survivor and is identified in up to 75 percent of individuals. 

Not only is the primary survivor greatly impacted, but also caregivers, as shown here in this table in a publication on PICS by Dale Needham and colleagues.  Importantly, many evidence-based practices which have been shown to reduce the likelihood of PICS, including prioritizing sedation minimization, daily breathing trials, early mobility, did not occur in overwhelmed ICUs during the COVID pandemic.  Therefore, we have a significant concern that there will be an even higher number of individuals with PICS after COVID-19 versus other causes of sepsis.

Encephalopathy is the most common neurological condition reported in hospitalized COVID-19 patients, with a recent meta-analysis showing over one-third of older COVID-19 patients presenting with or developing encephalopathy during hospitalization.  Encephalopathy is not only significantly associated with mortality, but also is an important risk factor for cognitive impairment in those who survive.

While early studies have shed important light on post-COVID-19 symptoms, critical questions remain.  Studies thus far have been limited by a lack of case definitions and criteria to assess post-COVID-19 effects.  A significant amount of selection and referral bias exists in cohorts which are drawn from specialized neuro clinics and survey-based questions that rely on subjective symptom reporting.  Most importantly perhaps, research efforts need to continue to work hand in hand with clinical care activities and public health to provide equitable care in this vulnerable population.

I want to briefly mention our study that we're developing in Northern Manhattan.  We work in a diverse and vibrant community of predominantly Hispanic, Latinx individuals and neighboring Harlem, which has a large Black community.  Our local communities were hit particularly hard by the COVID-19 pandemic, with one out of ten individuals being infected.  Our study is modeled after the decades of experience in community-based participatory research in the Washington Heights Inwood Community Aging and the WHICAP offspring study, which leverages staff which are bicultural and bilingual, provides home visits, and is based on community engagement efforts with social work services and clinical care.  We are going to use the WHICAP neuropsychological test battery, which has been validated over 16,000 times, both in Spanish and English, since 1992.

Finally, I'd like to thank the many individuals at Columbia, CDC, WHO, as well as the local and international collaborators and mentors.  Most importantly, I'd like to recognize our patients and caregivers.

Thank you very much.

DR. KORALNIK: Thank you for inviting me.  I am Igor Koralnik.  I'm the chief of the Division of Neuro-Infectious Diseases and Global Neurology at Northwestern Medicine in Chicago, and I will talk to you about neurologic symptoms and cognitive dysfunction in non-hospitalized COVID-19 long haulers.

This study was performed at the Neuro-COVID-19 clinic at Northwestern Medicine, which was open in May 2020 during the lockdown.  We assembled a clinical team, including neuro-immunology fellow, rotating neurology residents, APPs, nurses, MAs, clinical coordinators, scheduler, and administrators, and everybody says hello.

So before starting, I want to remind you that at that time, there was no gold standard test for SARS-CoV-2 infection.  The nasal swab RT-PCR detects SARS-CoV-2 RNA, but is dependent of nasopharyngeal shedding, and the initial serology test was available commercially from Abbott, was calibrated with hospitalized patients who had pneumonia, and it detected antibodies against nucleocapsid protein of the virus, which is not sensitive enough to detect individuals with asymptomatic and mild disease and the newer serology tests, for example those by Siemens, looking for anti-spike antibodies are more sensitive, but they may be falsely negative in patients exposed months prior, due to decreasing antibody titers over time.

So we studied prospectively the first 100 consecutive patients presenting to the Neuro-COVID-19 clinic at Northwestern Memorial Hospital between May and November 2020, between May and June in televisits only during the lockdown, and from July to November in a mix of in-person and televisits.  We wanted to give full access to the clinic.  So we did not require physician referral or a positive SARS-CoV-2 test to be included in the clinic, and at that time, 50 percent of patients were SARS-CoV-2 laboratory positive and 50 percent SARS-CoV-2 laboratory negative.

The inclusion criteria for this study was to have IDSA clinical symptoms of COVID-19 starting February 2020 or later, no hospitalization for pneumonia or hypoxemia, and neurologic symptoms persisting at least six weeks from symptom onset in the most recent definition of the CDC for post-COVID syndrome is at least four weeks from symptom onset.

The term long haulers was chosen, as you know, by the patients themselves, by analogy to those long haul drivers who are driving very long distances carrying very heavy loads.

So median age population, the mean age population of the patients was 43.2 years old.  Seventy percent were female; about half were seen in televisit and half in person.  The SARS-CoV-2 laboratory negative patients that you can see here were obviously negative by RT-PCR or by serology, and the SARS-CoV-2 laboratory positive were positive either by RT-PCR or serology, but they were not always positive, as you can see, 12 percent of patients were negative by RT-PCR, 8 percent were negative by serology, and only 32 percent were positive using both tests.

Comorbidities of the patient, it's interesting to note that 42 percent had depression and anxiety before COVID, which is higher than the expected U.S. population, and 16 percent had different type of autoimmune diseases before COVID.  The patients came to see us an average 5.3 months from symptom onset to the clinic, and interestingly those SARS-CoV-2 laboratory negative patients came a full month later compared to the SARS-CoV-2 laboratory positive patients.

We asked patients at the time of the clinic visit what is your subjective impression of recovery compared to pre-COVID baseline, and they said they were only about 64 percent recovered.  The median number of neurologic symptoms at the time of the clinic visit was 5, and 85 percent of patients said that they had four or more neurological symptoms.

Those symptoms are included for the ten most frequent: brain fog, headache, numbness and tingling, dysgeusia, anosmia, myalgia, dizziness, pain other than chest, blurred vision, and tinnitus, and only anosmia could distinguish patients who were SARS-CoV-2 positive more frequently than SARS-CoV-2 negative, and blurred vision more frequent in SARS-CoV-2 laboratory negative patients.

They had other symptoms, including very prominent fatigue, 85 percent of patients said they had fatigue, but they had also other pulmonary, GI, and cardiac symptoms, including shortness of breath, chest pain, insomnia, variation of heartrate and blood pressure, GI symptoms, and despite the fact that they never had hospitalization, need for hospitalization for pneumonia or hypoxemia.

Neurologic exam was abnormal in 53 percent of patients, especially because of deficit in short-term memory and attention.  Patients who were SARS-CoV-2 laboratory positive only had cranial nerve dysfunction, but otherwise the neurologic exam was not able to distinguish one population from the other.

We did not find anything revealing in diagnostic testing, but this was not done systematically in all patients, only part of their clinical workup.

What was more interesting is the result of the patient-reported outcome measure or PROMIS measure for cognition and fatigue you can see up here.  C is for cognition, F for fatigue.  We have results for SARS-CoV-2 positive patients, SARS-CoV-2 negative patients.  A T-score of 50 is average compared to a normative population in the United States, and you can see that patients had a worse cognition and worse -- so with lower T-score, and higher fatigue with higher T-score, compared to a normative population in the United States, both for the laboratory positive, laboratory negative patients.

These on the top right are the results of the cognitive test for processing speed at attention, executive function, and working memory on the NIH Toolbox.  And again, the SARS-CoV-2 laboratory positive patients, SARS-CoV-2 laboratory negative patients, a T-score of 50 is average according to age, gender, ethnic background, and level of education.  You can see a wide variation in the results, but as a whole, the SARS-CoV-2 laboratory positive patient tested worse for attention and working memory compared to their demographics. 

When we plotted the percent recovery compared to pre-COVID baseline with the time from disease onset, we were hoping that everybody was going to improve with time, but it was not the case.  You can see patients two months after disease onset, about 90 percent recovered, but some nine months after symptom onset, 10 percent only, 0 percent recovered.  We asked if patients had missed 10 or more days of work, and 48 percent said that was the case, which was actually more frequent in SARS-CoV-2 negative patients.

So in conclusion, we found prominent and persistent brain fog and fatigue in non-hospitalized long haulers.  These patients had impaired quality of life in areas of cognition and fatigue, based on those PROMIS measures.  They had impaired attention and working memory in SARS-CoV-2 positive patients, based on results of the NIH Toolbox cognitive test.  There is a diagnostic dilemma in the SARS-CoV-2 negative patients, because you can't give them a definite diagnosis, since they test negative for either SARS-CoV-2 primarily by RT-PCR or serology, but unfortunately, because they don't necessarily understand the limitation of those tests, those patients experience rejection and stigma and since 70 percent of those patients are female, it is really unfortunate.

There's a high female to male ratio and prevalence of preexisting autoimmune disease in this population, which is reminiscent to what we see in patients with multiple sclerosis or rheumatic arthritis or lupus where there is a higher female to male ratio, and this could be consistent with a post-infectious autoimmune etiology of long COVID-19.

We found that time from onset was not a good predictor of recovery, and patients tend to improve with time, but everybody is going on their own trajectory.  Since there are millions of people affected in the United States and probably dozens of millions of people affected in the world, this will have a significant impact on the workforce.

Finally, as of today, we have seen 650 neuro-COVID-19 patients in the Neuro-COVID-19 clinic.  Seventy percent are from Illinois and we see patients in televisits from 34 other states to date.  We see about 85 new patients per month, 20 percent are previously hospitalized patients with pneumonia, and 80 percent who are the non-hospitalized long haulers.  So this is not going to go away, and this problem is going to be here with us for the foreseeable future.

At this point, I want to acknowledge all my collaborators in the Neuro-COVID clinic.  Over the months we had to add about a dozen other neurology attending from the department who are coming to help us see those patients.  Those neurology attendings are from other divisions like multiple sclerosis, movement disorders, general neurology, and so on.

We have a dedicated neuro-COVID research team, including a number of medical students at Northwestern, and my laboratory team.  I'm also very grateful for all COVID-19 patients and their families and all of our funders.  Thank you very much, and I will be glad to take any questions during the Q&A session.

DR. SPUDICH: Thanks very much for inviting me to speak today, and as you know, I'm going to be talking the potential pathogenic mechanisms of these clinical syndromes you've heard about in the last couple of talks. 

I have nothing to disclose. 

I just wanted to remind the group about these conditions that have been reported both in the lay press as well as in the scientific literature, and that have also been the subject of an entire workshop at the NIH previously, talking about these long-term symptoms.

And you will also be hearing from a representative from this patient-led research for COVID-19 group, who is really going to share some of the neurologic issues and psychiatric issues that have been reported from this community, but I wanted to highlight the importance of the fact that these syndromes are diverse, and they're also affecting a number of different axes of the nervous system, from neuropsychiatric, cognitive, sense and sensorimotor, and also more primarily psychiatric syndromes. 

So really the question is what's causing these syndromes pathologically.  And I wanted to start with thinking about what we've learned from the neurologic complications of acute COVID-19, because we actually have in those biological information available about the syndromes during the acute phase of the infection.  Certainly the issues that might be lasting long-term would presumably have been set up or established or even caused by events that happen during acute COVID-19, and as a reminder, there's a wide variety of clinical syndromes that are seen in acute COVID-19, and this pie chart here shows a variety of the different kinds of clinical syndromes observed by myself and Dr. Lindsay McAlpine, a really terrific resident, when we took care of inpatients who had acute COVID-19 and neurological issues. 

One of the things that we observed, of course, were the corollaries with immune-mediated disease, and you've heard a lot about these yesterday and the pathophysiology related to immune-mediated injury in the nervous system, and we also observed a number of people with stroke and vascular-mediated disease.  As we've seen again yesterday, there's a lot of pathologic evidence suggesting that microvascular injury, widespread in the body, but then also in the brain, may be underlying issues in acute COVID-19.

So the rest of my talk is actually going to focus on thinking about these different potential mechanisms in people who have long-term COVID complications.  One is immune-mediated CNS abnormalities, and another is the possibility that microvascular injury may be playing an important role.  So what's the evidence that there are biological changes in the brain after COVID-19 in people who have recovered?  This is a very nice study recently published that used PET imaging to look at metabolism, cerebral metabolism, of FDG PET, in the brains of individuals who had neurologic issues that were persistent after COVID-19.  They looked at 45 people, and they looked at almost 100 days after onset of COVID-19, and found that there was hypometabolism in a number of different regions of the brain, compared to individuals who were well-matched healthy controls.

The other interesting thing in this study is they actually found that their PET metabolic values associated with the symptoms that they were observing.  So this is a hint that there actually may be functional changes in the brain in people who have recovered from COVID-19 and have neurologic issues. 

There's also a very elegant study that was published quite recently, or actually put on MedRxiv, by the UK Biobank, and this is a group that actually does surveillance imaging in individuals throughout the UK over time, and they were able to look at individuals who had pre-COVID-19 imaging studies and found a number of people who had tested positive for COVID after their initial and then follow-up scans, and then they also had very well-matched controls.  And this group has just reported in this non-peer-reviewed paper that there's a loss of regional gray matter in areas of the brain, particularly those that are along the orbitofrontal cortex and the insula, and this is interesting because this is a potential route of inflammation or even viral infection into the brain. 

So these are studies that have suggested that there truly are imaging brain abnormalities in people that have recovered from COVID.  So another question that I raised is whether persistent neuroinflammation may be in part related to some of the neurologic symptoms that people are having after COVID.  And this is a study of cancer patients that found that there were elevated levels of neuroinflammatory markers in the spinal fluid months after recovery from acute COVID-19, compared to cancer patients who had not had COVID.  There are a lot of caveats, of course, to this study, and the inflammation was not as high as those who had received CAR T-cell therapy, for example, but it did suggest that persistent neuroinflammation may be related to some of the persistent symptoms after COVID, and another study actually looked at blood inflammatory markers, and what they found was that baseline blood inflammatory markers during COVID-19 was associated with long-term depression and neurocognitive issues after recovery from COVID. 

So these are hints, although I think many more studies are needed to suggest that inflammation may also be playing a role.  It's uncertain how these relate to survival of milder forms of COVID-19 and longer-term symptoms. 

One of the things that we've done in the last months is establish a study focused completely on the understanding of the pathophysiologic mechanisms of people who have recovered from acute COVID-19 but have long-term symptoms.  I'm running a study with Shelli Farhadian, who's shown on the upper right and whom you heard from yesterday, and as you can see, we're using a wide variety of tools and we have vast array of terrific collaborators, many of whom are at this meeting, to look at brain imaging, blood and cerebrospinal fluid profiling, and also neurocognitive and neuropsychiatric inventories, to try to understand the biology that's happening in some of these patients.

To date we have enrolled 28 patients in our study, and you can see here that the majority of them are women, median age is around 150, and these people are usually about three months after they've had COVID-19.  A minority of them were ever hospitalized, and the primary symptoms that have plagued these patients after COVID-19 have been cognitive impairment, headache, and a few people have had psychosis.  Most of the patients have had clinically normal or nonspecific brain MRIs, but the research imaging is not yet complete or interpreted in these patients.

What is very interesting I think to focus on is the initial laboratory findings in these patients, and I will say in these study participants, the vast majority have normal standard clinical blood and CSF measures.  A few of these markers are slightly elevated.  You can see the C-reactive protein, the erythrocyte sedimentation rate, are slightly abnormal overall.  This is median values.  The blood absolute lymphocyte count is slightly low, and we have seen a number of people who have persistently low CD4 T cell counts after COVID-19.  The blood d-dimers are slightly elevated, and the Von Willebrand factor activity are slightly elevated.  Those are things that are hints of some vascular inflammation or vascular coagulation abnormalities.  You can see that the CSF white count, the CSF protein levels, are normal.  CSF fluid neopterin, in those we've been able to test it, have also been majority normal.  We have a few patients who have had elevated CSF IgG, and I think this is interesting with our final comment that I'm going to make on the last slide.

Most of this clinical standard imaging and laboratory tests in these participants have been normal, but the research assessments are ongoing, and in a very interesting collaboration with Sam Pleasure, Michael Wilson, and Chris Bartley at UCSF, we've been able to do some exploratory evaluation of autoantibody discovery in some of these participants. 

One of them is a case that we've already examined, who was a 30-year-old man with abrupt onset psychosis post-COVID-19.  All of his lab tests were normal.  However, when we used a mouse immunostaining method to detect novel autoantibodies in his spinal fluid, we found that there were autoantibodies discovered that seemed to be responding to a variety of cortical neurons -- for example, here in the upper layer of the cortex -- suggesting perhaps that in this participant, the neuropsychiatric manifestation was an autoimmune-mediated psychosis.

So I will end by saying there are a number of global studies of post-COVID-19 neurologic symptoms.  Only some of these are listed here.  We're going to hear about a lot of those later in this session later in the afternoon today.  And there are final questions that are persistent that we need to try to understand.

First of all, which are the clinical and laboratory biomarkers associated with these syndromes?  I think that there's evidence to suggest that there may be persistent perturbations in systemic and neurologic inflammation.  There may be autoimmune processes, particularly attacking the cortical neurons or attacking the nervous system.  Vascular inflammation and impact on regional blood flow I think is something that many people are now starting to study, and looking at vascular markers available in the blood and using neuro imaging to look at blood flow is very important.  And then of course long-term neuronal function and functional connectivity.

I think that what is really obvious from the small amount of data that's available so far, and the vast number of people afflicted by these concerns, is that we really have a research mandate to understand the biological substrates of these syndromes.  There are public health concerns, there's stigma associated with these conditions, and primarily we want to be able to develop targeted therapeutic interventions.

I'm going to thank my collaborators, you can see here that this is a team effort with many people in the COVID Mind Study, and all of the people in the field and all of the volunteers for the research.  Thank you very much.

DR. NATH: Thanks to all of the speakers, so now I'm going to open it up for the question and answer session.  So we have a lot of questions that have come through, so let me just start with the couple that are directly been asked of Dr. Thakur.  So I'm going to start with that.

First is from Dr. Nora Volkow, and she wants to know if in the inattention that you described, does that respond to stimulant medications?

DR. THAKUR: Yeah, I think the simple answer is we don't know, and I'd love to hear other people's thoughts, including Dr. Koralnik and yourself, about just your experiences.  I think right now it's an individualized patient care approach in terms of managing the effects.  I will say that what is likely needed for all potential treatments ideally is the gold standard, which is randomized clinical trials with regards to these treatments.  So that's the short answer, but would love to hear kind of other people's experiences.

DR. NATH: There is another question from Shelli, but looks like there is another speaker later on who would probably be addressing the same issue.  So Shelli, I am going to defer your question to later.  Then maybe this one I'll direct it to Igor, but any of you can probably address it, as well, and that relates to the definition of post-COVID syndromes, and the question really is that should the sequelae of acute infection, which is related to strokes or encephalitis, what-have-you, be included in the definition of post-COVID syndrome?

DR. KORALNIK: This is a very good question, obviously.  I think we need to pay attention that there's two distinct categories of patient, the first category who were hospitalized with COVID pneumonia, having the ICU, sometimes intubated, and had encephalopathy, all kinds of other complications like strokes, seizures, and so on, and after that, they survive, they become post-hospitalized COVID patients and they come to see us in the clinic.  These are older, predominantly men, with all kinds of comorbidities.

The second population of patient is the younger 40 years old, average, predominantly women, non-hospitalized patients who had never been sick with pneumonia or hypoxemia, and they have another type of neurologic complication, including brain fog, headache, dizziness and so on.  So we need to include both category of patient in the post-acute COVID symptoms, but they are different and they need to be studied with a proper set of controls.

DR. NATH: Thanks.  Dr. Spudich, this question is for you, and somebody wants to know what about the various variants of SARS-CoV-2 and their effects on the nervous system?

DR. SPUDICH: That is a really interesting and important question, and of course, it's something we've thought about in another virus that has variants, which is HIV, for a long time.  Do different variants actually have different levels of neurotropism or different immune responses that might determine differential outcomes?  In our studies to date, we have not started to consider the variants, and of course as population variants are shifting, it may be though that in our region where we have very high vaccination rates, most of the post-COVID people that we see locally will have really been infected with the original variants.  I think global studies will really need to take into account whether or not there are different variants with different outcomes, and I'm looking forward to some of the discussions of sort of global health types of studies here, but I think thinking about whether the variants that may be more infectious may cause differential rates of systemic complications, whether some of the things that we see triggered in the nervous system may be different in those patients, as well, and I think we don't know.

DR. NATH: Thank you.  I see Dr. Koroshetz has his hand up.  Walter?

DR. KOROSHETZ: Thanks.  I just had two quick questions.  One is can anybody comment on how much of what you're seeing is persistence of symptoms that started with acute infection versus people who had an acute infection completely got better and then get sick later?  Does that happen, the latter?

DR. SPUDICH: We probably each have different experiences, but Dr. Koroshetz, I've seen very few people who've got completely better and then had something emerge months later.  Most of the people we have seen described -- who have, for example, persistent brain fog months later -- said that they had even a more severe brain fog initially and then they sort of expected it to clear at the time that the rest of their symptoms cleared and that didn't recover.  But I would be interested in hearing what others have seen.

DR. KORALNIK: So our experience with the non-hospitalized long haulers who had the minor symptoms, then some had an interval free of any symptoms after having just cough with a fever and a headache, went away, and then a couple of weeks later could develop the long COVID symptoms, including brain fog, dizziness, fatigue, myalgias, and so on.  Those persist over time.  This is a very heterogeneous population of patients.  Some have anosmia, dysgeusia that lasts only weeks, and then have persistent brain fog, for example, for months or more than a year, and some people have no brain fog and headache and dizziness, but they have persistent anosmia that lasts more than a year.  So it's a heterogeneous population of patients, and we need to study those accordingly.

DR. THAKUR: I can just comment I think with the hospitalized patients we're seeing very much kind of similar picture to what we see with PICS and post-ARDS populations, those that were in a critical care unit and so have had very severe symptoms in the context of being out of the hospital, having to come back into the hospital.  So we just finished our data analysis of our hospitalized patients, looking at individuals similar to the NYU group, we saw a huge amount of readmission rates, mortality, as well as poor cognitive outcomes in those who were hospitalized.

DR. KOROSHETZ: I just put up the question, probably there's no answer yet, but we should be looking to see if people who have breakthrough infections, so infected after vaccination, whether they can also get these kind of more long-term symptoms or not.  It's probably too early to tell, but keep your eyes and ears open.

DR. NATH: Okay, that's a very good comment.  Maybe we'll just take one last question and then we'll try to answer them as we maybe in the chat box, the rest of this.  There are several questions for me, and I'll type my answers in.

This one is for Dr. Spudich, says what were some of the cognitive measures administered in COVID Mind Study and how were they administered, that is, in person or over the phone?

DR. SPUDICH: So I should say the COVID Mind Study is ongoing and still we have aspects that are being redeveloped and changed as we're sort of keeping up with what we should be doing.  So all of the COVID Mind Study assessments are done in person.  We have people come in, they spend time, they get a lumbar puncture, they get a blood draw, and we do evaluations in person.  We have actually a mostly tablet-based set of tests, which actually is about an hour's worth of cognitive testing, and then we have another tablet-based set of assessments of things like function, daily function, anxiety, depression, and those kinds of things.  We have a terrific -- Leah Rubin is a really experienced neuropsychology expert for infections, and she's developed a pretty detailed panel and we're happy to share that with anyone.

DR. NATH: Thanks very much.  So, maybe if each of you can look at the questions in the question and answer box and maybe type your answers in there, I'd appreciate it.

DR. NATH: Thank you.  Let's move on to the next session.  This session is titled Patient Led Research, and we have two individuals are going to talk about their experience and the first is Athena Akrami, and she is at University College London.  She is a group leader there, and also has a lot of research experience in memory and learning using animal models, and now with COVID, she has initiated a patient-initiated research group on cognitive dysfunction in the long haul patients.

The second speaker is Hannah Davis, and she is a team leader and researcher at a patient-led research collaborative, and she has expertise in machine-learning and she's in New York.  Look forward to your presentations.

Agenda Item: SESSION II: Patient Led Research

DR. AKRAMI: I am Athena Akrami, a group leader at Sainsbury Wellcome Centre in University College London in UK.  Today, I am going to talk about the work that I did as a founding member of the Patient-Led Research Collaborative, in collaboration with Body Politic COVID-19 support group and sponsored by UCL.

Our patient-led research team is formed by long COVID patients who all fell ill in spring 2020.  We have backgrounds in survey design, qualitative research, public policy, data science, machine learning and statistics, as well as medical research, psychiatry and neuroscience.  We conducted an online survey of people with suspected or confirmed COVID-19 and distributed our survey via various support groups and social media.

The survey was translated in nine languages, and launched in September 2020.  More than 7,000 respondents from 87 countries participated and completed our study.  In this survey, we had more than 260 questions to investigate disease duration and severity, symptom profile and time course, impact on work and life, as well as antibody testing, diagnostics, medical support, coping, and mental health.

The data that I'm going to show you today comes from a dataset from a cohort of 3,762 participants with illness onset between December 2019 and May 2020.  So we could characterize symptoms over seven months.  They were all sick for more than 28 days, and 92 percent of them were not hospitalized and they were distributed across a wide range of ages, and only 6.8 percent were recovered at the time of survey.

Our survival analysis shows that in our cohort, more than 92 percent of respondents still had symptoms after 25 weeks.  Those who recovered on average were sick for 91 days, and their symptom count kicked in week 2.  Those who weren't recovered by the time of the survey were on average sick for 144 days, and their symptom count peaked in month 2.  Out of 64 symptoms that were measured over time, the non-recovered participants had on average 14 symptoms after six months, and 21 percent of participants experienced these symptoms severe or very severe.

We investigated more than 200 symptoms in 10 different organ systems as listed here.  This table shows the overall symptom prevalence in these 10 organ systems.  The table is sorted by prevalence.  Almost all participants had experienced symptoms in neuropsychiatric, systemic, and head, ear, eye, nose, and throat categories. 

After that, musculoskeletal, pulmonary, cardiovascular, and gastrointestinal symptoms were extremely common, impacting more than 85 percent of participants.  Then reproductive, genitourinary, endocrine and dermatologic symptoms had prevalence of about 60 percent, and then immunologic, autoimmune systems had prevalence of about 21 percent.

So just to briefly show you the details, the symptoms, for each organ system.  So as you see that we had measured many symptoms and a lot of them were extremely prevalent.  Out of systemic systems, I'd like to highlight post-exertional malaise, which is worsening of symptoms after mental or physical exertion.  This is linked also, the relapsing nature of long COVID conditions, is extremely common, more than 80 percent of participants were experiencing a PEM, and there are various triggers and the onset can be variable, it can be a couple of hours, a couple of days, and can last several days.

Out of 200 symptoms, 64 were measured continuously over seven months, and as you can see, most symptoms had a prolonged probability of occurrence throughout the seven-month period.

We also estimated a distribution of onset time for each symptom.  This plot shows that mean onset and the 95 percent confidence interval around that, and as you can see, some symptoms start early, in the first couple of weeks, and some start at much later, after week eight or ten.

We also clustered symptoms according to the shape of their time course.  That is, changes in relative amplitude over time, ignoring the overall prevalence.  And symptoms formed three clusters.

Cluster 1 consists of symptoms that are most likely to occur early in the illness, which is a high point in the first two or three weeks, then decreasing in probability over time.  Cluster 2 consists of symptoms with a relatively stable probability over time.  Cluster 3 consists of symptoms most likely to increase sharply in the first two months, and their probability then may plateau or decrease slightly or increase slightly in later months.  I would like to note that symptoms with similar time courses are distributed across multiple organ systems.  So all clusters contained symptoms from multiple organ systems.

Focusing on neuropsychiatric symptoms, they were exclusively clustered in 2 and 3, meaning that they either had relatively stable probability over time, or the probability increased sharply in the first two months, then remained stable.  Moreover, remaining symptoms after month 6 were mostly systemic and neurological.  As you can see here, more than 70 percent experienced brain fog and more than 50 percent experienced memory-related issues.

Let's dive a little bit in the details of our neuropsychiatric symptoms.  So we have subcategories of neuropsychiatric symptoms, here sorted by their prevalence.  Sensorimotor is the most prevalent one, impacting about 90 percent of participants.  Then emotion and mood, cognitive dysfunction, with prevalence about 85 percent, then we have sleep, headache, and memory categories with prevalence about 70 percent, then smell- and taste-related symptoms, speech and language, about half of the participants, and at the end hallucinations, about 15 percent.

Among the sensorimotor symptoms, we have overall prevalence of 90 percent.  Vertigo and balance issues, as well as paresthesia, tremor, and numbness were the most common ones, but there were others with pretty significant prevalence as well.

Under emotion and mood category, with overall prevalence of about 90 percent, anxiety, irritability, and depression were most common.  Among cognitive dysfunction with overall prevalence of about 85 percent, brain fog, attention deficit, and problem with executive function and problem-solving were extremely common.  Please see Hannah Davis' talk after me for details on impact of memory and cognitive dysfunction on life and work.

Then we have sleep category, with overall prevalence of about 80 percent, and insomnia and interrupted sleep were the most common ones.  It's very important to note that only a small fraction of those who experienced sleep issues during the long COVID experience, they had preexisting prior symptoms before their COVID-19 infection.

Here are different subtypes of headache, with overall prevalence of about 76 percent.  Then memory issues with overall prevalence of 72 percent, and short-term memory loss was the most prevalent one in this category, and after than problems related to long-term memory recall.

About 60 percent of participants experienced various issues with their smell and taste sensation, some with total loss, some with altered sensation or phantom smell and taste.  About half of participants experienced speech and language-related issues, mainly with regard to difficulty finding the right word or communicating verbally or in writing, as well as issues with their nonprimary languages if they were speaking a second language.

About 15 percent of participants had visual, auditory, or tactile hallucinations.

So important to note that some symptoms that are grouped in non-neuropsychiatric might have neurological components, like sensitivity to light and noise, swallowing issues, temperature dysregulation, weaknesses, skin sensations, some breathing issues, postural tachycardia syndrome or in general symptoms related to dysautonomia.

At the end, I would like to add that from what we know so far about possible involvement of CNS in COVID-19 either by direct infection or indirect peripheral to CNS signaling, neuroinflammation or altered CNS function can cause myriad of ongoing symptoms that can be systemic, generalized, or cognitive neurological, as we have discussed in detail in an opinion piece in review article, which is now in revision.

In summary, respondents experienced symptoms in an average of nine organ systems out of ten, and all participants experienced neuropsychiatric symptoms.  Most frequent neuropsychiatric symptoms were sensorimotor, emotion and mood, cognitive dysfunction, sleep, headache, and memory.  The most frequent symptom after month 6 were mainly neurologic and systemic, and top three were fatigue, post-exertional malaise, and cognitive dysfunction.  All these symptoms had substantial impact on daily life and work.

I end here by thanking all members of the Patient-Led Research Collaborative and Body Politic and UCL for their support.  Thanks a lot for your attention.

DR. DAVIS: Hello, my name is Hannah Davis, and I'm from the Patient-Led Research Collaborative.  I'm also a long COVID patient.

My experience started on March 25, 2020.  I have been sick for 477 days.  My first symptom was actually that I couldn't read a text message.  I was unable to parse what the meaning actually was saying.  An hour later I took my temperature and realized I had a fever.  Over the next few months, I experienced severe brain fog, memory loss, I forgot my partner's game, I forgot to look both ways when crossing the street, I forgot how to cook.  I would regularly just forget that I was cooking something and regularly started fires in my kitchen.  I was completely unable to drive. 

I had severe dysexecutive functioning, a low-grade fever for over six months, loss of taste, loss of feeling in my arms and hands, tachycardia on minimal activity.  When I stood up, I would reach 150 to 160 beats per minute.  I had pain in all muscles and joints, heart palpitations, severe headaches, blurry vision, difficulty making meaning from text, talking and finding words, sensitivity to light and noise, a complete loss of attention span, insomnia, tinnitus, general slowness, difficulty temperature regulating, phantom smells, internal tremors, petechiae, a severe headache just from thinking; but these are just a subset of my symptoms.

At the beginning of the pandemic, neurological symptoms were not considered part of COVID.  At one point, I went to the ER and was sent home with an inhaler.  Before I got sick, I worked in machine learning, and I haven't been able to return to work.  I am an unusual patient in that I had done neuropsychological results before I got sick to see if I had ADHD.  A few months after I did the same testing with the same provider.  My processing speed had dropped from the 96th percentile pre-COVID to the 14th percentile post-COVID.  By everyone's guidelines and definition, I am considered a mild case.

I work with Dr. Akrami on the Patient-Led Research team.  One of the areas that we studied was cognitive dysfunction and memory loss and how these impact patients' daily life.  We found that most people experienced at least one of these symptoms.  Of people that experienced cognitive dysfunction and memory loss, 86 percent have their work affected; 85 percent have difficulty making serious decisions; 74 percent have difficulty communicating thoughts and needs; 68 percent had difficulty communicating and having conversations with others.  This also affected areas of life including maintaining medication schedules, following simple instructions, and being unable to drive.

To me, one of the biggest things we found was that there was no difference in memory symptoms by age, no difference in cognitive dysfunction by age, and no difference in the impact of these symptoms on life by age.  These are as common in 18- to 29-year-olds as in people over 60.  I think that brain fog is a really vague term to communicate the severity of what patients experience with this symptom.  I want to take a moment to read a couple of patient quotes.

Mother has started to help me take the medications I'm on, because I can't remember if I've taken them immediately after having the bottle in my hand.  I was trying to fill out a mortgage application form, and couldn't remember our rent.  I put $3,750 a month.  My partner said no, it's $1,375.  So I put $13,750.  My partner said no, so I tried several more times.  I was just guessing numbers.

Sitting on the toilet to pee and had to stop for a second to think if I was really there and not about to pee myself or the bed.  I forgot how to do normal routines like running a meeting at work.  I felt lost driving and had to stop and find my position in a GPS to be able to drive back home.  It's a route I have done hundreds of times. 

I can't hold multiple trains of thought.  If I tell myself I have to water my plants, I must do it before another though comes into my mind, because otherwise I will forget.  I had to terminate many phone calls because I could no longer comprehend the speakers, nor communicate clearly with them.

These types of experiences are happening in patients of all ages.

I wanted to talk about a few research directions and biases in long COVID research.  The first is that it’s vital to include OCR and antibody-negative patients in research.  We accepted both symptomatic positive and symptomatic negative patients and compared the two.  The primary difference in the cohorts was not in the symptoms, but in the time they were able to get tested.  As we all know, the PCR tests have high false negative rates.  They start at 20 percent.  Every day after the third day of symptoms, that false negative rate increases.

We found that the positive cohort got tested at a median of six days, and the negative cohort got tested at a median of 43 days.  The only statistically significant difference of 205 symptoms was loss of taste and smell.  Because this was a primarily first-wave cohort and there weas testing inaccessibility, this is likely because if you had those obvious COVID symptoms you were able to get a test and therefore be more likely to test early enough.

This finding of no symptomatic differences between symptomatic negative and symptomatic positive cohorts has been validated by six other global studies.  Additionally, there's research that has come out, especially in the last few months, that show that low antibody response might actually be a feature of long COVID.  The first study here shows that no or low baseline IgG levels were actually able to predict persistent symptoms at seven months in a non-hospitalized cohort.   

The second showed the same in a hospitalized cohort.  The third showed that there were additional negatively correlated immune responses, both T cells and select B cells, with long COVID.  The fourth showed that viral persistence in the gut was associated with lower levels of and slower generation of IgA and IgG antibodies, and the last one, curiously, shows that of all patients who seroreverted, meaning that they lost their antibodies, only 2 percent of PCR patients seroreverted compared to 27 percent of PCR negative.

Additionally, antibody tests vary wildly between male and female patients.  Males are four times more likely to retain antibodies.  In one study, 36 percent of female patients lost antibodies between month 3 and 6, compared to 8 percent of males.  Overall, 80 percent of those who lose antibodies are female.  Another study showed that antibody tests are more accurate on men between age 40 and 59, but least accurate on women, people under 40, and people over 70.  An additional study showed that antibody tests were validated against predominantly hospitalized patients and missed 10 to 30 percent of non-hospitalized cases. 

If we require antibody testing for long-COVID research, we will accidentally create a dataset that is biased toward male patients and female patients with a stronger immune response, which is just not the typical long COVID patient.  We also may potentially miss the clue of patients not seroconverting or seroreverting earlier, which actually might be a clue to the pathophysiology of long COVID. 

In two recent studies, those without lab confirmation of COVID experienced an eight-week delay in care, were less likely to have adequate time off, less likely to have adequate rest, more likely to experience lost income, more likely to be unable to live alone at six weeks, and more likely to have pain, anxiety, and mood symptoms likely from disbelief and lack of care.  Non-hospitalized patients are 75 percent more likely to not have had lab confirmation of COVID. 

Secondly, we need to build on existing post-viral research.  This is one of the World Health Organization's overall objectives for the long COVID global research roadmap.  Post-viral research is a understudied area, but in the last few years there have been findings in all of these areas that we need to build on. 

One is in neuroimaging.  Dr. Jared Younger and Dr. Michael VanElzakker have both identified neuroimaging techniques for post-viral patients, looking at brain temperature and neurovascular dysfunction.  It's important to identify neuroimaging techniques, especially where MRIs are coming back clean in most long COVID patients.  Other areas that need to be built upon and studied include metabolic profiling, cerebral blood flow, overlaps with connective tissue disorders, altered T and B cells, elevated blood lactate, reactivations of additional viruses, mitochondrial fragmentation, and many others. 

A few initial research questions for long COVID.  Are those with long COVID more likely to serorevert, to serorevert earlier, or never seroconvert?  Is there viral persistence in places like the gut, tissue, or elsewhere?  How is the immune response in non-hospitalized long COVID patients different than those in mild cases and those who are hospitalized?  What causes the hypometabolism that has been found in the brains of long COVID patients? 

What causes post-exertional malaise and relapses?  What is the overlap between connective tissue, collagen breakdown, the cervical spine, and long COVID?  And again, what imaging or diagnostic tools can identify these persisting neurological symptoms, particularly in patients with normal MRIs and X-rays? 

To conclude, we need a comprehensive selection of patients in long COVID research.  Most long COVID patients were not hospitalized.  Many didn't experience severe respiratory symptoms.  Many were not PCR or antibody positive, and a clinical diagnosed subset must be included.  Many had quote-unquote mild acute cases.  Many never had low oxygen levels. 

We need to include the right symptoms.  We still see a lot of research proposals that miss neurological, cognitive, and post-exertional malaise questions.  Often the miss questions on relapses, which are a core component of this experience.  And all of this is particularly true when using machine learning.  If we don't, algorithms will be biased without a representative patient and symptom dataset.

Thank you so much.

DR. NATH: Thanks very much for those wonderful talks, very insightful, and thanks very much for sharing your own personal experiences.

Now we should move on to the next set of talks, and that is again a personal description from one patient and then a journalist perspective.  So the first person is Chimere Smith, and she is a patient advocate, a Black long haul patient advocate, and consultant for urban communities.  She is also a middle school teacher and a member of the Long Haul Alliance and a board member of the Body Politic.

The next speaker is Pam Belluck, and she is a health science writer with the New York Times.  She is a Pulitzer Prize winner for her work that she has done with Ebola, and she's previously also worked with Zika and has done a phenomenal job on reporting on COVID.  So we look forward to these two presentations.

Agenda Item: SESSION III: Patient and Journalist Perspectives

MS. SMITH: Hello, I am Chimere Smith, form Baltimore, Maryland.  I'm a former middle-school teacher, and I've been stricken with long COVID for 16 months.  Thank you to the NIH and Dr. Nath for considering me as a speaker during this very important discussion.

Speaking before you today is challenging as I am experiencing my own health challenges, and for me, ironically, when this happens, there's a decline in my mental and neurological health.  Please bear with me.

Today I'll be speaking about the implications and the burden of a Black woman's broken brain.  The first five years I asked my momma, a single woman raising me in the projects of southeast D.C., during the height of the crack cocaine era, the definition of words in a book.  She lovingly told me.  By the sixth time, however, she replied with frustration while washing dishes, look it up, girl. 

At five, I learned that there was a mandate in her words, to not just read the words, but to understand why they were placed in sentences to tell stories in the first place, to understand what words meant, to correlate their value with the writer's message.  She had taken me as far as she could by reading to me almost every single night before bed.  The rest she left up to me.

Her admonishment fueled my obsession and hunger for words.  I became an avid reader.  I read books like kids eat lollipops.  I leaned into those books, while hiding in closets, under beds, and outside on stoops, not realizing then that I had constructed a clever method of escapism.  And those books saved me from the dangerous streets of D.C., from the troubles of gang violence, teen pregnancy, and death, from the loneliness, shame, and fear of not being good or pretty enough, and even from the cruel tone of an overworked, tired momma whose stern side-eye could often cut me into two. 

I soaked up stories, engulfing myself in international travel, romance, espionage, schizophrenia, and heartache, without ever leaving my home.  I became engrossed in the Washington Post's Metro section, mostly reading about friends who had been killed or who had been accused of doing the killing.

My brain became a sponge that soaked up novels and slave narratives, focusing on the primitive journey of the Middle Passage.  I knew my freedom from poverty, homelessness, and hunger was in knowing the story but also balancing it with the politics of reading comprehension and grammatical excellence.  Black girls don't get to peruse shelves of superheroes they wish to emulate, so I became a bona fide smart-ass, a know-it-all.  I created what I didn't see.  I crafted a unique protectiveness of myself by knowing words other people didn't know.  Cloaked with an extensive vocabulary and photographic memory, I shielded myself from being bullied, dismissed and ashamed.

If it's to know, I know it.  My brain is a rapid-fire of waves of knowing, believing, and healing words.  Other kids danced, but I ate words.  Other kids hung on corners, I ate words.  Other girls acted too fast and too grown.  I ate words.  Knowing and becoming words made it possible for my memory to soar. 

My superpowers included winning the fifth-grade spelling bee, aiding friends with English assignments all through high school, crushing Socratic discussions on Toni Morrison's Beloved, being the cherished niece who could recall any phone number, address, or information my great-aunts needed when their health failed.  Reciting my own poetry on the generous, yet overtly critical stages of seven HBCUs, and pressing my film critic professor at Morgan State on my dissection of Spike Lee's earlier works.  Writing for collegiate newspapers as the editor and the contributor.  Writing my own college essays, songs, research papers, and oratory speeches with little or no editing assistance.  And don't test me on my celebrity gossip, because I know it all.

No, this isn't a resume.  This is a salute to what my brain could do.  I was a word and informational powerhouse.  I was an underrated, underserved Black woman and girl with ghetto-impoverished roots, so I had to be.  Anything less, and I risked being thrown and stashed in a pile of brilliant Black women with absorbent, mesmerizing minds who got no shine and no recognition, who are usually underpaid with their ideas stolen by major corporations, run by less brilliant people with more money.

Yes, I talked too much then, but I knew lots of things and told dazzling stories.  My brain and my words attracted people.  All my life, I have been called nerdy, intelligent, and too damn smart.  Don't mess with a Black woman with a powerful brain.  My brain was amazing, functional, analytical, albeit annoyingly so, and beautiful, until March 22, 2020.

My brain gradually became a burden.  COVID ate away these beautiful parts of my brain, leaving in its shadow a pool of mania and disorder.  For me, the neurological effects of this virus occurred over three to four months, and that may be the most torturous, damning aspect of this entire ordeal.  I would rather have experienced the swift destruction of my brain, because watching myself lose my superpowers month by month was a traumatic experience, and it still is, one that makes speaking with you today extremely difficult.

Reliving my experiences immerses me in the same waters I've been striving to leave since last March, but I knew something was terribly wrong when I stopped reading books.  The day after I first fell ill, I tried to read the ending of a book.  My vision was so blurred, the words on the pages so distorted, that I decided to stop trying to read the same pages over and over again.  In March the left side of my face felt frozen, numb, and broken.  I likened my pain to having my head smashed on concrete with Ben-Gay used as a salve afterwards.  Tingling would come like waves across the front of my head, squeezing my temples like rubber bands pressed across my skull.

If you've ever had an uncle or granddaddy jangle quarters in their pockets to give to you, my head felt like those coins jangling from night till day.  In April, dizziness caused me to faint on my bathroom floor.  I awoke many times from sleep believing I was dead, with no consciousness of who I was or where I was.  I relied on my phone to remind me of time, people, and dates.  And still I could not connect the dots.  I lost words, they would not come to me.  My extensive vocabulary became a distant memory. 

My memory -- what memory?  I could not remember to turn off faucets, to brush my teeth, to arise from bed.  I could not remember my momma's name or my favorite auntie's name.  I lost the vision of my left eye, on the same side as my frozen yet pained face.  I stopped speaking, I stopped answering phones, and I stopped trying to communicate.  I stopped eating and drinking.  Swallowing felt like a day's worth of work.  I was too weak to work. 

In May, I didn't sleep for hours.  I paced around my laundry room floor, convinced I was being chased to my untimely death.  I begged whomever to stop chasing me, to let me live.

When I would try to lie down, I was faced with black figures in my line of sight, sitting in the corners of my room, sneering at me.  I heard voices telling me to create a cocktail of all the pills doctors had prescribed to me since March, to end my life.  During those psychotic episodes, I heard these voices so clear that I once gathered pills together just to further construct my plan. 

It is only because I decided to tell my very best friend, Sequoia Thompson(?), my fears of this plan, that I am here with you today.  I was delirious, holding no remembrance of any form of reality.  I knew nothing or anyone that was real to me.  I stopped being able to cry or produce tears, although my heart was shattered at how much I had already lost.

In June, my brain started to burn as hot as the weather we are currently experiencing in the D.C. and Baltimore area.  My skull was set ablaze, causing my scalp to begin to become tender to the touch.  The fire radiated from the back of my head to middle of my spine.  During breaks from the blaze, my head was icy and cold, it felt numb.  My neck was stiff, crunching at every turn.  My back ached.  I developed an aversion to light on a level that vampires could empathize.

In July, my burning brain sent me to a hospital, where an attending physician swore that COVID did not cause any neurological implications.  If only he could see me now.

I stopped being able to add or subtract in my head.  The ringing in my ears, weakness in my limbs, and full-body tremors were all ignored by doctors.  Asking me a question meant waiting through awkward silences for answers.  I asked people more than twice to repeat themselves or reframe their questions.  I couldn't comprehend their words or the appropriate response to their ideas or thoughts.  I didn't know my own.  I had no idea or thoughts.  I rustled through paperwork I no longer understood.  I stopped being able to do the very things that gave me wings; I stopped being able to teach.

When a Black woman's brain is broken, the incapacity of her ability to think, explore, create, lead, challenge, and change destroys the ecosystem of success and worthiness which is already threatened by the racism and sexism she constantly experiences because she she's simply Black in America.  And as a middle-school teacher with a sharp photographic memory and penchant for well-written essays and routine writing, to develop students' critical thinking, I was the people's champ.  But now, since my brain is broken, I am nothing more than a burden. 

There's a different kind of weaponry that is derived when a Black woman's brain is broken, the kind that has turned itself on me.  The tragedy of a Black woman's broken brain is far greater and prolific than I can ever present to you in words.  This broken brain has created social, emotional, and financial barriers that prevent me from caring and providing for my family.  I once envisioned myself helping my momma retire.  Now I can't help her with too much of anything.  It disrupted a journey of a successful, promising career that would see me striving for principalship or curriculum writing in Baltimore City public schools by 2026.

In 2019, I was the only middle school English teacher in Baltimore to achieve an increase in 8th grade standardized testing scores.  I was on the right track.  Now my classroom and my job have been replaced.  It undermined the progress I made to never to be homeless, broke, or undervalued again.  Before I became ill, I had nearly $10,000 in savings, with plans to earn more teaching summer school.

My broken brain also robbed Black middle school students in Baltimore, those who relied on me to be their family, their friend, their basketball coach, their mentor, their teacher, of the presence of a Black woman who didn't shun or belittle them, but who loved and cherished them.  Studying education and English as a fellow at Stanford University, I learned what I always knew: Black students excel more and behave better when they are taught by a Black teacher.  The closest I've gotten to my classroom in the last 16 months is by being my students' virtual commencement speaker as they were promoted to the ninth grade. 

I am now a burden, now depending on government assistance to decide if I'm unwell enough to receive the same money I poured into it as a single Black working woman.  I am now a burden, unable to gather words as ingredients to great sentences.  I'm a burden, unemployed, feeling helpless and lost.  My mental health is under attack, flanked by bilateral occipital neuralgia, migraines, memory loss, cognitive impairment, and so much more that I can't recall now.

COVID corrupted my ability to think, reason, and rationalize for myself.  It showered me with paranoia and PTSD, becoming overly prepared, wordy, and confused during doctor's visits.  I am now irritable, impatient, and rendered incapable of educating anyone.

When a Black woman's brain is broken, the infrastructure of this country's workforce, style, and culture is under siege, and when those of us in power to create research protocols, mental health resources, financial assistance, and neurological studies fail to willfully investigate the brokenness of a Black woman's brain at the hands of COVID, we'd better be prepared to atone for much more than her absence in every facet of society.

Now the question I leave with you is who is going to help me carry this burden of my broken brain?  Thank you.

MS. BELLUCK: Late last year, I wrote what was apparently the first article in the mainstream media to describe a phenomenon that even most doctors hadn't heard of yet: post-COVID psychosis.  Symptoms of paranoia and delusions that were happening to some people who had never experienced mental health issues before.  It seemed rare, but nonetheless real.

The next day I received an email.  I wanted to reach out to you and let you know how timely your article was, a woman wrote me.  She said that her husband was, at that very moment, an inpatient in a hospital, suffering from a sudden onset of acute psychosis.  We have three children who were minus their dad over Christmas, as he spent the last week in the psych ward, she said.  And she added, my main point in emailing you was to thank you for writing about this.  Clearly the medical teams are learning on the fly.  His integrated care team of physicians, psychiatrists, and social workers in Seattle all devoured your article. 

It was incredibly moving to get such a note, but as I've explored, learned, and written about the neurological and psychiatric effects of COVID-19, I've actually received similar outreach from many people.  How the virus and the disease process can affect the brain is still not entirely clear, but what is clear is that many people are experiencing post-COVID effects on their cognition, memory, ability to summon words, concentration, and their mental health.

I've made it part of my journalistic mission to share their stories with the wider world, in hopes of helping others understand and recognize these conditions.  And it's really been an honor to spend time talking with COVID survivors who are experiencing these challenges and to listen to them as they open up about what they're going through.

Many of them are motivated by the desire to raise awareness and help others, and I have boundless respect for their courage and generosity.  One of the first pandemic pieces I wrote along these lines was about the terrifying delirium some people experienced when they were hospitalized for severe cases of COVID-19 that required them to be on ventilators for a period of time.  Kim Victory told me that she hallucinated that she was paralyzed on a bed and being burned alive, that she'd been turned into an ice sculpture, and that she was being attacked by cats.

Ron Temko became convinced he had been kidnapped and his horrifying visions including nails being hammered into a rotating human head.  And Anatolio Jose Rios thought he saw the devil in his hospital room and that there were dead bodies on the floor and that medical staff outside the door were armed with guns and threatening to kill him.

Not long after I wrote that piece, I began learning that even people who had mild initial reactions to COVID infection were being plagued with symptoms that were lingering for months.  Often they had previously been active, busy, hard-working people who were suddenly finding they could not focus, remember, or effectively do their jobs.

Erica Taylor, a 31-year-old lawyer, tried to return to her job at a nonprofit that helps low-income tenants, but found she couldn't concentrate or read emails and had to take an extended leave.  She told me she had episodes where her brain turned to static, and that one day she couldn't even recognize her own car in the parking lot of her small apartment complex.  Once, she said, I was sitting on the edge of the bed crying and feeling something's wrong, I should be asking for help, but I couldn't remember who or what I should be asking.  I forgot who I was, and where I was.

Bridget Hayward, an operating room burse, told me that for a while after COVID she was so brain-fogged, that instead of asking for a scalpel, she would say give me that sharp thing we cut with.  She would also briefly pass out while bending down to fix a patient's intravenous line or plug in the cord of a hospital bed.

Michael Reagan had to take a leave from his job as a vascular specialist for a company that makes stents and catheters because he had finger tremors, seizures, and in meetings he couldn't find the words he wanted to say.  He also forgot the details of a whirlwind trip he and his husband took to Paris just before the pandemic.  He told me he would look through all the pictures from Paris and say it looks like we had a great time.  We went and saw a Madonna concert, we went to the Eiffel Tower, we went to the catacombs, and I remember nothing.  Nothing at all.

And when I spoke earlier this year to Samar Khan, who was only 25, she was trying to handle her job in financial services while grappling with symptoms like blurred vision, ringing in her ears, trembling fingers, and brain fog so intense she would have to stop in the middle of a conversation with her husband because she couldn't remember what she was trying to say.  She told me, waking up every day in this body, sometimes hope feels a little dangerous.  I have to wonder, am I going to recover, or am I going to just figure out how to live with my new brain?

In my reporting and writing about these experiences, I try to learn as much as I can about the scientific understanding so far, and I'm grateful for the insights of the many thoughtful and diligent researchers and medical experts who talk with me, including a number of the people presenting at this conference.  I'm also committed to learning about the inequities of this landscape, including the communities and people who cannot get access to medical care, insurance coverage, or fair treatment in the workplace.

Overall, I come at this issue through a lens of respect.  Respect for the complexities involved in trying to get to the root of these long COVID symptoms, and respect for the many different challenges COVID survivors are facing in their efforts to get well.

Circling back to the woman who emailed me about her husband with post-COVID psychosis.  His name is Ivan Agerton, and for the two-and-a-half months I was able to follow his journey as he shared his frightening experience with paranoia.

(Video recording.)

MS. BELLUCK: Ivan and his wife Emily described how he thought that people were following him, that SWAT teams were hiding in the bushes outside their house, that FedEx drivers were hacking his cellphone, that antennas on light poles were surveillance devices.

(Video recording.)

MS. BELLUCK: I spoke with the very dedicated psychiatrist who treated him in the hospital, Dr. Veronika Zantop, and I kept in touch with Ivan as he achieved what appeared to be a successful recovery.  And then one day Ivan reached out to me and asked me to call him.  I responded immediately, and Ivan told me that his psychosis had come screaming back.  The next day he went to the psych ward for another week.  But since then I'm very happy to report he's been doing much better, and since that piece has run, so many other people have reached out to me, including psychiatrists wanting to interview me about these conditions, and people who either experience similar symptoms or have a friend or loved one who has. 

It's really rewarding to know that sharing these stories of COVID survivors is making a difference to others.  Thank you.

Agenda Item: SESSION IV: Special Issues Related to Neuro-COVID

DR. MEJIA: Thank you for this invitation.  My name is Nicte Mejia, and it's an honor to talk with you today about racial and ethnic disparities in COVID-19.

I receive payment as editor for the journal Neurology and research support from Biogen Foundation.

Since January 2020, our world has witnessed over 182 million cases of COVID-19 and close to 4 million COVID-related deaths.  With this we've also observed a huge magnification of longstanding health and healthcare disparities, including in neurology.

Marginalized communities around the world continue to be disproportionately affected by COVID-19.  In the United States, Black, indigenous, and Latino populations bear the largest proportion of COVID-19 cases and COVID-19 related deaths.  And it is Black, indigenous, and Latino patients who remain three to four times more likely to be hospitalized for COVID-19 care. 

The United States has experienced over 600,000 COVID-19-related deaths.  Black, indigenous, and Latino communities carry two to three times the burden of death compared to their proportion of the population.  And in neurology, we have very little but important research documenting disparities related to COVID-19.  For example, Black patients are more than twice as likely to die from COVID-19-related stroke.  Importantly, research suggests this is not because of clinical reasons, but rather associated to low rates of thrombolysis and thrombectomy among Black patients.

There's also data suggesting worse functional outcomes and 30-day mortality at nonacademic hospitals, and here again, this is not driven by patients' burden of neurologic disease or their comorbidities, but rather systemic factors, including gaps in access to critical and specialty care, as well as systematic differences in assignment and discussion of goals of care.

And mortality is really the tip of the iceberg.  Over the course of the pandemic, the neurology community has documented gaps in access to neurology care, whether it's decreases of about 20 percent at some point of patients coming to emergency rooms for acute stroke care, to significant decreases in access to outpatient neurology care for people with chronic conditions, including Parkinson's disease and multiple sclerosis.

Economic hardship and a lot of other challenges are really going to have long-lasting consequences well beyond this pandemic, and they are affecting and will continue to affect people living with neurologic conditions.

And science gave us a glimmer of hope with the advent of vaccinations, but the reality, in the middle of 2020-19, is that Black and Hispanic communities continue to be significantly underrepresented when it comes to COVID-19 vaccinations.  And we as scientists and clinicians need to take a step back and recognize that the common thread in all of these problems is systemic or structural racism and that we, in this moment of time, are facing hundreds of years and still ongoing issues with regards to segregation and unequal distribution of power and resources that then translate to gaps and barriers in access to neurology and other specialty care, barriers in the quality of care we provide patients, and at the end, disparities, including in neurology. 

And as scientists and physicians, we also need to take a step back and think of what we can do beyond documenting these problems.  I believe this framework for action presented by the Centers for Disease Control decades ago is an important starting point to think of how we move forward.  What I share with you in this pyramid, all of it matters.  Recognizing that as you go down in it, the interventions will take more effort, may take more investment, but will reap greater long-lasting benefits.

So yes, we all need to learn and teach antiracism and go from feeling uncomfortable with these conversations to acknowledging that there is systemic racism as a common thread for the problems that we're facing in the midst of the COVID-19 pandemic, to acting and moving beyond that discomfort with really relocating power and resources.  As clinicians and scientists living in a clinical sphere, it is very important for us to think of how we can desegregate healthcare, and part of this is, yes, broadening the diversity of the neurology workforce, but alongside, we need to be proactive in fostering ways to facilitate access to neurologists, neurosurgeons, psychologists, physical therapists and other neurology-related professionals, for marginalized communities. 

In addition to that, we need to foster access to neurodiagnostics, including EEG, MRI, as well as neurotherapeutics, including neuro-interventional treatments. 

And it's very few times that in that CDC pyramid that I shared with you that we have the opportunity to focus on long-lasting protective interventions.  The only other example I can think of in neurology is polio vaccination.  So here, we have this marvelous option of having COVID-19 vaccines available.  The reality in 2021 is that marginalized communities are still at a great disadvantage when it comes to having access to COVID-19 vaccination, and that in part this has to do with a public health system that needs to be reimagined. 

So with that, many professionals of color across the country, including many medical students and physicians, have stepped up to the plate and led very important efforts, not only engaging with communities but partnering communities to foster increased awareness, education, and helping them make informed decisions, as well as facilitating access to those COVID-19 vaccines in their community.

As we go down in the pyramid, it will be very important to think about how to change the context by fostering healthy decisions, and us as neurologists and scientists need to be thinking of the bigger picture and how to advance efforts to facilitate access to universal healthcare, recognizing that there are millions of Americans that remain uninsured and with poor access to neurology care, and really reimagine public health infrastructure, not just for this pandemic, but for the pandemics ahead.

In a world where universal healthcare exists and where public health infrastructure is magnificent, we'll still be facing the reality of many laws and policies that have to catch up to this century, and so I ask you to also learn more about efforts to update licensing requirements, particularly as it pertains to providing telemedicine services across state lines. 

Finally, the bottom of the pyramid, socioeconomic interventions, we need to be proactive and better distributing and more equitably distributing power and resources, and I ask you to join me in finding ways to offer opportunities for quality education and good-paying jobs for people from marginalized communities, and to engage in the broader conversation of finding ways to dismantle residential segregation and find a path for repatriations. 

So I thank you for your time and interest.  I look forward to your questions and ideas as we aim to move forward with equity and justice.  Thank you.

DR. DRAVID: Good morning, everybody.  Namaste.  I am Doctor Ameet Dravid from Noble Hospital, Pune, India, and the topic given to me, which I'll be talking about, is neurological issues in COVID-19 in resource-limited settings like India.  We will be presenting the research which we have conducted from our institute, Noble Hospital, Pune, India.

As you know, India has just recovered from a deadly second wave of COVID-19 where we saw 400,000 cases a day and around 4,000 deaths a day.  We are now at the lowest ebb, and we are reporting around 40,000 cases a day.  The second wave was almost four times more in number as regards to the first wave.  Luckily, the vaccination has picked up, and we have vaccinated around 25 percent of our population with the first dose and around 5 percent of the population with both the doses. 

This is where I work.  Pune is in the state of Maharashtra, which is a high incidence state for COVID-19 in India, and this is my institute, Noble Hospital and Research Centre in Pune, which is a private hospital, and I'll be presenting our neuro-COVID-19 data, which we have collected over the last 15 months.

So Noble Hospital is a tertiary level private hospital.  It's a 330-bed hospital with 280 beds reserved for COVID-19, and it has a 70-bed COVID ICU.  As I've already mentioned, Maharashtra state is one of the epicenters of the COVID-19 epidemic in India.  As of 28 June, 2021, we have seen 6 million cases of COVID-19 and more than 121,000 deaths.  At our institute, Noble Hospital, we have had 5,416 COVID-19 patients admitted, with around 400 deaths, with an in-hospital mortality rate of 7.3 percent.

We have maintained a neuro-COVID-19 database at our hospital, because we believe that central and peripheral nervous system involvement in COVID-19 has been increasingly identified.  We have tried to elucidate the unique characteristics and challenges encountered by physicians in India while managing neuro-COVID-19.  This data is about the first wave, because we have still not been able to collect the entire data of the second wave as well.

So in the first wave, by November 2020, we had admitted around 2,800 patients, of which 515 patients had severe COVID-19.  That means their oxygen saturation at baseline was less than 90 percent.  They had tachypnea and required respiratory or cardiovascular support.  Data about neurologic comorbidities, neurologic symptoms, and complications in patients with severe COVID-19 was collected and entered into an electronic database.  This data was published in two research papers.  One was published in Neuroscience Letters, which was titled Neurological issues during severe COVID-19 in a tertiary hospital in Western India, while second is still at medRxiv in preprint, talking about tocilizumab and steroids in patients with cytokine release syndrome, where we have looked at neurological complications of COVID-19 as well.  Both these research papers are available on PubMed.

So if you go to the data which has been published, we have found that out of the 515 patients with severe COVID-19, around 4 percent had preexisting neurologic comorbidities.  Not surprisingly, cerebrovascular disease like prior stroke or prior intracranial hemorrhage was the commonest neurologic comorbidity seen in our patients with severe COVID-19, but surprisingly, past history of poliomyelitis was the second most common neurologic comorbidity.  This association of poliomyelitis with severe COVID-19 has not been described before.  As you know, India is a country which eradicated polio in 2013 but prior to that, we have a large pool of young patients with preexisting poliomyelitis and residual neurologic paralysis whom we believe are at high risk of COVID-19 and are at high risk of severe COVID-19.

The other neurologic comorbidities like Alzheimer's disease, Parkinson's disease, schizophrenia, cerebral palsy, myasthenia gravis, and epilepsy were also seen in patients with severe COVID-19.

What were the commonest neurologic symptoms seen in our cohort of patients with severe COVID-19?  It was myalgia, around 49 percent of patients had myalgia.  This was higher than the number mentioned in other cohort studies all around the world, where neurologic symptoms were seen in around 30 percent of patients.  Other neurologic symptoms which were seen was headache, hypogeusia, which was seen in 11 percent of patients, anosmia in 4 percent of patients, and lightheadedness or unsteadiness during walking which was seen in 4 percent patients.

I want to mention that those patients who neurologic comorbidity and severe COVID-19, they had a mortality rate of almost 40 percent as compared to the mortality rate of 26 percent in the entire cohort.  So having a preexisting neurologic comorbidity was predisposing you to a higher risk of death if you have severe COVID-19.

When we looked at the incidence of secondary neurologic disease or neurologic complications after COVID-19, we found that encephalopathy was the commonest neurologic complication seen in our patients who were admitted with severe COVID-19.  We have defined encephalopathy as alteration of sensorium, alteration of personality, alteration of behavior, leading to intervention.  So without evidence of brain inflammation.  So encephalopathy was the commonest neurologic complication seen in our patients with severe COVID-19.  It was seen in around 8 percent of patients.  This encephalopathy was steroid responsive in around 10 patients, that is, 22 percent of patients.  So that (indiscernible) methylprednisolone would reverse encephalopathy even if the patient had severe COVID-19.

Other secondary neurologic complications seen were large vessel ischemic stroke, acute disseminated meningo-encephalitis, seizures, intracranial hemorrhage, acute transverse myelitis, and Guillain-Barre syndrome, or GBS.

When we looked at the relative risk analysis, we found that in patients who had died of severe COVID-19, the incidence of encephalopathy, incidence of stroke, or incidence of secondary neurologic complications was much, much higher.  Encephalopathy was seen in 25 percent of patients who had died because of COVID-19, while it was seen in only 3 percent of patients who had recovered from severe COVID-19.  So in relative risk analysis, we found that developing encephalopathy during admission was almost having a relative risk of 10 times higher risk of death in patients.  If you don't have encephalopathy, you are much, much safer.  So encephalopathy was a risk factor for death in patients with severe COVID-19.

Moving on, this is another research paper which our group, along with other hospitals in Pune has published in India, is trying to publish in India in Academy of Neurology, and here we have reported cerebral venous sinus thrombosis as a complication of SARS-CoV-2 infection.  We have reported 34 COVID-associated cerebral venous sinus thrombosis cases during the last 15 months of COVID-19 admissions in Pune.  We have found that incidence of cerebral venous sinus thrombosis in COVID-19 was much, much higher than the incidence of cerebral venous sinus thrombosis in the non-COVID era, where 46 per 10,000 patients per year was the incidence in the COVID era amongst COVID patients, while 25.2 per 10,000 patients was the incidence in non-COVID patients.  So definitely there is an uptick in cerebral venous sinus thrombosis in patients with COVID-19 in Pune.

Surprisingly, males are affected by CVST in excess of females, and we know that CVST is a female predominant disease.  So this is another new thing which we have observed.  Also, we know that there are risk factors associated with CVST, but in almost 75 percent of our patients had no conventional risk factors associated with cerebral venous sinus thrombosis.  Only 25 percent of patients had routine risk factors like postpartum status, alcohol abuse, or anemia.

Fifteen percent of patients had symptoms of cerebral venous sinus thrombosis, but no symptoms of SARS-CoV-2 infection, while 19 had symptomatic COVID and symptomatic cerebral venous sinus thrombosis.  Out of these 19 patients, 14 developed cerebral venous sinus thrombosis during admission for COVID-19 pneumonia, while five patients developed cerebral venous sinus thrombosis after discharge from COVID pneumonia.  The mortality was seen in cerebral venous sinus thrombosis and COVID in only the symptomatic patients, and the mortality was around 21 percent.  So four deaths occurred only in the symptomatic COVID symptomatic CVST group.

Three postpartum female patients developed cerebral venous sinus thrombosis after contracting SARS-CoV-2 infection.  All these three survived after therapeutic anticoagulation and oral anticoagulants.

Moving on, we have also reported coinfections along with COVID-19, and this is the first case report where we have reported three cases of mild COVID disease and CNS tuberculosis coinfection.  All these three patients had no evidence of pulmonary tuberculosis.  They were seronegative for HIV infection.  They had mild COVID disease, but their symptoms suggestive -- symptoms like headache, fever, vomiting, altered sensorium, for which they got admitted.  The imaging studies showed that it could be CNS tuberculosis, and when we did the CSF, it was positive for mycobacterium tuberculosis on the CB-NAAT test.

We do not believe that COVID-19 has contributed to the CNS tuberculosis.  It is just an incidental finding in a country which is high COVID/high TB burden setting.  Out of these three patients, one progressed to coma and died, while two patients made a complete neurologic recovery.

Here is the imaging appearance of the CNS tuberculosis.  You can see grapelike conglomerated lesions in the left parietooccipital lobe along with severe (indiscernible) edema and meningitis.

We are also in the process of publishing our COVID-19 associated mucormycosis data where we have reported 57 cases of COVID-19 associated rhino-orbito-cerebral mucormycosis.  As you know, India is the diabetes capital of the world, and we believe that COVID-19-associated immunosuppression, concomitant diabetes mellitus, irrational use of steroids for management of COVID-19 have contributed to an upsurge of mucormycosis, especially rhino-orbito-cerebral mucormycosis in India.  Fifty-one percent of the patients have had orbital involvement, and 33 percent of the patients had cerebral involvement in patients who had developed rhino-orbito-cerebral mucormycosis. 

Seventeen patients in our cohort needed exenteration of one eye, while 6 percent patients needed neurological intervention, neurosurgical intervention, to remove cerebral abscesses.  The mortality rate was 21 percent in the entire cohort, but if you have rhino-orbito-cerebral mucormycosis with cerebral extension, then the mortality rate was almost 47 percent, despite use of liposomal amphotericin B, posaconazole, and neurosurgical intervention.

These are the MRI pictures.  You can see frontal lobe abscesses because of mucormycosis, and here we look patients who have had exenteration of the eye for removal of the eye involvement and the frontal lobe abscess in patients.  Similarly these are the frontal lobe abscesses developing in patients who had COVID-19 with diabetes, received steroids, and developed frontal lobe abscesses because of mucormycosis.

What are the other challenges which we encountered?  One was an overwhelmed healthcare system and inadequate workforce because of which neurologic symptoms and comorbidities would have been underreported.  Neuroimaging, CSF examination, nerve conduction studies are not routinely available in semi-urban and rural settings of India because of which the real neurologic load would have been underreported.  Neurologists are not routinely available at bedside or by remote assessment, which is another problem, and treatment modalities for management of acute disseminated encephalomyelitis or GBS with IVIG plasmapheresis was not routinely available in poor resource-limited settings of India.

In conclusion, preexisting neurologic comorbidities in our cohort of severe COVID-19 patients were associated with high mortality.  Neurologic symptoms were seen in almost 50 percent of patients as regards to 33 percent in the reported cohorts.  Secondary neurologic complications like encephalopathy and stroke have developed in approximately 9 percent of patients with severe COVID-19 and are associated with higher mortality. 

Cerebral venous sinus thrombosis is an uncommon but significant complication of SARS-CoV-2 infection, and in resource-limited settings like India, you should not forget other CNS infections like CNS tuberculosis and rhino-orbito-cerebral mucormycosis, which have been increasingly observed.

Thank you for your patient listening and I will take any questions which you have in the future.

DR. NATH: Thanks for those wonderful talks.  It was very informative and can't say how much I learned from each of your personal experiences, as well.  So now, if all the speakers could have their videos on, we have several very interesting questions that have come through the question and answer session.

So the first one, I'll put it as an open question, because a number of you could probably answer that, and that is related to suicide in patients with COVID.  It's a terrible end to this illness, but I'd like for some of you to comment upon what you think drives people to that, how common is it, what the factors may be contributing to suicide in this population.

DR. DAVIS: I'm happy to start.  We had asked about suicidality as kind of a symptom in our study and found that 12 percent of this cohort, which is mostly not hospitalized patients, had considered suicide.  I think especially for first wavers we are facing just a complete overwhelming amount of stigma and dismissal, disbelief.  You know, for something that is just completely life-altering, so many of us can't work, so many of us can't participate in daily life.  We see researchers kind of looking in the wrong directions.  It looks like our answers are going to come really far down the road, and I think there's a lot of reason to be depressed in that way, and I think also there is a neuropsychiatric neuroinflammation component that is also causing these feelings, kind of from a biological standpoint.

MS. SMITH: I would like to also concur with what Hannah said.  I know last June and July, I was deathly afraid of speaking to the doctors at the hospital I kept going to about my suicidal thoughts, because I was already being placed as a psychosomatic patient, which is anxiety is my problem.  So to then tell a doctor, hey, I have suicidal thoughts, I'm thinking about downing all of these pills, I feared that it would push me into a realm that I couldn't come back from.  So I did not share it until this year with doctors that I was suicidal, for about a six-month period.  And still today, still today, I still suffer once or twice a month with thoughts of suicide.

DR. NATH: That's truly unfortunate.  Thanks for sharing that with us.  I can share with you that I saw one patient and I remember very vividly, that was an employee here at NIH, and older individual, never had any psychiatric history, there's no reason for him to be depressed, and recovered from COVID and then says he got afraid of himself.  Says that he might actually commit suicide, got himself admitted.  He had insight into it, so he managed to get himself some help.  It took him a month to get better.  So the new-onset psychiatric symptoms are also a major problem here, it looks like.

DR. MEJIA: I would like to add very briefly, I think that socioeconomic implications are tremendous.  People are losing jobs.  They're losing housing.  They're facing food insecurity.  All of these traumatic experiences pile on top of everything that all of you have shared.

DR. NATH: I think that's absolutely true.  Okay, the next question is related to diagnosis of COVID.  I think several people were struck by the fact that the antibodies come back negative.  So the question really is that how can one diagnose COVID if the antibody test and the PCR test is negative?

Would either Hannah or Athena, would you like to address this?

DR. DAVIS: I really think we need to be including clinical diagnosed subsets at every stage.  It just otherwise is going to create a disproportionate dataset toward -- or a bias against women in particular.  We know that women are less likely to retain their antibodies.  Like 80 percent of people who lose their antibodies are women.  They have lower levels in general.  These tests are just not perfect.  So it almost feels in some cases like a medical provider education, because we constantly see providers trying to do antibody tests, and in research, what I had presented earlier we're starting to see that this lack of antibody response might actually be a feature of long COVID.  So we really need to include a clinically diagnosed subset and then compare those to the PCR positive or antibody positive.  It's really just as simple as that, but what can't happen is that they get excluded.

DR. NATH: I think what you're trying to say is that we could develop clinical criteria for COVID and for many diseases we do that, where you don't have a diagnostic test.  If you have Parkinson's, there's no test you can send out for, right?  So you have definite, probable, or possible, and then include them as a cohort.

Okay, thanks.  Okay, then there was one question regarding scores.  Has anybody tried to develop a whole score for post-COVID syndrome?  My guess is maybe people are talking about scales is what they mean, and would anybody like to address that?  My guess is for example there are scales for subsets of symptoms.  I don't know if anything is there for the composite of post-COVID.

Athena, you just published some important stuff.  What do you think?

DR. AKRAMI: I don't think there is a scale so far, because as we are discussing how complex the whole condition is, how multifaceted it is, and therefore when we -- are we talking about which type of symptoms, right?  If it's a symptom spread over so many different organ systems, it's difficult to come up with a kind of a simple one number scale to measure all of that.  But on the other hand, there are some efforts, we know, Hannah and I, we are involved in a committee at WHO that we are talking about the core outcome set, how we can standardize a set of outcomes that then all long COVID clinics or GPs, basically, all over the world, can make sure that at least a minimum set of outcomes need to be measured.

So we are working on that, various groups are working on that, and as you said, in our study, for instance, we had -- we used the standardized scores for various mental health-related symptoms for coping, for fatigue assessment, but it's very difficult to come up with one scale that would capture the complexity of the long COVID condition.

DR. NATH: That makes sense.  There's a comment from Larry Honig about T cell responses and he says that maybe that's another way.  So as soon as those tests become widely available, that may be another opportunity.  Certainly Amit Bar-Or's presentation yesterday highlighted the importance of T cell immune responses compared to antibody responses in the MS patients who are treated with anti-T cell therapy.  So that's another opportunity.

Then there's another question that relates to the media, and so I'll present that to Pam, and so I'll take a little twist on that.  I think the theme behind that question really is that how do you decide which story to run with.  So for example, if somebody, this person is interested in getting highlighted, wants to highlight the fact that there are all these antibody-negative individuals, maybe we should be doing something about them, how do you pick what story is important, and then tell us also maybe what happens then?  What is the process?  Is it a one-person show?  Do you have a team?  How do you finally publish your story?  Because your stories are very detailed and there's so much information there.  So I'm always in awe what you're able to do, Pam.

MS. BELLUCK: Thank you.  I could not do it without the help of scientists and the help of folks like Hannah and Chimere and their networks and their insights really have been so helpful in kind of guiding me, either directly to stories or to just kind of think about what might be the next thing to write about.  So it takes a village.

But to answer, I think, the question that was posed, so at the Times, we're fortunate we have a science department with -- I don't know, I think maybe about eight or ten of us, maybe more, have been covering COVID in some fashion, and some are focusing a lot on vaccines, a lot of my colleagues are focusing on vaccines.  I haven't been doing that so much.  I've been focusing mostly on survivors and also on writing a lot about children and some of the experience of people being hospitalized earlier in the pandemic.  So that's kind of been my kind of wheelhouse.

But what happens is I think all of us to one degree or another are trying to keep aware, keep up to date, about research that's being published, preprints, all of that stuff, and a lot of things come in to us and a lot of things we sort of look for based on what we're hearing.  So if somebody comes to us, say, with a study or some research, we would evaluate that based on a number of different criteria.  We would look at kind of is the conclusion something new or something that we think is really a public interest.  This is partly because there's so many things that come in that we really have to kind of triage.  So we can't write about everything.

But we try to evaluate based on kind of what the significance might be, and then we will evaluate the work itself as much as we can.  How large is the study?  Was there a control group?  Was it peer-reviewed?  In the COVID world, that isn't a dealbreaker, as it might have been pre-COVID, because so much research is coming out now that we are trying to keep up with and they're saying important things and there's just not time for peer review, but we are trying to kind of have some lens of how substantial and how rigorous a study is, and a lot of the ways that we do that is take soundings from experts that we trust and look at other things that might be out there along those lines.

So that's kind of how we decide whether or not to write about studies.  In my case, because I really find a tremendous value in writing human stories and kind of marrying that with what is known about the science or even what is unknown, what questions should be asking, so my stories take maybe a bit longer.  That's why they're some of the ones that you're referring to and that I talked about, they take time, because I really try to spend time talking to patients, talking to doctors, getting a good sense of the nuance and the complexity.  This is not a one-size-fits-all phenomenon by any means, and trying to get a sense of the patterns and the different struggles that people are facing based on some of the things that Chimere was talking about, and other hurdles that people are facing that Hannah was mentioning, as well.

So it takes some time, but I think it's so valuable, because our readers are able to really get a sense of what the human experience is like and feel empathy and connect and so that's kind of the thing that I -- while I do write about sort of short stories about studies, I do a number of those, the thing I love to do the most is that type of story.

DR. NATH: Thanks very much.  Very informative, very insightful.  I must say that there are a lot of positive comments in the chat box as well as in the Q&A for each of you there.  So when you get a chance, do read them.  It tells you how appreciative the audience has been of all that you've done and all the information that you shared about yourself and the disease.

Let's take one more question here.  This is that have any of the panelists observed or experienced helpful psychosocial interventions?  Anybody want to talk about that?

DR. DAVIS: I think for the most part, most of us are pretty wary of that, given the history of psychosocial impact in post-viral illness.  It's historically been something that has been kind of misused to redirect biomedical research or misused to kind of focus on the psychosomatic narrative, which is just not the case.  Like this is a biomedical illness, and I think one thing that's really unique about long COVID patients is we are well educated, we've been really building on the work of past activists, past chronic illness communities, who have all supported us kind of along the way, and I think we're all really pushing for biomedical research and treatment.

DR. NATH: I think it is an important thing for us to discuss, because it is quite often what frustrates most patients, and a number of you have mentioned that yourself, that you go to a physician's office, and they do whatever testing is available to them, oh, this is all negative, and so maybe this is all psychiatric in some nature or, say, a functional disorder.

And that frustrates both the physician and the patient, and it's also true there are some patients who truly have a functional disorder, but if you then dig deep in there, there's actually a biological illness there, but oftentimes patients don't know how to really get attention.  So they may exaggerate their symptoms a little bit, but then the physician is only seeing the exaggerated part and not really diving deep into trying to find out what the underlying problem might be.

So it's a difficult problem.  It's not easy for the physician or for the patient.  Physicians need to do their part, and when they can't anything, maybe that's where research studies come in and research organizations are important in playing a role.  As later in the day we will talk about all these various cohorts that are being established across the country, maybe there's an opportunity there for these patients to seek help and participate in studies and we can learn from them.

MS. SMITH: Dr. Nath, I'd like to add something, too.  I learned a lot from you recently when we had the discussion with Body Politic where you lent a lot of your expertise to that conversation, and what I think also is important that can -- where we could see a change in the partnership between doctors and patients is if doctors are really, really telling the stories in medical notes that patients are telling, as well as their clinical diagnosis.  

I can't express how often I was -- I had to in the midst of blurry vision and not being able to cognitively comprehend what I was reading, I had to go back and ask doctors to tell -- don't tell us a tale of what you think is just happening, but also tell what I'm telling, as well as the clinical diagnosis, and that has been helpful for me.  So I would also advise people to check their medical notes, to make sure that what is being written about them is as accurate as possible.

DR. NATH: Yes, you are right.  History taking is an art, and 90 percent of medicine is actually listening to the patient, and that's important in how you then narrate the story, put the narrative in your own writing, is just as important.

Nowadays we have electronic medical records, we have an opportunity for patients to actually look at them, and quite often patients will correct (indiscernible). And then we will add an addendum to it.  I think that has actually helped tremendously as well.  So you shouldn't be afraid of letting people know, and physicians want to do the right thing.  So it's a partnership.

DR. AKRAMI: Can I add just one note?  I think you three covered everything.  I just wanted to add that it's actually very unfortunate that this kind of help via psychosocial treatments and interventions has become such a kind of a polarized topic, because I don't think anybody would kind of disagree that, yes, if you try to relax and meditate, you will feel better.  It's not a cure.  It would just help, right?  And nobody wants to kind of disagree with that. 

But unfortunately what is happening, as Hannah mentioned, that like throughout the history of other post-viral complications, it is replacing treatment and it is at least used as a tool to just like kind of gaslight basically the real problems that the patients are dealing with in order to reduce it to some sort of psychological, psychiatric conditions, and when doctors unfortunately don't have any solution to offer, they then kind of use psychological excuses to just shut down the patient.  And that's a very unfortunate actually this story happening, because on the other hand, as a neuroscientist, as a human, as a person who I have meditated many times in my life and I found it useful, I really would like to use that as a tool in my inventory of other things like coping mechanisms to use that as well, but it became such a polarized topic, which is unfortunate.

DR. NATH: I think that's very well said.  It's a good adjunctive therapy, but not the sole therapy for a biological illness.  So even if you have a stroke, these other measures, they might help you also, that need other intervention.

Now one last question, and that relates to the issues about health disparity, and I think both of you spoke so well about these issues.  But your audience here is largely physicians and other researchers, and so we're not public health experts, but we're seeing patients at the other end, and so I'd like to hear from both of you to say what advice do you have for us and where can we make a difference to decrease the issues related with disparity and healthcare?

DR. MEJIA: Thank you for that question, because I think there's several parts to my answer.  First and foremost, we need to be collecting data, analyzing it, and reporting it.  There's so much race/ethnicity, language, and other important data that is just not being collected and researched, or if it's being collected, there's a lot of missing data, and then the possibility is high that it won't make it to the tables in the paper or that it won't make it to the sub-analysis of data.

When I did a review of disparities midway through the pandemic and we published this in Nature, it was really hard to find studies focusing on neurologic consequences of COVID where race/ethnicity were collected and then analyzed, and you find huge disparities.  It's really striking what you find when you collect the data.  So that would be my biggest message for everyone doing these data repositories and inventories and any other publication, even to the media, really pushing all of us as a scientific community to obtain the data and report it and analyze it.

And then I think the second message would be to act, because we cannot keep just saying there's a problem.  We need to act, and that's why I added some of our colleagues doing amazing job increasing access to vaccinations in communities that we've left behind, because we need action yesterday, and we're part of that action beyond the documentation.

Then finally, Ameet, and I'm sure he'll comment on this, the world is so much bigger than the United States, and we left so many countries behind, not just with vaccinations, but with the research and the diagnostics and the treatments and we need to think about and invest resources, meaningful resources, to change that, too.

DR. NATH: Thank you very much.  That's very well said.  And so along those lines, Ameet, maybe one last question for you.  So your data that you presented was very impressive, and the amount of complications you're seeing is incredible.  The healthcare deliveries are different in different parts of the world.  So how much -- I think the important question that we want to know is is there a difference between these various variants of the virus, one, we know that transmissibility is certainly more of a thing, but are the neurologic complications also different or not?  Do you have a sense for that at all?

DR. DRAVID: The second wave in India was totally because of the delta variant, which was the reason why we had so many cases.  Though transmissibility was higher, the pathogenicity was also very high.  So we came across patients with very bad pneumonias, very bad ARDS, but surprisingly very few CNS complications.  So maybe because they were so seriously ill that we did not have time to look at their CNS complications, we don't know.  But this wave definitely people came in with very, very bad CT scans, very, very bad respiratory pattern, and the mortality rate was almost double as compared to that in the first wave.  So we had a very bad effect. 

That's what I wanted to comment, my earlier speaker as well, that the neuro-COVID in the resource-limited settings like India is very, very different from what we have presented in the resource-rich settings, and I think clinical trials should also include patients from resource-limited settings to have a real understanding of the full spectrum of neuro-COVID.

DR. NATH: Yes, that makes a lot of sense.  Thank you very much.  Maybe we should end this session now, and can we reconvene at 1 o'clock?  Thank you so much.

(Break)

AFTERNOON SESSION

SESSION V: Resources for Neuro-COVID Research: Summary of on Going Global, National, and Investigator-Initiated Studies

DR. NATH: Okay. Maybe we should go ahead and get started. So this next session talks about resources, and actually it has a wide variety of subjects that we’re going to cover in this session here. And so the first talk is given by Dr. Joseph Mankowski. He’s the Director of the Department of Molecular and Comparative Pathobiology at Johns Hopkins University. He has done an extensive amount of work using macaques as animal models for studying HIV neuropathogenesis. And today he’s going to talk about animal models related to COVID.

The next talk is going to be given by Dr. Lara Jehi, and she is the Professor of Neurology at the Cleveland Clinic, and epileptologist by training, and has established the COVID-19 Registry, which is a rich data source and has been instrumental in producing a large number of publications from that registry. And so she is going to talk to us about the cohort that they are establishing at Cleveland Clinic.

And then we’ll hear Dr. Eliezer Masliah. He is one of the co-organizers here, and you’ve heard him twice before. But he is the Director of the Division of Neuroscience at the National Institutes of Aging. He’s a neuropathologist by training, he has done a lot of work on HIV infection, on Parkinson’s and Alzheimer’s disease. And he’s going to talk about the initiative at National Institutes of Aging related to the Neuro COVID Cohort.

And then next it’s Dr. Sharon Meropol. She is the Program Director of the COVID Neuro Databank, and she is a pediatrician and epidemiologist. And she is also an assistant professor in the Department of Population Health and Division of Biostatistics at New York University, and she’ll tell us about the databank that they’ve established.

Next will be Dr. Tarun Dua. She is the Unit Head of Brain Health Unit in the Department of Mental Health and Substance Use in the World Health Organization. And so she has a large portfolio on neurological diseases and mental health issues, and she’s leading all the efforts of the World Health Organization in coordinating the Neuro COVID Portfolio.

And then lastly it will be Dr. Elizabeth Oelsner, and she is the Herbert Irving Assistant Professor in the Department of Medicine at Columbia University. She is a respiratory epidemiologist, and is also the PI of a collaborative cohort of cohorts. So for COVID-19 research. And this spans across 14 sites all over the country, so we’re looking forward to all these talks.

DR. MANKOWSKI: COVID-19 animal models are essential for studying the impact of SARS-CoV-2 infection on the CNS. In this overview I will highlight a few published reports to illustrate a couple points, but want to acknowledge that many other published studies also are highly relevant for understanding neuro COVID.

COVID-19 animal models will be pivotal for addressing many pressing questions, including neuroinvasion, blood-brain barrier changes, including physical, metabolic, or immune function alterations. The role of microglia and astrocytes as innate immune responders. Evaluating the role of age and sex on disease outcomes. And finally linking molecular and morphologic assessments with behavioral evaluation, neuroimaging, and emerging biomarkers.

The most widely used COVID-19 animal models fall into three categories: mice, hamsters, and primates. The K18 human ACE2 transgenic mice developed by Pearlman and McCray at Iowa and available from Jackson Labs date back to the SARS era, and thus were a natural model to pursue for COVID-19 despite the initial limited availability of these mice. Of note, neuropathology was reported in the pre-COVID-19 SARS infection studies of these mice. SARS-CoV-2 infection of transgenic human ACE2 mice is a lethal disease model, with most animals surviving until day six post-infection. The contributing roles of pulmonary disease versus CNS disease during acute infection leading to this lethal phenotype remain to be established.

An alternate mouse model is delivering human ACE2 receptor via AAV vectors to target organs, including the lung and the brain. And this offers the advantage of using immune altered mice, such as Rad1 knockouts, or even humanized mouse models to dissect the immunopathogenesis of COVID-19. Another approach is to employ mouse adapted SARS CoV-2, exemplified by Ralph Baric’s efforts at the University of North Carolina.

A study by Zheng, Wong, Verma and colleagues in a group led by McCray and Pearlman at Iowa showed that human ACE2 transgenic mice developed severe lung disease as well as brain lesions in a subset of the animals. In the brain the pathology includes evidence of cell death and thrombi reflective of vascular damage, and they’re seen in multiple regions, including the thalamus.

Immunohistochemically positive infected cells were shown in multiple brain regions at day six post infection, and infected cells were also reported in olfactory sustentacular cells in the olfactory epithelium, and not within the olfactory neurons themselves.

And of note this study reported very interesting scent detection assays that were able to uncover the phenotype of anosmia and hyposmia in the mouse model. So the ability to bring function to their morphologic and molecular studies was really critical.

Another study by Song and Zhang and colleagues, and Akiko Iwasaki’s group at Yale used a crosscutting integrative approach to study neuroinvasion. It included a combination of the K-18 transgenic mice, AAV transduced ACE2 mice in which the brain was transduced via interventricular injection, human organoids using human hiPSCs and hNPCs, and finally postmortem brain samples from COVID-19 patients.

So they were able to combine and integrate across all of these platforms. And they showed widespread cell infection of neurons and neuronal progenitor cells as well as radial glia in the different model systems. They showed a lot of evidence of neuronal cell death. And this was associated with metabolic alteration of neurons, and of tissues they showed evidence of vascular network changes as well. So again, a great strength of this study was its ability to combine animal models in these cross-validation approaches that will be crucial for studying moving forward.

The golden Syrian hamsters in contrast with the transgenic hACE2 mice are a robust and reproducible COVID-19 pulmonary phenotype with long-term survival. These animals don’t die during the first week, but they last well beyond chronic infection stages.

At Hopkins we’ve established the SARS-CoV-2 hamster model to study immuno-pathogenesis. We infect golden Syrian hamsters that are six to eight weeks old with the Washington One SARS-CoV-2 isolate intranasally. We use equal numbers of males and females in group. And we look at endpoints in two, four, seven, 14, and 28 days post inoculation. Our typical group size at each of these study endpoints is eight SARS-CoV-2 infected animals, again half male, half female, and four mock-inoculated hamsters of both genders.

In this model there’s a very reproducible phenotype of loss of bodyweight, infected animals shown in red lose approximately 15 percent of their bodyweight at day six PI, and then they recover, and statistically they catch up to the uninfected blue mock control hamsters by day 28 post infection.

So very reliable phenotype that we don’t show any kind of behavioral phenotype to date in the model established at Hopkins. We can uniformly detect infectious SARS-CoV-2 in nasal turbinates, trachea, and lung, early infection from day two to day four, rarely at day seven, and we can detect viral RNA at later time point after date 28 PI by QRTPCR.

These are the lungs at day seven PI, you can see how marked the consolidation is. And then they resolve. So by day 28 it’s very difficult to even detect any residual pathology in these animals. So we’ve been looking in this animal model for evidence of CNS alterations, and we have found that if we immunostain for GFAP in white matter, shown on the top panel, at day two we detect background GFAP staining, but at day seven shown by the upper panel right image we can see abundant GFAP immunostaining.

And if we measure this GFAP immunostaining by digital image analysis we can see a progressive increase in GFAP from day four to day seven post infection, and this elevation in GFAP and white matter persists out until day 28, again it’s about twice what we see at day two post infection.

We don’t see any changes in IBA1 expression reflective of microglial activation, nor do we see any evidence of viral infection by using RNA scope in situ hybridization in these animals. We have not looked by QRTPCR. So in our hands the phenotype that we see is astrocytic activation that persists. We do not see overt neuropathology in this model, and we do not have a behavioral phenotype to date.

Other groups studying the hamster models, again like those transgenic ACE2 mice, have reported tests to detect anosmia, and again there is evidence in these studies coming from the Institute Pasteur from Lledo’s group that the olfactory realm may be one way that the virus can enter the way. So they have reported infectious virus detected at day four PI, and again this clinical phenotype of anosmia as well as ageusia in this hamster model. So the hamster model remains in development for CNS disease.

Finally, amongst these animal models I would like to talk about the primates. So the lead models right now are in African green monkeys. They have the most severe pulmonary phenotype. However, rhesus macaques also do develop pulmonary disease. It’s a much milder form with no associated mortality. In particular the AGM phenotype seems to map to age, so the older animals appear to have more severe phenotype based on studies coming out from the consortia group at the Tulane Primate Center.

There’s some evidence that baboons may be useful as a model, but one animal species that we can take of the list at present are common marmosets. Though they’re smaller primate models and perhaps more tractable in certain ways they do not show any clinical phenotype with infection.

So just a quick nod to two different COVID-19 animal models in the primate space that are coming out. There’s evidence that the olfactory route again is a path for neuroinvasion of SARS-CoV-2, and that SARTS-CoV-2 replication can be detected in the olfactory bulb of monkeys. And another report, just an abstract report in FASEB recently from the Tulane group showed recently there’s evidence of perivascular hemorrhage, neuronal damage and loss, and perhaps neuroinflammatory upregulation in particularly the African green monkeys, and a relatively small set of animals that have been studied.

Quick overview of organoids. There are many reports out now on using brain organoids as I mentioned. Initially these are human iPSCs and NPC classic organoid development models. The emphasis on these reports is that there is evidence of neuronal infection as well as damage and loss of neurons in their systems.

As these systems evolve and start looking at other regions such as the choroid plexus by Guo-Li Ming’s group at Penn, they’re showing that they think infection actually may be dominant in the choroid plexus and not in neurons per se. And still other reports have shown that glial cells rather than neurons may be the primary sites of infection too. Again, that’s coming from the Shay group at Texas.

So there are some differences in these findings to be reconciled, and I’d just like to close by saying it will be really crucial to map the organoid findings back to in vivo systems, including animal models and patient-based studies. Thank you.

DR. JEHI: Good afternoon. Thank you for the time to present our Cleveland Clinic Neuro-COVID Cohort. I’m Lara Jehi, I’m Professor of neurology and Chief Research Information Officer for Cleveland Clinic. I will share with you what our cohort can offer, and some of the work that we have done so far. Hopefully you will see opportunities for this resource to help with your research and to collaborate with our teams.

Our Neuro COVID Cohort is a subset of the Cleveland Clinic COVID Registry, which now includes more than 86,000 COVID positive patients, close to 250,000 COVID negative patients, who are matched to the COVID positive ones by age, gender, race, and testing date, within plus or minus two weeks.

This registry has supported numerous research projects across 14 different workstreams, originating from sites across our health system. It has led to more than $150 million in grant funding submitted, and most importantly we generated deliverables with immediate patient care implications such as a clinical decision model adopted by Epic, our electronic health record vendor, and made available to its users worldwide.

Our registry started with the beginning of the pandemic in Ohio in mid-March, leveraging our research data warehouse, which already automated data abstraction from the electronic health record. For the purposes of the registry we used the initial five months to manually validate new natural language processing algorithms that we developed for COVID specific symptoms and for test results and data.

These algorithms continue to be rechecked every two months to ensure more than 90 percent accuracy. This automation was essential to sustain data abstraction at scale. As you see in this graph showing a timeline of the size and progress of our data collection, we now have data on more than 300,000 patients.

It’s impossible to collect this much information with manual abstraction alone. We continue to collect information on COVID negative controls, but we reduce the matching to a ratio of two to one around December due to changes in testing protocols and in disease epidemiology.

You see here the breadth of the information that we collect, and the specific neurological diagnoses and symptoms that we capture. We focus on headache, loss of taste, loss of smell, confusion, and memory loss to capture brain fog, fatigue, epilepsy, and stroke. Altogether, depending on whether COVID resource in the outpatient setting or whether patients get hospitalized or transferred to the ICU, each patient will end up with anywhere from 300 to 800 data points.

Given this infrastructure and its automated alignment with our enterprise-wide biorepository, and with our clinical trial management team, the registry has catalyzed a research pipeline where observational data, translational research, and clinical trials are coordinated. In the next few slides, I will share with you some examples of what has been possible to give you ideas for what this resource can be used to.

In the first group of projects, the registry provides data needed for optimum propensity weighting analyses applied to observational cohorts. For example, we published the first paper, at least the first paper that was not subsequently withdrawn from the literature, supporting the safety of ACE inhibitors and angiotensin inhibitors, blockers, in patients with COVID.

More recently we have collaborated with a team at the Brigham’s to study T cell cross reactivity between COVID and vaccination against MMR and Tdap. Our observational data from close to 74,000 COVID positive patients supported a reduction in COVID disease severity in patients previously immunized by the MMR and Tdap vaccines.

We were able to propensity match for 44 different potential clinical confounders, so 44 confounders were adjusted for, and study variability in relation to age and gender, providing a very helpful, robust, human pillar to add to the Brigham’s experimental evidence.

We just responded to the reviews from Cell Press, so this pre-print will soon be available in its peer reviewed form with some additions. The point is that we have used our data either for hypothesis generation as in the first example, or for supporting experimental findings from basic science research, as in the second example.

Another use case is in epidemiology. In the second set of research applications, we used our data to support genomic epidemiology research in collaboration with our pathology and genetics departments. We correlated SARS CoV-2 clade assignments with disease outcomes. At the clinical research drawn we have applied methods of natural language processing through work supported by NINDS to map out the temporal course of neurological symptoms of COVID, both in the acute phase and more chronically.

I show here the results for fatigue only because the paper is still in peer review. Patients entered in the registry are seen across 18 satellite clinics in Ohio, and five hospitals in Florida where we serve a larger Latino community. So our demographic patient distribution actually mirrors that published by the CDC for the national distribution of COVID positivity, allowing us to study diverse patient populations and focus on disparities.

Developing a model for individualized prediction of a COVID positive test was one of the first papers published by our group on COVID. This paper has since been highlighted by the British Medical Journal as the promising diagnostic prediction model of 118 other models published and prioritized by the BMJ based on statistical rigor.

This model was the foundation of our partnership with Epic, I mentioned earlier, and for a current partnership with CONDOR, an initiative tasked by the NHS at the UK to create a single national route for evaluating new diagnostic tests. We are applying the same statistical rigor to create a nomogram, an individualized risk prediction model that is, that predicts an individualized risk of chronic fatigue. Our team has a particular interest in predictive modeling, with an eye towards direct patient impact.

Lastly, we have supported network medicine-based analyses looking into mechanisms of COVID related cognitive impairment, as in the top paper you see there linking SARS-CoV-2 infection to brain microvascular injury and neuroinflammation as a mechanism for the cognitive impairment that is observed there. Or in identifying potential therapeutic targets through drug repurposing analyses.

This is the bottom paper, where one of our computational scientists identified through computational AI based tools a list of potentially repurposed drugs that could be used, some of which we ended up validating in the COVID registry, and now we have an ongoing clinical trial looking at them, in particular melatonin.

These observational findings do not provide definitive answers as we all know, but they can help inform the design of the needed experimental research or clinical trials. The main takeaways are these: we have a large cohort of COVID positive patients with COVID negative controls that are matched for age, gender, race, and testing period. We have at least 300 datapoints per patient allowing deeper phenotyping, more thorough matching, and prediction modeling.

We identified anywhere from 6000 to 50,000 patients with different neurological symptoms, so the range here depends on the symptom in question, or chronic complications. Through our biorepository about 1000 COVID positive patients and 1,500 COVID negative patients have available biospecimens. As you see form the presentation we love to collaborate, so collaborations are welcome. And if this presentation triggered any ideas that you want to pursue please reach out, this is my email, and I am looking forward to the Q&A session and to the conversation that will follow. Thank you for your attention.

DR. MASLIAH: Hello, my name is Eliezer Masliah from the national Institute on Aging, and it is my great pleasure to be here today with you. Thank you very much for joining us for this very exciting meeting on neurologic and psychiatric effects of SARS-CoV-2. I will be talking to you today about the NIA and other collaborations on NeuroCOVID cohorts and Alzheimer’s disease.

As you will know, the NIA is the main institute charged with the national plan to advance Alzheimer’s disease, that has the main objective finding treatment and prevention for Alzheimer’s disease by the year 2025. And the plan also involved ADRD, such as dementia with Lewy bodies, frontotemporal dementia, vascular dementia. And for these purposes we also collaborated with NINDS, that is the main institute that helps us with ADRDs, but also NIMH, NHLBI, and many other institutes listed here, to advance the national plan, both that includes the ADRD and mixed dementias.

Our approaches with these dementias, is to better understand the mechanisms of aging, the genetics, as well as environmental factors that include not only toxins, pollutants, heavy metals, but also infectious agents like SARS-CoV-2 and the role of both proteinopathy and neurodegeneration in the process of Alzheimer’s disease and related dimensions that could lead to diagnostic and therapeutics.

We actually know from recent studies conducted by NIA funded investigators, and this is based on electronic medical records, that actually individuals with dementia, in particular Alzheimer’s disease, posttraumatic dementia, vascular dementia, have a greater risk for developing COVID-19. And also we know that seniors and African Americans are at major risk of developing COVID-19 in these populations, to the relationship between ADRD and COVID-19 and understanding how COVID could lead to neurocognitive alterations, both in acute and chronic phase is very important.

So we are leveraging several cohorts and infrastructures that have been supported by the National Plan to Address Alzheimer’s Disease, both at NIA, NINDS, NHLBI and other institutes, toward a goal of better understanding NeuroCOVID both under acute and chronic conditions, and for this purpose for example we have the Alzheimer’s Disease Research Center, this is a network of 35 centers in widely distributed geographical areas, 15,000 participants of diverse backgrounds for which we collect clinical, neuropathological, imaging, biomarkers, genetics, and other types of data that is centrally distributed, and now we’re also including COVID-19 testing and remote testing in these populations, and all these data are deposited in a national coordinating center.

And the genetic component is important because our Alzheimer’s disease genetics program that includes 68,000 whole genome from diverse populations, we’re hoping will have 100,000 by 2025. Actually, many of the participants on the ADSP are part of the Alzheimer’s disease centers population, and the data for ADSP distributed to NIAGADS.

And ADSP actually have been involved in discovering many of the new risk factor genes involving Alzheimer’s disease, many years ago one of the first genes was APOE, but since then many genes involving neuroinflammation, endocytoses, synaptic signaling, mitochondrial function have been discovered, and it is interesting understanding how the genes might confer both susceptibility and resistance to Alzheimer’s disease, but also maybe to the complications of COVID-19.

So for these reasons we’re also leveraging the ADSP cohort for COVID-19 study, both to understand the impact of COVID-19 on AD/ADRD risk and progression in the context of ancestral gene variation, to better understand the genetic and protective factors as I mentioned before for acute and chronic lung COVID, and to develop algorithms to harmonize with CMS EHR data and deep phenotyping of COVID-19, and also to integrate a more diverse gender and ethnic population, understanding the relationship between COVID-19, genetic ancestry, and AD/ADRD.

And we currently have approximately 50,000 individuals that might be participating on this study. About 10 percent of them have cognitive impairment of Alzheimer’s disease, and the rest are many controls, and many of them are from diverse populations, the large majority still in white but also we have a number of African Americans, Hispanics, and so on.

This is really very interesting because for example recent data have shown that APOE, which is a major risk factor for Alzheimer’s disease, actually plays a role in SARS-CoV-2 for example, the APOE4 of Alzheimer’s disease has been linked to increased permissiveness of neuronal and glial cells to SARS-CoV-2 infection. And recent studies also in the UK biobank data have shown that E4 individuals have a greater mortality due to COVID-19, particularly if they have a history of dementia or Alzheimer’s disease.

So NIA has four major hubs of data for data distribution and sharing, including AMP-AD, NACC which will be distributing these data from the Alzheimer’s centers, LONI that is distributing the biomarkers data, and NIAGADS that distributes the genetics data from ADSP and are also include COVID-19 data.

In addition we’re also very interested in supporting a number of funding opportunities to create more research and infrastructure on the role in infectious diseases and inflammation, ADRD and its relationship with COVID-19. Right now we have an RFA on infectious etiology of AD/ADRD, we had one in collaboration with NIMH on HIV related neurodegeneration and neuropathogenesis, the role of the microbiome in AD/ADRD that could also be extended to COVID-19, and we actually have a couple of announcements to studying neurodegeneration in COVID-19 and its relationship with AD/ADRD, and here probably we’re interested both in the role of acute and chronic SARS-COV2 in the proteinopathy, on the vascular component, on inflammation, and also on cell senescence and DNA damage and the interaction between COVID and AD/ADRD, and here we want to collect neurological and neurocognitive data, understand better the mechanisms of SARS-CoV-2 neuropathology, and develop some therapeutics at the blood-brain barriers.

NIA with NINDS is also collaborating with NIH in this cohort of cohorts, C4R. You’re going to hear more about it from Dr. Oelsner in a few minutes. That includes many cohorts that are supported through the national plan, and NIH collaborating with NINDS and NHLBI in this regard.

And also we are collaborating with NHLBI and NINDS, NIAD and many other institutes in this very large, NIH wide effort to understand the post-acute sequala of SARS-CoV-2 infection that is now the COVID cohort, and this is a congressionally mandated study for long COVID, over $1 billion investment, this is going to be a very large meta cohort that includes adults, pediatric, and other population.

It will include a recovery cohort, autopsy cohort, EHR, and it has already a clinical science cohort, data research cohort, biorepository, and administrative and coordinating center, and probably will hear more about these from Dr. Amy Patterson at this meeting.

I just want to close with some links to our website, our concepts and opportunities, and the Division of Neuroscience. Please feel free to contact me, we are really very interested in hearing from you, and thank you again for being here with us today. Thank you.

DR. MEROPOL: Good afternoon. I am Sharon Meropol, I’m glad I have the chance to tell you about our program, the COVID-19 neuro Databank/Biobank, or as we like to call it, NeuroCOVID.

For the past two days we’ve heard a lot about the neurological conditions associated with the SARS-CoV-2 virus, both the acute symptoms as well as a growing interest in the post-acute symptoms. These symptoms cause patients on a population level a large degree of disability and distress. As scientists there are many research questions that we have about this illness.

For example, what are the neurological manifestations associated with SARS-CoV-2, what is the clinical course, are certain of our patients more vulnerable, such as for example maybe patients with preexisting neurological conditions, are there certain biomarkers that are associated with illness and recovery, are infants born to mothers with infection during pregnancy at higher risk of neurological sequelae, and what are the characteristics and course of the post-acute sequela.

As the virus moved from city to city, from academic medical center to academic medical center, astute clinicians began to collect data on their own patients. Unfortunately, these small silos of patient data were insufficient to answer questions about these relatively uncommon conditions, especially because they were gathered using various different data elements and different data standards, making it hard to combine data cross sites.

Also, they mostly involved patients at large, urban, academic medical centers, which may not be representative of patients as a whole. They also were regarding mostly severely ill inpatients, and didn’t represent the experience of patients who were never hospitalized.

So NINDS funded us to create the COVID-19 Neuro Databank/Biobank, with the following objectives. First, to collect data and linked biospecimens for patients with new or worsened neurological conditions associated with COVID-19 infection. Next, to overcome the limitations of the existing research resources. And to average the talent, commitment, and experience of all of our collaborators. And ultimately to promote collaborative science and publications.

We’re interested in four patient populations, three of which share inclusion criteria for non-pregnant adults, pregnant patients, and children, the inclusion criteria are that the patient has to have had a documented COVID-19 infection and an associated neurological condition that’s new or worsened according to the patient’s clinician.

Our fourth population is children born to mothers with COVID-19 infection during pregnancy. We’re also collecting biorepository specimens that are leftover from patients’ clinical care, or that are collected by other research programs that are eligible for sharing.

Data are abstracted directly from patients’ medical records directly into our REDCap Database. Our data elements were developed in collaboration with NINDS and national and international subject matter experts, and are designed to harmonize with data standards such as CIDSC, PhenX, and LOINC. We use preexisting data elements whenever possible.

We have a set of core variables and then a larger set of supplemental variables. We’ll also accept existing datasets by a secure transfer, and then map those data elements to our own as much as possible. Our NeuroBioBank collects deidentified specimens leftover from clinical care or other research projects. We prefer if sites aliquot the specimens themselves to avoid multiple freeze/thaw cycles.

After shipping to NYU, they’re stored at our Center for Biospecimen Research and Development. Our Labvantage system barcodes and tracks all of these samples. If sites would prefer to keep their own specimens for patients for whom we have data, we will maintain a virtual biobank for these specimens to know where they’re located. We’re using a Global Unique Identifier or GUID. The way this works is at the clinical site the patient’s identifiers are entered into the local GUID platform, which creates a one-way hash. This hash cannot be back translated to identify the patient.

This hash is sent to the centralized GUID server, which provides the GUID. This GUID is specific to this individual patient, so if the GUID recognizes the patient has been encountered before it will provide that patient’s previous GUID instead of creating a new one. This way all the identifiers stay at the clinical site, and this GUID links our data to our biospecimens, maternal to infant records, and records from the same individual across sites, over time, and potentially can help us identify duplicate sources of data.

There are many incentives for us to collaborate. First, we do have limited reimbursement for data entry and biospecimen submission. Next, there’s the opportunity for shared authorship and publication. But most important for our participants is the ability to be part of a dynamic learning community. Clinicians are excited about sharing their patient experiences, and we have the opportunity to adjust what we’re collecting to meet the needs of our collaborators’ research interests.

So far we have 33 sites onboarding from 19 states, from patients across the lifespan, from both academic affiliated and non-affiliated institutions. So far about one third of them are non-affiliated. You can see that most of our site PIs are neurologists, but we also have a pretty good representation from other specialties.

Ultimately the goal is to share data and biospecimens with scientists to answer research questions. So a scientist with a research question will identify the NeuroCOVID resources, and initiate a proposal online. This will be evaluated by a publication and resources committee, and then after approval, access will be provided to the data and biospecimens, and we will be able to track the progress through analysis and publication of all of these projects. So for our next steps we’re currently starting to meet with international sites, and we’d like to bring on an additional wave of US sites, especially targeting children and newborns.

As our interest in post-acute sequalae grows, we’re reaching out to our colleagues in other specialties to be able to standardize the way data are collected in the clinical setting.

So in summary, we’re collecting data for patients with new and worsened neurological conditions associated with COVID-19, and link biospecimens using common data elements for people across the lifespan from diverse clinical sites. We’re interested in acute symptoms and post-acute sequelae, with the potential for longitudinal follow-up, and we look forward to being a robust and fruitful resource for the scientific community. Thank you.

DR. DUA: Greetings from the World Health Organization. My name is Tarun Dua, and I will be talking about the WHO Global Forum on Neurology and COVID-19. So why this forum? The forum is a platform for convening partners with four objectives. One, to generate discussion and facilitate knowledge exchange. To build and link existing partnerships in the area of neurology. To enable harmonized approaches to different aspects that are required for NeuroCOVID, and to influence policy and systems so that care is provided for people with neurological disorders, especially in low resource settings.

So when the pandemic started the forum was established, we have membership from 27 countries and it’s growing, weekly meetings have been happening, working groups have been established, and let me go through some of the networks and consortia that are part of this forum. Many of these are international, with partnerships from low- and middle-income countries.

Some of them are disease specific, so for example Worldwide Fingers focusing on dementia, there are certain ones that are looking at both neuro and psychiatry aspects, so for example the Alzheimer’s Association International Cohort Study of Chronic Neuropsychiatric Sequelae. Many are Europe based, like the European Academy of Neurology, or like the World Federation of Neurology.

So this has been a platform that many of these consortia, many of these networks have come together. In the forum we established four working groups, one on clinical care, two on essential services, three on surveillance, and four on long-term impact.

The idea was to identify what are the gaps, what evidence reviews are required, what kind of research needs to be facilitated, and how do we enhance and improve the clinical exchange, or other types of exchange and sharing of knowledge in these areas. I’m going to give you some of these examples in my next few slides.

So the most important part, which was about the acute clinical manifestations, and this has been the forum contribution towards the WHO Guidance on COVID-19 Clinical Management. It has been released in 2020 and was updated in ’21. There is a chapter on mental and neurological manifestations and its management within (indiscernible). Together with other partners such as Brain Infections Global, the Global Health Network, neuroclinical exchanges have been organized.

These have included case discussions from both high resource settings as well as low resource settings. Some of the examples for example have been around CVST in context of COVID vaccination, so that’s an example of a topic that has been discussed in such clinical exchange. Evidence has been summarized in terms of a systematic review of neurological manifestations associated with COVID-19.

And an important issue that has come up is the disruption of essential services for people living with neurological conditions. A couple of pulse surveys have been carried out by WHO.  Specific survey was on the assessment of service delivery for mental, neurological and substance use disorder.

Disruptions were seen worldwide, including for emergency services, access to medications, vulnerable population groups, children and older adults, they were not receiving the services that are required. Literature review carried as well as the survey that was carried out involving many of the NGOs working in this space showed similar findings.

When we looked at some of these causes, and this was a rapid review that was done by the members of the forum, these were summarized as the travel restrictions because of the measures that have been put in place, closure of services, and sometimes patients not presenting out of fear.

Various mitigation strategies have been used in these countries, such as telemedicine, about using novel dispensing approaches for medications, or for example giving medications for longer duration, or the direction of patients to alternate care sites. Some of this has been summarized in the guidance that WHO has pulled together on maintaining essential health services, and as I speak these guidelines are being updated.

WHO has published case record forms for core CRF for pregnancy, for multisystemic inflammatory syndrome, and the last one on post-COVID-19. And these have been made available for various groups to use, and a clinical platform has been also established.

Some of the other work has been for example looking at the issues that are emerging. One such example is the thrombosis with thrombocythemia syndrome following coronavirus disease vaccination, and WHO is coming up with an interim guidance on the clinical case management as well as case degradation, which is being done in collaboration with the Brighton collaboration.

One of the things this conference has been discussing as an important issue is what is our understanding of post-COVID condition and how can we enhance it better. A series of webinars have been carried out by WHO focusing on three areas, recognition, research, and rehabilitation. A Delphi exercise for defining post COVID-19 condition has been carried out, and we are also working on defining the core outcome set.

So to summarize, a lot has been happening in the space of COVID-19 and looking at the neurological impact and what guidance needs to be available from WHO. We have been working in disseminating this guidance to many of the low resource settings, and I take this opportunity to thank all of the NeuroCOVID forum members as well as the members of the WHO’s Brain Health Unit. Thank you very much.

DR. OELSNER: Thank you for inviting me to talk to you today about the collaborative cohort of cohorts for COVID-19 research, or C4R. my name is Lizzy Oelsner and I’m from Columbia University in the City of New York. Over the past year and a half, we’ve made tremendous progress in understanding the COVID-19 pandemic using a range of observational study designs. Nonetheless we’ve also seen some classic selection confounding and information biases impact on the results, sometimes leading to some spurious conclusions.

In this context we designed C4R to minimize biases inherent in observational studies of COVID-19 by performing near complete case ascertainment of COVID-19 in a large US general population-based sample that had extensive pre-pandemic phenotyping performed using standardized objective measures.

C4R brings together 14 NIH funded cohort studies, including those that were initially focused on heart, lung, or brain disease, although there are even more participants still alive in this cohort, we expected that 53,073 adult participants might be able to participate in C4R. These participants were expected to come from across all 48 continental US states, and altogether we have 40 academic institutions involved in the C4R initiative.

The racial/ethnic composition of the C4R target population was expected to be five percent American Indian, two percent Asian, 24 percent black, 21 percent LatinX, and 47 percent white. These participants were known to have extensive pre-pandemic phenotyping across multiple domains, including brain, lung, heart, and blood health. They also have extensive multiomics, in part within the TOPMed project, and they are highly characterized with respect to social determinants of health. The cohorts have over one million person-years of follow-up.

The icons for each cohort are shown at the top of the screen horizontals, and vertically we have calendar time running from 1971, when the first Framingham offspring study visit was, all the way down to the bottom at 2025. You see that there have been a large number of in-person exams over the past 50 years in these cohorts, and many of them have planned exams during the pandemic period. I’ve shown here how surgeon exams that are shaded in blue had neurocognitive testing.

The ones shaded yellow include brain MRI, and the green shaded boxes are exams where both neurocognitive tests and brain MRI were performed. In other words, there is an incredible amount of neurocognitive phenotyping from the years prior to the COVID-19 pandemic in addition to measures already planned in the future.

C4R was setup to use this data to answer some fundamental research questions about COVID-19. We want to understand what are the major determinants of the incidence and clinical severity of SARS-CoV-2 infection and related disparities across the US general population, and plan to study the long-term complications of SARS-CoV-2 infection and COVID-19 illness.

And furthermore, we know that the COVID-19 pandemic has had major impacts on health-related behaviors and other issues relating to social determinants of health, so we want to use our data to understand how the COVID-19 pandemic has altered trajectories of health and disease among persons both with and without SARS-CoV-2 infection.

C4R has been funded since October 2020 and continues to be funded through May 31st, 2022. We’re doing data collection on COVID-19 via questionnaires, events ascertainment, and a SARS-CoV-2 serosurvey. In fact, our first wave of questionnaires started back in April 2022, ahead of the official study start, and we are completing that wave now.

We’re also starting up with a second wave of questionnaires to capture later waves of the epidemic in the United States. Our COVID-19 events ascertainment program is ascertaining primarily COVID related hospitalizations and deaths to adjudicate them as to whether COVID-19 was the true cause of the event, to assess the severity of COVID-19 and any organ specific complications, including stroke.

The serosurvey for SARS-CoV-2 antibodies is being done by dried blood spot, which is mainly being sent to participants homes to complete independently and is allowing us to measure antibodies to both nucleic acid and spike proteins, and therefore to be in a position to study the effects of both natural infection and COVID-19 vaccination.

As of June 2nd of this year we had completed the wave one questionnaire in 43,059 participants in a highly diverse population, with 29 percent Hispanic Latino participants, 22 percent black participants, four percent American Indian or Alaska Native participants, two percent Asian participants, of this group 59 percent were female and 65 percent were in the particularly high-risk group that was greater than 65 years old.

We continued to complete the wave one questionnaire in selected cohorts and expect a final sample size for the wave one questionnaire data of over 45,000 American adults. Meanwhile we’re also harmonizing pre-pandemic data focusing particularly on the decade prior to the COVID-19 outbreak here. As you can see this is the number of participants with the phenotype being along multiple domains of biomarkers, sleep, neurologic measures, cardiac, CT and physical function measures.

And I just wanted to highlight for you that over 34,000 have neurocognitive testing over the decade before the COVID-19 pandemic, and over 8000 had brain MRI. We’re bringing this data together on the C4 analysis commons in order to perform phenotype harmonization and analysis and to open up to collaborations. Our collaborative model is modeled after CHARGE and is located on Biodata Catalyst powered by Seven Bridges. It builds on prior harmonization work in the NHLBI pooled cohort study and in the TOPMed project.

Access to our data is available to approved investigators, and we have a paper proposal process that we look forward to sharing with interested investigators. If you want to learn more about C4R please check out our website at C4R/NIH.Org. We’ve also pre-printed our study design paper on MedArchive and hope to have that published soon. Thank you to our funders at NHLBI, NIH, and NIA, to the Connects Program, Biodata Catalyst and to all of our incredible cohorts who are making this work possible. And I look forward to questions. Thank you.

DR. NATH: That was a wonderful set of talks. Now if all the speakers could get their video on that would be good. So wonderful talks. Maybe I’ll start with one, and then I’ll pick others from the chat box and from the Q&A. The first one is for Dr. Makowski. You talked about these animal models. I was struck to see how these hamsters get infected but not much of the brain.

But traditionally in neurovirology for various organisms, if you don’t see much pathology you take it and you serially keep passaging it from one brain to another by intracerebral inoculations until you develop a neurotrophic virus, that way you can study the determinants and develop a better animal model. Are there similar plans like that to SARS-CoV-2 or are there ethical concerns to doing something like this?

DR. MANKOWSKI: There are certainly the concerns about what variants we could be generating Avi as you well know. But serial intracerebral passage is a classic technique to study neuroinvasion to amplify phenotypes. It is being done in mice quite a bit right now. To the best of my knowledge, I haven’t seen those reports in hamsters nor in the primate models, but a possible route forward for sure. Again, the question always is does that really reflect the disease we really see in the population though. How relevant do we keep these models to natural infection studies.

DR. NATH: They’re there for HIV also. You guys were the pioneers.

DR. MANKOWSKI: We absolutely did. We think it’s highly valuable again. I think the point being that we’re able to then validate these studies by looking across other model systems and ultimately linking them back to patient-based studies.

DR. NATH: The next question is for Dr. Jehi. The question was can your calculator be used, does it incorporate the date of illness.

DR. JEHI: Yes, as I imagine all of the prediction modeling work that we do matches the negative or positive patients by date of illness within plus or minus two weeks, so it adjusts for that. The date of illness itself is not a predictor for infection.

DR. NATH: Dr. Masliah, with regards to the data that you showed about APOE4, it was very interesting, but how do you think the two are intersecting there, with COVID and APOE4? I didn’t quite get that. Do you want to elaborate on that further?

DR. MASLIAH: I think the answer is it is not clear yet, I think it is being investigated, there could be direct and indirect mechanisms, it’s possible that APOE4 might regulate the expression of some of the SARS-CoV-2 receptors in endothelial and non-neuronal cells, astroglial cells and so on. And there are some transcriptomic studies that have shown that type of data.

There is also these other very interesting data based on proteomics and transcriptomics and pathway analysis that suggest that APOE4 individuals have a much lower interferon mediated antiviral responses than E3 or E2 individuals, and as such are less protected from SARS-CoV-2 and more susceptible to spreading of the infection.

Those are two of the potential mechanisms. Certainly there might be other possibilities. I saw one report on ACE2 SARS-CoV-2 receptor that also the expression might be different, I don’t know if there is a direct effect of APOE4 on SARS-CoV-2.

DR. NATH: Two questions for Dr. Sharon Meropol. I think the specimen repository you put together is actually a quite useful resource, it’s a tremendous amount of effort, great service to the research community. I think one of the questions refers to someone who sounds like they probably have a very busy practice and they like to get these specimens, but you know if somebody has a busy practice it’s very hard for them to fill out these questionnaires, get the specimen. So what this person is wondering is can they refer the patient to some other site where all the data and specimens can be collected, are there specific list of sites that are available for that purpose, or what do you suggest?

DR. MEROPOL: I would suggest contacting me directly. That’s a really great question. There are many answers I have to that. We’d love to help you in any way possible, we have an array of resources that we can help. It’s the places with the less traditional academic resources that are the ones that we potentially are the most interested in because they’re so valuable, they’re much harder to get. We would love to work with you either by using a different site or by helping you with your own site. So if you put your email in the chat potentially or send it to me some other way, I’d love to talk with you more about that.

DR. NATH: Thank you very much. Maybe with that regard something might be put on your website that might be helpful too, maybe too complicated, but some simple way of being able to access that information would be good. And the second question again is to resources, so trying to read between the lines, the person was wondering that if they submit a proposal to you and the proposal gets approved for specimens, are there some additional resources you can provide them. I’m not sure exactly what resources they’re looking for, but my guess is maybe there’s some kind of funding or something that can be associated with it.

DR. MEROPOL: Another good question. We are not associated with any specific research proposal, such as we don’t have a hypothesis testing project of our own. That said, our investigators, our sites who are partners are very interested in those. We have limited money available to reimburse for expenses collecting data and biospecimens, but we don’t directly have funds for supporting research projects, however our partners, for example NIH potentially does.

I mean the whole point of collecting these valuable tools are to be able to use them, and so we could certainly try to work with you to give some advice about where to go. And just to follow up on the last comment, my contact information and our contact information of the PIs, et cetera, is indeed available on our website.

DR. NATH: The next question is for Dr. Tarun Dua. It’s amazing, the amount of work that WHO is really doing, and it’s probably a fraction of what you were able to present to us So one of the questions that came up earlier was in the developing countries, what efforts are or can be made to gather information on neurological complications of COVID, particularly in the long COVID type of symptoms where longitudinal data can be collected, is that possible or is that being done, where do we stand on that?

DR. DUA: Thanks Avi, I think that is a very important point that you are raising. Very often there is urgent, you know this very well, there is little involvement of research from low- and middle-income countries, from al the funding that is going for COVID-19.

And so one of the things that we have seen some success stories with recovery trial or solidarity trial where there have been these networks and consortia that have been established, and I think there is as we are now looking at the data that is emerging, the numbers that are being impacted because of long COVID, I think there’s a case to be made, that we need to have these multi-country consortia using standardized protocols.

And also thinking about this question was in the chat box, and I was thinking about what do we think in terms of a minimum diagnostic criteria, where how do we accrue these patients and how do we build up the capacity. Also because what we are investing today in the capacity building for low- and middle-income countries will help in better epidemic preparedness for future.

And I think the license is (indiscernible) code of many of the funders, to see how much of this particular funding goes towards establishing these multi-country consortia, and WHO, all of you are very well aware, we are big supporters of this and would like to see that maybe there could be a consortium of funders like we’ve heard about, a cohort of cohorts, with maybe a consortia of consortia, involving funders that can help in getting this funding to low and middle income countries. So really something. And we’ll have huge database that will even be established using these opportunities.

DR. NATH: There is one other really important question. That is we are collecting data now on acute patients, and now the long-haul patients, but one of the people in the audience have brought up the issue of what about the effects of vaccines on patients who may have existing neurological manifestations, is there any attempt to collect data on them as to whether the vaccines have a positive or negative effect on their neurological symptoms. Anyone aware of collecting that data?

DR. DUA: I think an interesting question. Some of this information will come from the postmarketing surveillance. I would say that’s a very important research question, and we need to look at all the different adenovirusbacter vaccines as well as MRNA vaccines and see what is the impact of people who have any of this symptomatology of long-haul COVID. None of this has been published or brought to our attention yet, but I think that’s something, data is being collected and something very important to look at.

DR. NATH: There is always a little bit of a lag time in these things. Now that people have become aware of the fact that there are these issues, I’m sure many of you would like to look into it. Do any of the other panelists have any questions? You can unmute yourself and ask a question if you would like, or any of the other organizers, Sarina, or Jeymohan.

DR. SPUDICH: I would like to ask a question. I think this was a terrific session by the way, and I learned so much about the activities that are happening. A question that I have for you, and maybe this is also a question for the NIH panel to come later, it sounds as if we heard about a number of studies where neurological assessments of some kind, or either in the case cohort where basically people are having diagnostic criteria for certain neurologic symptoms, or some of these other studies, are integrated into larger studies where the dedicated funding is actually for the overall cohorts.

And then we also heard from Dr. Masliah about an entire network of I know a very longstanding ADRC funding where people have been multiple sites dedicated directly for Alzheimer’s disease research. I’d be interested in hearing from the panelists about whether or not you think that there needs to be dedicated funding set aside for the neurologic issues, or whether these are best studied in the context of overall for example post COVID issues.

DR. MASLIAH: I think that we’re following both pathways. I think we’re following one model where we’re leveraging existing cohort for which there is already very sophisticated neurocognitive, neuroimaging biomarkers type of data, the example, the ADRC or genetics as an example with the genomics program, ADSB, but also creating completely new cohorts from scratch that include very sophisticated neurocognitive but also cardiovascular, pulmonary, et cetera, all kinds of studies, and that is actually the so-called Recover study, which started as a task for both acute SARS-CoV-2 syndrome, and this is a very large cohort, over a billion dollars from Congress were put into this, and probably over 10,000 individuals with post-acute COVID syndrome will be included, both across the lifespan, and really very sophisticated Neuromedical studies at all levels that are actually integral and part of that study following common data elements, et cetera. So I think we’re following the two models, but I think that Recover is probably going to be something quite revolutionary.

DR. SPUDICH: I agree Dr. Masliah, but do you think the studies will be having some component where really strictly enrolling participants, or focusing on enrolling participants that have neurologic issues, or psychiatric issues?

DR. MASLIAH: I don’t think so. I think it’s more global. But I think the idea of focusing on something that would be NeuroCOVID specifically, sort of like this conference, and developing a cohort like that, I think is a very interesting idea. Probably we should think about it more.

DR. NATH: one more question for Drs. Jehi and Dr. Oelsner. The question is that in your cohorts, in your databank, do you also include patients who are antibody negative but may have other symptomatology of COVID?

DR. JEHI: In our cohort we specifically limit it to people who are COVID positive or PCR positive. We debated early on to include a group that was, I think we called them suspected COVID, because earlier on the diagnostic criteria that mandated testing, testing was just not available, and there were many people we knew had COVID but weren’t tested, so we don’t have the PCR on them. And then we do include those patients. But somebody who was tested, and it was negative, but they go on to have COVID, those we don’t have.

DR. OELSNER: So regarding participants in C4R, it’s a general population-based cohort with probably around 45,000 respondents, of whom the majority are uninfected, consistent with the general population. And then of individuals infected we include people with and without positive testing by any measure. So we are certainly including individuals who fall into the category of having clinical COVID-19, but no prior or current testing that is confirmatory.

DR. MEROPOL: I can speak about the Neuro Databank Biobank. We deliberately are including patients who had some kind of positive test. It can be PCR, it can be other positive testing, recognizing that certainly there are questions you can answer with that type of denominator, and questions that are best answered with a denominator that includes presumed positives as well.

So I think that NIH is funding many of us to do different things, and I think that’s one of the advantages, as long as we’re careful to ask the type of research questions and develop the conclusions from that that are appropriate, recognizing the pros and cons of different types of looking at the problem. We opted to be really precise about our denominator.

DR. JEHI: Our denominator is everybody who got the test, the PCR test. So that’s how we ended up with 100,000 who are COVID negative, and then the 80,000 who are COVID positive.

DR. NATH: We are pretty much close to the time, so maybe we can end the discussion here, and I’m going to hand this over to Dr. Spudich for the panel discussion. And you already heard from her, she did a fabulous job organizing and moderating the sessions yesterday. But Dr. Spudich is the Gilbert H Glaser Professor of Neurology, and the Chief of the Division of Neuroinfectious Disease and Global Neurology at Yale University, and she’s going to moderate this panel discussion now.

Agenda Item: Panel Discussion

DR. SPUDICH: Thank you so much Dr. Nath. I am really excited to have this discussion. I will say to our panelists, so please Dr. Dua, Ms. Davis and Dr. Gisslen please turn on your cameras. I’ll say thank you so much for taking on this panel, because this is actually going to be a challenging one I think. We have a lot of complicated issues to discuss.

And as we had sort of talked about a couple of days ago in preparing for this meeting, we thought we would identify some important issues that we see are big takeaways from this meeting, and really what we wanted to do was identify research priorities and have some discussion about research approaches, and talk about some of really the thorny issues related to studying some of the post-acute COVID issues as well as global inclusion for research relating to these topics. So this is going to be tough because I don’t think there are straightforward answers, but I really look forward to having all of you contributing on this.

And as you’ve met each of these panelists already, but I’m going to just introduce each one again. Ms. Hannah Davis, she’s a researcher, and she’s actually an artist. She’s a research in data analyst and machine learning. And she is also cofounder and team lead of the Patient Led Research Collaborative that you heard about several times already at this meeting. She’s also as she described eloquently so many times today a survivor of COVID and someone who has experienced post COVID symptoms. So really excited to hear her voice today.

Dr. Magnus Gisslen you also heard from yesterday. He’s a professor of infectious diseases, and also Head of the HIV COVID-19 Unit at Sahlgrenska University Hospital at University of Gothenburg in Sweden. And he’s an experienced clinician who ahs taken care of patients. He’s also an experienced investigator that does clinical and translational research, and he can talk a lot about insights into biomarkers and those kinds of studies.

And finally, Dr. Tarun Dua who you also heard from so eloquently just now is the Unit Head of the Brain Health Unit in the Department of Mental Health and Substance Abuse at the World Health Organization, and she is in charge of coordinating WHO’s response and work in the area of neuro COVID.

So there are a couple of things that we wanted to start by talking about, and again these topics have been very informed by the discussion over the last two days particularly I think today. So I think that we’ve heard a lot about both clinical research, clinical reports, and also sort of even basic science research that’s been based mostly in the US and western Europe. And also I think a lot of clinical research that’s presented does tend to include primarily certain upper middle class and predominantly white populations, at least in the US.

So I think what we wanted to talk about are, one of the gaps and the challenges that we have related to catalyzing more research and better clinical care for people in low- and middle-income countries and also even in the western developed countries that include underrepresented individuals. And I think Dr. Dua you spoke about that just a moment ago a little bit in response to Dr. Nath’s question, but maybe I’ll ask you first to comment on this question.

DR. DUA: Let me start by saying that the discussions today have been very interesting. Some of the presentations touched on these issues today, on the disparities that exist, and also as I have been listening to presentations and people who have been involved in analyzing the evidence or reviewing the evidence that very little information is coming from low- and middle-income countries. And I think if we look at COVID-19, it’s a global trend. And especially the health systems that are underperforming, it’s much more an issue.

Let’s say that if we look at the human resources, neurologists, if we have seven neurologists for 100,000 population in high income country, it’s one per million in low- and middle-income countries. So what it means is that there has to be a paradigm shift in our thinking of our research. So we cannot take it for granted automatically that testing has to be done by a neurologist or a complementary diagnosis will be required by a neurologist. I think that’s one challenge in relation to the workforce availability of diagnostics.

The other issue is that I think it is about the health systems that are overwhelmed with COVID-19. They were already weak to start with. Is that how research gets embedded into the public health in the clinical activities.

And I think whatever research we need to organize in low- and middle-income countries, it has to be part of the system rather than be a vertical research. The third point I think that I mentioned earlier is ensuring that we have international and sufficient funding that goes towards identifying local research priorities, and not the kind of parachute research, that there’s a priority that is from high income countries and being studied, but it is coordinated identification of research priorities and then coordinated implementation that happens. And I think we have a long way to go. But if we have to be prepared for upcoming epidemics, I think we have to have this involvement of low- and middle-income countries and low resource settings. I’ll stop there, I can go on and on, but I’ll stop there.

DR. SPUDICH: I think it is important to have your perspective, and obviously you really know what’s out there in terms of what their priorities are and what the resources are. Maybe I’ll ask Hannaa to comment, because I know you have successfully integrated international sites into many of the projects that you’ve been conducting. Can you tell us about how that has worked and what you see the challenges are?

DR. DAVIS: Absolutely. That is a big priority for us. I would still say even though we do have a large cohort it’s still not as global as we would like, although now at this point we have about 8000 responses from about 85 countries. And this was doable only because we connected with other long COVID patients in other communities really early, we’re talking like April-May last year, and I think that we have a lot of patient advocates in countries like the US and the UK, but some of these advocates in countries like Indonesia or South Africa, there are a couple patients doing this alone, and so one thing we’ve done at Body Politic and Patient Led Research is found those patients and tried to support them as much as possible, and they conversely have worked for us doing translation, so translating the same long COVID surveys into the relevant languages, which really helped get more responses from those populations. So we ended up translating our survey into nine languages, and then we worked with those kind of existing networks to distribute the survey.

And then once you have that data it becomes much more possible for those patients to reach out to and find sympathetic doctors who will then go forward with the research. But I think a lot of it is related to kind of communication, science communication, and networking of existing networks. And I think that’s true for the US too.

One thing we really have to do which is not being done right now is prioritize black and BIPOC patients, and that also is going to be based on funding and highlighting existing community networks. And really importantly I think a lot of conclusions have been based on available data which comes from support groups, comes from long COVID clinics, and is disproportionately white.

We really do need to actively fund community leaders in these spaces to get a better understanding of how this is affecting BIPOC communities, because it’s just not going to be the same in those white patients who are able to get into long COVID clinics who were able to get PCR tests early enough. One major issue of having PCR positive research is that you do get a cohort that has a better access to healthcare. So this really needs to be an active process, this is not something that we can do passively.

DR. SPUDICH: Very interesting to bring up those specific things that then select exactly who we’re studying and how. I have a question for Dr. Gisslen, because I think about how we can sort of incentivize higher income countries or governments, so for example the NIH, to say it’s really important to do these studies elsewhere, and to actually pay for studies elsewhere. And our experience with something like HIV is to identify certain things that you can only study somewhere else.

And then often the NIH will say we’ll put a lot of money into that site and those local investigators because this is the opportunity to do this kind of work or that kind of work. And I wonder if you think that that might also happen with COVID, that people may be able to ask for example a question about the variants.

Or maybe even the issue of continuing to study complications of acute COVID, since many of the higher income countries, unfortunately there’s such inequity in vaccination access. But I wonder if you have thoughts about how we can incentivize higher income countries to fund studies in lower income countries or middle-income countries.

DR. GISSLEN: This is a very important question. As you mentioned, also when looking in US and in Europe, for example in Europe it’s similar to US, the most vulnerable population here is immigrants, mainly from Sub-Saharan Africa or the Middle East. But they are not represented in studies. So that’s one important point. But also because we want to generalize the results, and we can’t do that if we don’t study the disease in different settings, because there are so many differences, and we know that.

There are socioeconomic differences, there are host differences, there are a lot of differences. Variance is one thing, that’s sort of a different thing, and I think that is important to study because we don’t know if different variants influence the brain in different ways, so we have to study that. But also, all the other things.

And I think one thing is the key into how to do this, is like Tarun Dua mentioned, to integrate the research in the clinic, I think that’s the only way. That is what we have found for HIV. Without doing that, it doesn’t work. Because you have so much work to do in the clinic, and you can’t do separate research projects.

I mean some of them work but they are often short projects that end up and don’t give this long-term effect or long-term results that we want to have. So I think what we have to do is sort of to include countries outside US, Canada, and Europe into the studies. In a way it’s pretty easy, we just have to harmonize our efforts and start to collaborate.

And I must say that in the previous session I was sort of very encouraged of the very nice cohorts that have been built up, most of those were in the US, but the willingness to collaborate that I think has been so important when it comes to COVID-19, we have to remember how much we have learned in acute COVID-19 in one and a half years, and without this collaboration it wouldn’t have been possible.

DR. SPUDICH: So can I follow up with a comment that you made, Dr. Gisslen? You said that in Sweden the immigrants that are from Africa and elsewhere are not in studies, but you have a nationalized health system, correct? And so I wouldn’t have expected that people would have less access to healthcare, the way we have such horrible health disparities in the US, I think some of the lack of getting people into research also has other barriers, and there’s a lack of inclusiveness in the way we do our studies and things like that. But what are the barriers in a place like Sweden to having immigrants and others that are less commonly studied integrated into research?

DR. GISSLEN: I think because it is not the possibility to get healthcare, because that is sort of general and everyone gets it. But I mean it’s socioeconomic factors, it’s language factors. People that don’t speak English or Swedish, we can’t take them into studies. Also, the willingness of people, from different cultures and so forth, it’s harder to get them into studies. So therefore, they are underrepresented.

It’s probably a lot of other reasons too. I mean it’s a similar problem when it comes to vaccination. Most of, I think we have 70 percent, something of the adult vaccination population vaccinated here now, but in certain areas where there are a lot of immigrants it’s much lower. And I think it’s the same in the US, it’s different in different parts, which is a problem when it comes to vaccination, of course to the COVID.

DR. SPUDICH: I think that brings up this next portion of the discussion that we want to have, that has about ten questions embedded in an overall theme. This relates to how to actually design and implement studies of post-COVID syndromes. So I think what we were just talking about relates to everything across the spectrum, from acute COVID to clinical care to post COVID.

But the post COVID puzzle is so challenging for all of us, those that have lived through it, that we heard about so eloquently today, and many people who have tried to take care of patients who are having post-COVID neurologic or psychiatric issues, and also study people.

And I’d like to think about how do we actually answer some of the really important fundamental questions by designing studies the right way. We heard just now I think a number of different studies that have clever study designs, really wonderful data before and after COVID, excellent comparison groups in these very largescale database type studies.

But if we were able to design the ideal way for example to get critical biological and psychiatric and behavioral information about the biological underpinnings, the natural history, the treatment of post-COVID issues, how do we do that? Who are the comparison groups? How long do we need to study people, are we going to be able to see effects in one- or two-year studies, or do we need 10- or 20-year studies? And maybe Hannah, if you wouldn’t mind starting with that question and saying from your perspective, from your experience, what do you think?

DR. DAVIS: I think there is a couple components. Definitely I do think we are going to need to look at long-term studies, I think two years is going to be the baseline, but I think like a lot of people said we don’t know the long-term effects, we don’t know if this is going to end up in a big wave of Alzheimer’s or dementia, hopefully not, as someone affected, but I think we need to be looking long-term.

We need to be looking at I think as many people as possible before restricting it as I mentioned by PCR positive and antibody positive. As I mentioned in my talk there are a couple studies that have come out now that actually show that low or no antibody in the acute phase of COVID actually predicts persistent symptoms, which is one of kind of the only real answers we have around long COVID.

And I really think that despite there being such a high focus on respiratory symptoms one of the main things we found is that when we looked at all of these 200 symptoms over time some of them like the respiratory symptoms actually decrease pretty rapidly over the first seven months, where the systemic and the neurological symptoms are significantly more likely to either not change over time or actually increase over time.

So I think that we really do need to be focusing on kind of neurologic specific studies, and also funding studies that kind of have been based on the neurologic and neuroimmune work of Myalgic encephalomyelitis, which with dysautonomia is one of the most common diagnoses in the long COVID population.

And there have been so many neuro studies in ME, especially over the past five years or so, that are directly relevant to long COVID, including brain and brainstem inflammation, what are the appropriate neuroimaging techniques, hypoperfusion and cerebral blood flow findings, elevated blood lactate in the brain overlaps with connective tissue disorders, craniocervical obstructions, all of these things that these ME experts just know like the back of their hand. And these are all areas that are just not well known to long COVID researchers.

So one thing I really want to see is researchers in ME kind of know a lot of these answers that to us look really foggy and unsure. If I could change, I think one thing about how long COVID research is being done it’s to include ME biomedical experts in these research processes.

DR. SPUDICH: That is a really interesting observation. I can say that for myself and for many others, Dr. Nath, Dr. Gisslen, et cetera, we’re coming from a perspective of studying viruses in the brain, and haven’t actually had, at least in my experience, Dr. Nath has but I haven’t had a lot of experience with ME CFS. I think you’re absolutely right, I think there are different approaches to thinking about questions, biological questions, etiologies, presentations and things like that.

And actually integrating across those disciplines, which should have a lot of overlap naturally, but I think historically they haven’t, is probably something extremely valuable, and I appreciate your point and in fact your email yesterday to me educating me about some of these issues which I really am not that knowledgeable about, and it’s an omission I think.

I think it’s interesting though to talk about how do you operationalize all of this. I think we all feel we should be taking all these different things into account. The way you’re describing studying all these things, first of all is extremely diverse. So you need to have neuroimaging, you need to have electrophysiologic testing, you need to be able to do autonomic testing and cognitive testing and all these kinds of things.

So that makes it immediately very expensive, time intensive, difficult for participants to get involved in. it also means that it’s almost impossible to sort of open up for studies that are global, multi-site studies all around the world where many limited resources would prevent a lot of these kinds of tests.

So are there common elements that we can say are really critical and could be rolled out that could provide some basic information that could be easily obtained to maybe then identify a subset of some phenotypes of populations that could be studied more intensively?

And I’m reminded actually that a couple of posts in the Q&A remind me of a very nice paper by Dr. Luset Sazik(phonetic) who is a neuropsychiatrist, again has worked a long time in NeuroHIV but has really done some nice work in this area, who has even suggested in a recent publication whether or not there’s harmonization of research methods that could be used in global studies. Could we as a community and as an investigative and clinical community identify some certain types of assessments that might be consensus assessments?

I know this has been tried by this Task Initiative and the Recover Cohort initially, but again neuro was not the focus right now of that study, and I think there are things that are probably not going to be captured unless we put something together. So I don’t’ know, Dr. Dua, do you have any thoughts about why there is such kind of harmonization of approaches? And things again that don’t necessarily have language requirements, things that could be instituted, is this total pie in the sky?

DR. DUA: I think this is a great opportunity for us to think about standardized and harmonized approaches. Because COVID-19 is a global problem I think we should be moving towards harmonization. And I think the other thing that I was thinking as you were talking is that we can also then take the approach of a minimal dataset, not stopping researchers to have five or six research questions, but then there could be two or three research questions which require a minimal dataset, and that requires that people agree to share their data.

I think we have seen in COVID-19 that more and more people have been able to do that. But also the things that have changed compared to HIV research or other research is the more and more use of innovation and technology and research methodology. So I think I would say this should be the kind of a step that should come out, a call for action of this conference, that there is a standardized and harmonized protocol that’s being implemented for NeuroCOVID, be it in any cohort that is being established, or be it a specific study, so that we are not losing the information that is going to be generated in the next coming years.

DR. SPUDICH: The challenges Dr. Gisslen was talking about, busy clinicians, are they going to have the time to do this, where is the funding going to come from to even train people to understand the protocols. We’re involved in the NIH funded AIDS clinical trials group that has had 25 years, maybe 30 years of infrastructure where trained people are funded at each site to pick up protocols, to harmonize things. Everyone is so busy.

COVID threw onto everyone’s laps just an additional pile of work and effort and time, everyone was already doing other work, and I think that you can’t do something, even adopting harmonized methods, you can’t do that without some effort in funding. I think that’s really some level of support for staff. As you say, it doesn’t have to be a neurologist, it doesn’t even have to be a physician at all, but I think having somebody who can implement some of these things.

Dr. Gisslen, I wonder if you will comment on something that you brought up in the discussion which I think is critical is how do you identify also, so there’s one type of study that you do, which is collecting data from patients who are coming in, and you have to take that for what it is, there are all sorts of biases and selections for who the patients are in that kind of thing.

But how do you design a study where you then identify who the correct comparison groups would be? And to answer some of the questions you raised, such as how actually getting infection with SARS-CoV-2 is different from getting influenza, that kind of thing. So what would you say in terms of the comparison groups for studies?

DR. GISSLEN: There are a lot of different aspects on this actually. I think a very important thing is that we should have some kind of biomedical approach to this. I think it was Hannah that mentioned before, I think this is totally correct, we have to learn what this is, that’s the first thing. Then we also have to remember, now we have hundreds of millions of people that have had COVID, and we see a lot of sort of complications.

But we don’t really know is it different from for example influenza or pneumonia, or is it just that we have so much COVID right now, it might be, and it probably is, but we have to figure it out doing studies, and that is not easy. I mean it’s easy to study COVID right now, but all the other infections, we don’t have that many patients but we have to consider that. So that’s one thing.

And doing the studies, I think we should try to, what we need, we need a lot of different approaches to this. I think the perfect way to look at it is to have the prospective approach. If we have patients from the beginning, those that are positive, that are negative, or whatever we have for inclusion, and then follow longitudinally. That will give the most reliable results. But we need huge studies to do that, and they might be superficial in a way. But then you have to do more in-depth studies up from that.

Then of course we need also other type of studies that have been discussed here. But I think it’s too early to harmonize too much. I mean I think we need different type of approaches, and that is very important, because we don’t know actually what the clinical correlates are, they are so diverse when we look at it now, but maybe it’s not, maybe it’s easier than that, we have more research that is needed to come to conclusion I think.

DR. SPUDICH: Are there certain key biological measures that you would say might shed light on that? We talked more about biological, mechanistic studies yesterday in acute COVID, and then there was some handwaving by me and others today about biological measures in post-COVID. But what do you think are some of the key biological measures that we need to collect to identify really what’s underlying this from a biological perspective?

DR. GISSLEN: I think we have to have multiple approaches on that. We need biomarker studies, we need imaging studies, we need a lot of other type of studies to understand what it is. But also, and what I’m trying to say is that those very large studies, prospective studies will give the clues of how common it is, what symptoms are most common, how long will the symptoms last and so forth. So they are both in parallel very important.

But I don’t exactly know sort of methods, but I think we have to look. We have different expertise, and we need to collaborate and sort of do what we are best at and try to come further into this, and I think we will. It’s so important and also an interesting area, a lot of people, very intelligent people are very interested, so we will have results in this space.

DR. SPUDICH: I think Hannah has raised that there are these overlaps with other syndromes that have been plaguing patients for many years who have not had answers for the biological causes. So I think in that sense this is actually a really exciting time because of course if there is a lot of interest and focus in investigation in this area, it could potentially provide insight into some other conditions that are so important.

But going back to the question, should we be comparing people who have had, there’s been a lot of discussion in the Q&A as well as a little discussion here in the group of do we only select people who have had proven COVID by PCR testing, which excludes a large number of people, including people who didn’t have access to PCR testing, because tests weren’t available, tests still aren’t available.

Many places in the UK, people if they didn’t have to get hospitalized, they were told to stay home, they didn’t get testing for example. Or do we take people based on clinical syndromes. And again as a neurologist seeing these patients I find that really complicated, because I have a lot of patients who I’ve been taking care of patients with HIV for many years who have some subtle symptoms.

I think it’s really difficult sometimes to say is this related to their HIV or not, and in this era of the pandemic there are so many other things happening with patients that they come in and they have some symptoms, they don’t have a positive PCR test, they don’t know if they were antibody positive or they were not antibody positive, for me it’s very hard to categorize those patients.

But I absolutely understand the voices of those who feel so frustrated by those kinds of criteria. We’ve had to exclude patients from our studies who are really disappointed not to be involved. So I would be interested to hear what others thing about how do we decide who to be included in these studies.

DR. DAVIS: I think unlike HIV and AIDS there’s just a much shorter timeframe between acute COVID and this long COVID syndrome, and that really makes the difference, and I think it’s really hard to communicate as a patient that this is just not like anything I’ve experienced before. One of the things we’ve found is that patients experience literally dozens of symptoms basically overnight. It doesn’t make any sense to attribute it to just lockdown. A lot of patients got sick before lockdown, especially from the first wave.

And it’s a recognizable condition, especially once providers start working with long COVID patients, you can tell, you can understand, the dysautonomia, the brain fog, any breathing issues, you can recognize them pretty easily. And there have also been several studies validating that there are not symptomatic differences between these populations that I think needs to be listened to.

My concern is that we might be wasting time just debating this, where I know this was a thing in other illnesses, where there’s kind of a gap between your virus onset and your symptoms, but that’s really not what we’re seeing here, we saw less than four percent of patients even had a gap in symptoms, and when they do it’s within a month they’re symptomatic again. So I think we need to base our decisions on that.

DR. GISSLEN: I’ve always thought it’s better to just include those who are positive, because otherwise it’s a risk for messing the studies up. Although we miss some that are positive. But hearing Dr. Koralnik from Chicago, he made it in a very intelligent way, not mixing those groups up but presenting them as two different groups. And that’s a very good way to do it, I think. I was changing my mind when I heard Dr. Koralnik doing this. So I think that’s a very wise way to do it.

DR. SPUDICH: That’s what we’ve done as well, and it has been validated in studies in London and Moscow, and Dr. Koralnik’s and multiple global studies.

DR. KORALNIK: If I may had, since you mentioned me and I was listening intently all the discussion, I think it is also part of a mandate from NIH in the past ROA to include control groups that are consistent with the type of population that we’re seeing but that are SARS-CoV-2 laboratory negative, so that you can either have a post viral syndrome that is occurring at the same time, subjected to the same stressors as the other during the pandemic.

And it turns out, and we are doing this research in my lab, where we’re studying the T cell response against those patients, that some people who are RT-PCR negative, serology negative, have T cells that really show that they have seen SARS-CoV-2 before and so it’s only doing T cell assay which are cumbersome, costly, and time consuming that you are able to show that these patients have been actually exposed to the virus, although the commercially available tests are negative, and I think that’s very important.

DR. SPUDICH: I think that is really important. This is exactly why we are having this two-day conference, is to listen to each other’s experiences, to really understand first of all some of the perspectives of how common these symptoms are, and I’ll say for Ms. Davis’s quotes that she shared it’s exactly the same things that we’ve heard from all of our patients.

They are very stereotyped, some of these experiences, and then to hear from Dr. Koralnik about some of his insights, and there have been other comments in the chat about looking at T cell responses. So I think having us change our mind about some of these things to expand our thinking is actually the purpose of getting together and having these talks.

So we need to wrap up because we have a very short break before the next session, but thank you, Ms. Davis, Dr. Dua, and Dr. Gisslen for this brief conversation talking about some hard topics. I think we’ve taken away that there’s a real research mandate in this area, potentially a real research mandate to try to develop some sort of harmonized data collections, and I think some of that might be encompassed already by many of the wonderful efforts that we’re seeing, but maybe there should be things that are dedicated directly to neurologic studies. And I think this issue of still needing to really understand the biology to help reduce stigma, to help to identify treatments, and to move forward is obviously a critical goal as well.

So thank you for the discussion, and we will break until 3:05 eastern time, where we will then be starting a fantastic roundtable with NIH leadership, so hopefully we can continue with some of these important discussions. Thank you.

(Break)

Agenda Item: Roundtable with NIH Leadership on IC Interests and Resources for Addressing Neurologic and Psychiatric Effects of SARS-CoV-2 Infection

DR. NATH: Now it is the last and most important session here, on NIH interest and funding opportunities for NeuroCOVID research. And it is my distinct pleasure to introduce the cochairs, which are Dr. Walter Koroshetz and Joshua Gordon.

You heard from Dr. Gordon yesterday at his opening remarks, he is the Director of the National Institutes of Mental Health, and Dr. Walter Koroshetz is the Director of the National Institutes of Neurological Disorders and Stroke. It’s fitting that both of them are the cochairs, as NINDS and NIMH have both collaborated extensively on HIV infection previously, and now with COVID, so we have a very strong working relationship. And I’ll just name all the other panel members here, just to make sure everybody is here.

And we have a really esteemed panel. Nora Volkow, the Director of the National Institute on Drug Abuse, George Koob who is the Director of the National Institute on Alcohol Abuse and Alcoholism, Helene Langevin is the Director of the National Center on Complementary and Integrative Health. Eliezer Masliah who is the Director of the Division of Neuroscience National Institute on Aging. Alison Cernich, and she’s the Deputy Director of the National Institute of Child Health and Human Development. Andrea Lerner, who is a Medical Officer in the Immediate Office of the Director of the National Institute of Allergy and Infectious Diseases.

Susan Sullivan, who is the Program Director of the National Institute on Deafness and other communication disorders. Lillian Shum, the Director of the Division of Extramural Research in the National Institute of Dental and Craniofacial Research. Yolanda Vallejo as the Program Director of the National Center for Advancing Translational Sciences. And Sean Cody as the Deputy Branch Chief of the National Heart, Lung, and Blood Institute. So I’ll turn this over to Dr. Koroshetz and Dr. Gordon.

DR. GORDON: Thank you very much Dr. Nath. It’s really again a pleasure to join you today. I’m going to start off with a brief introduction to mental health in COVID-19 and NIMH interest, then I’ll turn it over to Walter who is going to talk mostly about the PASC Initiative. Then we’ll have a panel discussion and comments.

Mental health in the era of COVID-19. So the first thing you need to know about mental health and COVID-19 is we kind of knew what to expect at least in the general population. And we knew what to expect because of studies of previous disaster, traumatic events and epidemics.

We knew that most who are exposed to traumatic experience have some level of psychiatric symptomatology. For most of those symptoms improve with time. A significant minority have long-term or chronic experiences with mental illness in the aftermath of a disaster. And that social inequalities and health disparities increase both trauma exposure and the likelihood of subsequent mental health needs. That’s to do with the general population.

What about those infected with COVID-19? We know as you probably saw throughout the last day, this is old news for you, is that in the aftermath of the infection with COVID-19 there’s an increase in the rate of mood, anxiety, or psychotic disorders in the ensuing weeks and months that outstrips that for other forms of respiratory illness.

And that are dependent at least in this study upon the presence of encephalopathy during hospitalization, but aren’t present during a matched cohort hospitalization without encephalopathy or cohort without hospitalization. So it does seem that there’s a special psychiatric morbidity consequent to COVID-19 infection.

We also know of course the general population is experiencing anxiety, depressive symptoms, increases in suicidal ideation, substance use and trauma, and that these have persisted throughout the course of the pandemic, all the way from last summer through to early this spring, late this winter.

So that’s the background on which you’re measuring these increases in psychiatric morbidity. That is, we’re seeing increases in morbidity in the general population, and that has to be disentangled from the direct effects of infection per se.

One quick note that many of you are probably interested in, a lot of fears that increases in suicide rates might accompany the pandemic, either from the general effects in the population or from individuals who have been infected since so many have been infected. And the bottom line is rather surprising, that overall suicide rates have not increased, but like we would expect with any disaster, those most vulnerable are also those with the greatest psychiatric risk.

This data from Maryland is similar to data from several other states where in the time of the early days of the pandemic, March of last year, suicide rates in white Marylanders actually dropped rather than increasing, but suicide rates in black Marylanders increased, stabilizing only after reopening in Maryland and the return of many elements of their economy. So that’s been a consideration, is that the effect of course is unequal in different populations.

I’ll point out another often less appreciated element of the pandemic, and actually Dr. Volkow has done research on that herself, this is work from another group showing that those who get infected, who have a preexisting psychiatric disorder, have higher mortality than those without. And this is especially pronounced for individuals with schizophrenia, who by the way as I mentioned yesterday have a tenfold increased risk of contracting COVID-19, they also have a threefold increase in death risk once they contract it.

In terms of funding opportunities, we put out a number of funding opportunities focused on the psychiatric and other behavioral and economic impacts of the COVID pandemic, mostly focused on underserved populations. One initiative is of course the SBE initiative, where we funded both supplements and primary grants to measure and importantly develop and test interventions that mitigate the impacts of the pandemic.

NIMH has also put out supplement requests and notice of interest in research. In particularly lately we’ve focused our efforts on trying to increase the number of grants that we’re funding in areas to study the impacts of the pandemic and school disruptions, et cetera, on children, because that’s an understudied area when we look at our portfolio. And that was done in concert with the National Institute of Child Health and Human Development.

We’re also participating in other funding opportunity announcements around vaccine hesitancy, around simulation modeling to address health disparities in the context of the pandemic, and the RADx effort which is aimed at expanding testing and now vaccine acceptance in underserved populations.

So some examples of the work that we’ve funded include looking at mental health impact of COVID-19 intramurally, both in NIMH research participants and healthcare workers, as well as looking at the impact of anxiety and motivation of COVID-19 particularly on individual responses to the pandemic.

This is all work that we’ve done through our intramural research division. So broadly there’s been a big impact in the general population of the COVID-19 pandemic on mental health symptoms, and with some evidence of inequality of the outcome measurements, and we continue to fund research looking at the    impacts of the pandemic on mental health.

And that’s all general, we’re talking about the general population, and I’m going to now stop my slideshow and stop my sharing because Walter is going to talk to you now specifically about efforts, really trans-NIH, that we and other institutes are participating in, but which the NINDS is leading to study the neurologic and psychiatric consequences of long-term COVID. Walter?

DR. KOROSHETZ: Okay, so thank you Josh. I have had a chance to listen in to some of the workshop both today and yesterday, and I’m not going to talk to anybody here about the neuro mental health aspects of COVID, because you guys know a lot more than I do.

Instead, I’m going to talk to you about this one initiative which we call Recover, that is focused on understanding the post-acute sequelae of COVID infection. And I will just start off by saying that I initially hoped that this would solve all our problems, and now I don’t think it will, so I think we’re going to need a lot of people working in RECOVER and outside RECOVER.

And as you probably can imagine, COVID is a problem that affects multiple different organ systems, and the recover program was primarily aimed at getting large numbers of people in to be studied, and the people who won the awards, amen, were studies that promised thousands of people, and the neurological and mental health components of those studies, they are there, but clearly we have to kind of push them to the top, because there are so many other competing organ systems in this space. So I want to just start off by saying that.

Now, what we really want to do with this large cohort study is to understand three main things. One is what is the clinical spectrum and the biology underlying recovery from SARS-CoV-2 infection, and then for those, so why do some people recover, why other people don’t, why do some recover quick, others slowly.

And then for those who do not fully recover what is the natural history of the incidence prevalence and the broad clinical spectrum and underlying biology of this condition. And of course, we don’t know the answer to any of these things, we have to kind of put out a really broad net and see what comes, and then kind of follow the clues down until we see something that really looks causative and potentially actionable in terms of developing treatments.

And then the other question that is probably separate from what people are thinking about so far, but I think because COVID hit 34 million people in the US and many millions more around the world, we have to setup to try and study what are going to be the long-term effects of having suffered through this infection, things like is it going to increase your chance of developing dementia, because you have this inflammatory effect in the brain, is going to affect your chance of developing atherosclerosis given that endothelial cells have ACE2 receptors for the virus. So we have to setup to look long-term for the effects of COVID. But in the short-term what we’re trying to do is to bring in two major cohorts of people.

One is people who have an acute infection or pretty close to having an acute infection, so that we can study what is the heterogeneity of recovery after COVID, how does the immune system recover, the kidney, the liver, the brain, and the immune system, and try and distinguish what drives fast recovery from slow and no recovery.

And the truth of the matter is this is we hope the most time sensitive aspect because we’re hoping that the number of acute infections will go down. Now it may be that the researcher may be luckier in that people are unlucky in the sense that there are still acute infections.

The second area is to study people who actually are now many months out and still have symptoms, and that’s the long COVID syndrome. But we lump everything in under we call post-acute sequalae COVID. So if you develop dementia because you had COVID 10 years from now, that’s also PASC. PASC would include the long COVID syndrome, but it’s bigger than that. And the goal is to understand enough that we can make some rationale treatment trials and put them into the cohorts and test things to see if we can help people.

Also this may be very time sensitive because generally, us who work in the brain, your chance of helping someone is going to be this critical window that closes, and so trying to develop clinical trials for treatments, they’re probably going to be more effective, higher effect sizes if they can be tested early on and not two or three years after someone has already had COVID and now has persistent symptoms.

So there are multiple different components. There’s a big push to have strong community engagement, a big push to enroll a good number of children, along with the adults, and including pregnant women, and to have a very diverse patient group in the studies. And on top of the cohort studies there are two other aspects. One is autopsy studies.

So we talked a little bit, people talked about MCEFS, chronic fatigue syndrome, been studied for many years, no-one has a clue what the causes are. There’s really no autopsies that have ever been done to know if there’s a virus sitting there. And with COVID I think it could be that the money is going to be seen in the pathology and there’s no way of getting to that in living people.

So we did write in and to fund autopsy studies of people who die, hopefully they’re not going to due of post-acute sequalae COVID, but they’ll die from another cause, and also have that, given the large numbers of people. And then to do the long-term studies and also to get the good numbers in terms of incidence prevalence, we’re going to try and setup electronic health record level studies as well that can look at millions of people.

And what’s going on in the two main cohorts, the acute cohort, so that’s people recently infected or still infected, and the post-acute cohort, is that the groups that we think they’re chosen, it’s not completely official yet, but there are groups that have been chosen to start working out what are the common data elements and what we call tier one data that everyone would collect.

The NIH people have been working behind the scenes to try to do some common data elements work that would move this quickly. And then there’s kind of a tier two which would be more than just baseline studies but something that almost everyone would get. And then the tier three are the deep dives into particular organ systems.

And those would not be done by everyone in the cohorts, and in one single cohort they might be done for a short period of time, if they don’t see anything then they move on to something else, and there I think a lot of the discussion that was held today is going to be very important in terms of what to look for in spinal fluid in fdgPET scans and MRI scans, neuropsych testing, potentially EMG studies looking for myopathy, small fiber neuropathies.

But those kinds of thing would be the tier three, not things that everyone would get. But those I think are the in-depth studies that will give us clues as to the potential pathophysiology, if we make some real good discoveries we can bring them into the bigger cohort and test them and validate them and really move progress quickly.

So right now the clinical science core, which is the clinical coordination group that’s been working with all the cohorts, that has been announced, it’s going to be NYU. The data resource core, all the data is going to flow through the data research core, which is at Mass General, and then it’s going to flow out to different archives.

There will be an imaging archive, there will be a clinical data archive, telehealth data archive, an electronic health record archive, but all that will be stitched together so that people who want to do investigations can come to one portal run by the data resource center.

And there will also be a large biorepository core where we’ll have spinal fluid, blood, potentially tissue, and then autopsy core again with tissues. So this will be a resource for the country and the world to do research on potential drivers of the post-acute sequelae, and then hopefully get us to the point that we can start doing clinical trials.

There’s also a push as I mentioned for strong patient engagement, and then to work with, there’s actually a callout now for mobile health platforms that can potentially be given to patients for reporting their symptoms or collecting sensor technology data that’s real-time, not just at the office visit type of data.

So this is pretty ambitious, Congress appropriated 1.15 billion for it, and so it’s a very ambitious launch problem, but with the eye towards not just collecting a whole bunch of data but actually finding out what is wrong with people and moving to clinical trials as soon as we can to test any kind of hypotheses that come out of the data. So I think that’s it. There are websites that we’ll try and keep everybody up to date on.

And the neuro piece that people that are part of these cohorts that are being funded, we have a lot of faith, there’s no pressure but they’re going to have to step up, the neuro and mental health people are going to have to try and take a strong leadership role and push the cardiologists, the infectious disease people to the side. No disrespect Andrea. That’s it for me, thanks.

DR. GORDON: We are going to go down the list of presenters and offer each a chance to talk about what their institutes bring to the table.

DR. VOLKOW: Thanks a lot Josh, and thanks a lot Walter. I think this has been a pretty remarkable meeting, I have been able to listen to many of the sessions and I do want to congratulate both NIMH, NINDs, and all of the researchers for amazing presentations. And what it made me aware as I was listening to all of these sessions is that here we have a disease that we didn’t know that has enabled us to understand better the interactions between the immune system, the vascular system, and neuronal and brain activity.

And whereas we’ve been very aware of how important the immune and the vascular systems are for neurological diseases, it has been less clear in the case of psychiatry, even though there is increasing evidence that immune reactions are fundamental in many of the expression of psychiatric symptoms. And that’s actually relevant even for substance use disorders.

What is the relevance of COVID for substance use disorders is multiple, but in thinking about it in terms of the neurological and psychiatric aspect, it is recognized, just as Dr. Gordon was mentioning, that individuals with mental illness are at higher risk for COVID infection, and if they get infected are at higher risk for dying.

Similarly individuals with a substance use disorder, regardless of whether it is an illicit or licit drug that is responsible for the addiction, are at increased risk of getting infected, and if they get infected they are at increased risk of dying.

So from the research perspective we want to understand why this vulnerability among individuals with substance use disorders, why the adverse outcomes in this group. How is the efficacy of vaccinations in these groups. Why is there sensitivity to breakthrough in vaccination if they get infected.

And as I was listening to all of the sessions, what is that vulnerability for individuals that are using drugs for long-term symptoms. And this becomes very relevant because we are observing clearly that during the pandemic the consumption of drugs has significantly increased. And so (indiscernible) as is the case of cannabis, this may be utilized even for therapeutic purposes.

So it is our responsibility to understand whether the consumption of these drugs will have deleterious effects, accelerating the severity of long-term symptoms from COVID, and some instances if they do have as has been purportedly stated for cannabidiol anti-inflammatory properties, whether they could be beneficial in particular for elderly people. So research is going to give us those answers. So we have been requesting supplements for researchers into this area of investigation.

Now I want to ponder on another aspect that we have again, a very important responsibility and opportunity to advance the science, which is to understand how COVID affects the developing brain. And we are working with multiple institutes at the NIH to actually have created two major infrastructures that will facilitate our ability to do so. Let me share my slides at this point.

So the first study that we have in this respect is the ABCD study of the Adolescent Brain Cognitive Development, which was launched in 2016 and basically recruited close to 12,000 children, nine to ten years old, that are going to be prospectively followed for 10 years, with periodic measurements of their behavior, their cognition, their social interactions, their sleep, their activity, and they will receive imaging, a battery of imaging interventions that basically every two years.

And this has given us the opportunity to supplement these researchers and starting in May of 2020 so that they can start to investigate how the COVID pandemic is negatively affecting their everyday life, how it’s affecting the families, and also importantly how it is ultimately affecting their brains in those cases that have been infected.

So we now have more than 500 children from this cohort that have been infected with COVID-19 and who we had images before the COVID pandemic hit and we will be able to monitor them accordingly. So we want to understand the influence of the SARS-CoV infection on brain and cognitive development, and since we have actually pre- and post-pandemic information this will facilitate our ability to do so.

And there is now this data has become already the first results from the imaging for the first and second set have already been placed on open access for anyone to look at, and we have also released in open access the data from the surveys of close to 75 percent of the children that have been involved in the ABCD study.

In parallel we have another study that we piloted two years ago that is about to start full-blown at the end of the year that will do also a longitudinal study on brain development starting in infancy. And this is also very important because we know (indiscernible) was giving a fantastic presentation (indiscernible) about how we have come to recognize that viral infections in pregnancy have been associated with later emergence of psychiatric diseases.

In particular the von economo encephalitis, as well as we have the recognition that there was an association from the study in 100 individuals who had been born of mothers who had been infected during the Spanish influenza, that they had higher rates of schizophrenia. Von economo follows on that and that led to one of the origins for schizophrenia being associated with viral infections.

Through the Spanish encephalitis it’s the first time also that led to the diagnosis of what would later be recognized as hyperkinetic syndrome or hyperactive ADHD, which made researchers try to understand what were the mechanisms associated with the later emergence of these syndromes in the children of mothers that were infected. What it is now believed is this was not necessarily due to the viral infection, but actually that this was the result of immune responses, systemic as probably we’re also learning now from COVID, some of them central.

Now we have the opportunity to do this prospectively, and there’s already data that has started to emerge from one of the PIs, Cindy Arnik(phonetic) who has been able to actually image infants that are three months old, this is a sample, this is preliminary, but this is 38 infants that were born of mothers that had been infected with COVID, compared to 65 controls before the COVID pandemic hit.

And it shows here in colors the area where the level of myelin is reduced in those neonates that were born out of mothers that actually were infected with COVID. The extent to which this is going to be meaningful of course requires higher samples and it also requires prospective evaluation, and very importantly a better understanding if there are narrative consequences to brain development and what are the mechanisms.

So this is an amazing opportunity that we all have to learn how the human brain responds to infections, to immune responses, and ultimately what are the interventions that we can actually do to try to prevent them, and also understand what are the factors that make someone more vulnerable.

As we look forward it is clear that as we are actually in control with the COVID pandemic we will be facing the challenges of these long-lasting effects from COVID. And we have heard very eloquently how devastating this can be, and we can understand how this will be influencing not just the neurological and psychiatric wellbeing of the person but also of the family and their surrounding.

So it is a unique challenge, it is from the scientific perspective an incredible opportunity, and for all of us it is a responsibility so that we can advance the science and help others. Thanks very much. And now it’s a pleasure for me to introduce the next speaker who is going to be Dr. George Koob who directs the National Institutes of Alcohol Abuse and Alcoholism.

DR. KOOB: Thanks Nora. I just want to share a few slides in the process. So my message to everyone is a very simple one. I would really like you to get some measure of alcohol use or misuse into your cohorts. And I’ll expand on that in a minute. But alcohol addiction or alcohol use disorder I like to say is the addiction that everybody knows about but nobody wants to talk about. And I’m going to take my little discussion here from a slightly different perspective but play off what Nora was just referring to at the end there. And it has to actually start pre-pandemic.

So we know that there is this phenomenon known as the deaths of despair. The graph here shows you the 2015 now classic paper from Ann Case and Angus Deaton, showing that increases in mortality in white non-Hispanics ages 45 to 54. But we now know that this increased mortality is observed across many racial and ethnic groups and age groups.

And alcohol contributes and has a prominent role in the deaths of despair pre-pandemic in three areas. About 15-20 percent of all drug overdoses, 26 percent of suicides, and half of liver disease. And alcohol related deaths doubled between 1999 and 2017. I’m not going to go through the little bullets there, but basically, we are seeing increases more in women than in men, and a closing of the gap in drinking between men and women, such that now women pretty much have caught up in consumption and misuse with men.

In fact, college age women now in a number of studies have been shown to be binge drinking more than men for the first time in our metrics. So these statistics align with other recent reports that have highlighted the changing trends in drinking patterns and increased consequences of alcohol in women and also the aging population.

So how does this interface with COVID-19 or the SARS virus? And the impact is in four ways. And I’m not going to dwell on the first two, but obviously there are biological effects. Alcohol affects the immune system. I didn’t know this before the pandemic, but chronic alcohol consumption increases the risk for acute respiratory distress syndrome, with increased need for mechanical ventilation, prolonged intensive care unit stay, and higher incidence of mortality. And this sounds very familiar since it’s one of the main pathological effects of individuals hospitalized with COVID-19.

One that’s starting to fade away, not completely, is disinhibition. So alcohol is the great social lubricant, and of course individuals under the influence of alcohol in a closed setting are likely to take off their masks, shout, and get close to people, and not engage in physical and safety distancing.

But the two others that I really want to focus on are the impact of the COVID-19 pandemic on alcohol use and treatment in the context of isolation and stress, and treatment and recovery. So physical distancing can lead to social isolation or loss of social support, which can lead to stress. And stress leads to drinking to cope because of the boredom, the isolation. We’re primates, so one of the most prominent reinforcers in our world is another primate, and we’ve been denied that reinforcer.

And then in the alcohol field, and certainly in substance use disorders as well, treatment and recovery, physical distancing has posed challenged for those with alcohol use disorder and emphasizing the need for telehealth and virtual meeting options for individuals seeking treatment or in recovery from alcohol use disorder. And I might add this applies to all mental illness for that matter.

So I think you can see from my little diagram that social isolation, stress can contribute to alcohol misuse, alcohol misuse can contribute to behavioral disinhibition, impaired immune function, which can increase the risk of viral infection, and the loop closes.

And so are people drinking more during the pandemic? Well studies suggest that some people are drinking more during the pandemic, while others are drinking less. What we pick up in a lot of now small studies is about 20 to 40 percent of individuals are drinking more during the pandemic, 20 to 40 percent are drinking less. But stress is a common factor for those drinking more, to loop back to my original premise. So a survey by the American Psychological Association found that nearly one in four adults reported drinking more alcohol to cope with stress during the pandemic.

In a survey of 12,000 physicians 42 percent reported they are experiencing burnout, and one in four of them, almost a quarter, a little more than a quarter, indicated drinking alcohol to cope with the burnout and the stress. In another survey 29 percent of respondents reported drinking more, and the odds of increasing were higher with those with symptoms of anxiety or depression. And other studies suggest that having psychological wellbeing impacted negatively by the pandemic is associated with more drinking days and more drinks per occasion.

And so these findings are concerning because drinking to cope places a person on a slippery slope to alcohol use disorder. And I might add it places you on a slippery slope to opioid use disorder and cannabis use disorder and the interaction with other mental illness. And then finally, addiction context is critical. Addiction is rooted in the brain, but understanding why it develops and how to prevent and treat it requires examining the broader context of people’s lives.

Maybe this is more in Elaine Langevin’s domain, but as with many other conditions there are social determinants that influence the likelihood of developing and recovery from alcohol use disorder. Social determinants include aspects of the social environment, income, access to education, social support, exposure to discrimination and violence, the physical environment, and health services or lack of them.

These factors can contribute to health inequities and can also serve as allostatic loads on the brain systems involved in stress, emotion regulation, increasing vulnerability to alcohol use disorder. And as I said, such stressors can drive alcohol misusers to cope, which in turn exacerbates the initial problems, further fueling alcohol misuse.

And so we wrote a paper at the end of last year for the American Journal of Psychiatry superimposing on the addiction cycle where we think some of these elements of stress interacting with the isolation and the infection impact the addiction cycle, and it’s what I call the withdrawal negative affect stage, the argument is that biological and experiential factors add to the allostatic load on stress circuitry, increasing the likelihood of alcohol use disorder and the degree of hyperkatifeia, which is a word I coined for negative emotional states experienced during the addiction cycle.

I just want to repeat what Nora and Josh said, these are influenced, this negative emotional state situation is associated with addiction and alcohol use disorder in particular, the loads on this system are genetic, epigenetic, but childhood trauma and psychiatric comorbidity are major factors, not to mention drinking too much. So we are supporting COVID-19 research, we have several RFAs out to improve public health in the near-term by informing responses on the COVID-19 pandemic.

We do have a number of studies, we are supporting supplemental studies, which is the second bullet, we have administrative supplements and competitive revision supplements on COVID-19, and many of those are actually looking at the effects of the infection on alcohol intake, but some are also looking at the effects of alcohol on infection, and we really like to see interactions in both directions because as I pointed out earlier I really think that alcohol can facilitate some of the pathology associated with COVID-19, but COVID-19 because of all these other factors, particularly isolation, can facilitate alcohol misuse.

And so basically that’s all I wanted to talk about, but I want to emphasize two things. We have metrics like the audit C, which is part of just a subset of the full-fledged audit that takes about one to two minutes to administer to someone. It’s three questions: how often do you have a drink containing alcohol? How many standard drinks do you have containing alcohol on a typical day, and how often do you have six or more drinks on one occasion? If you all could put those in your cohorts I would be eternally grateful. And I know I keep saying this, but that’s my final word. So thanks very much for listening, as they say in Alcoholics Anonymous.

DR. LANGEVIN: Thank you very much. Dr. Koob that was the perfect segue into my talk. I’m the Director of the National Center for Complementary and Integrative Health, and we’re very interested of course not only in stress but also stress management.

So NCCIH is as I said, very much interested in how do you manage stress, how do you mitigate its effects. And we’ve been talking about a lot of these wonderful talks in the last two days about all these various manifestations of both acute SARS-CoV-2 infection and the various components of this for inflammation, of course viral infection, inflammatory component, vascular component, but also of course acute stress, especially in patients who are hospitalized, intensive care unit.

And it’s really not clear at present which if any of these components may be related to the development of the symptoms and abnormalities that we see in the post-acute syndrome, for example whether persistent, we’ve heard a lot of evidence actually that persistent neuroinflammation may underlie some of the fatigue and brain fog in many past patients and whether perhaps some vascular injury or inflammation in specific parts of the brain could result in autonomic or endocrine dyscirculation.

And the important thing also is to think about there are some symptoms, for example pain, which haven’t been really looked at very closely, but could result from specific interactions of the virus with the peripheral nervous system.

I think we really need to look at that, especially the dorsal root ganglia that reside outside of the blood-brain barrier that could be impacted by the virus. A lot of we know that dorsal root ganglia neurons express ACE2 receptors. So I think this is an area that should really be looked at, because we know that pain is a prominent symptom in patients who have post-acute symptoms after COVID.

But of course, another really important consideration is that the acute and post-acute SARS-CoV-2 infection are occurring in the context of this extraordinary pandemic that has caused unprecedented constellation of grief over lost lives and social isolation, economic instability, social inequity. And if that wasn’t enough, we’ve lived through a year of increasing societal polarization, distrust, racial tension, and the chronic stress resulting from these combined factors really could be contributing to this syndrome that we’re observing in these patients.

So it’s really important to remember that stress is not just psychological, that it can affect every single organ of the body, and this is one of many examples in the study in rabbits, for example exposed to chronic stress over four months, and who developed increasing levels of TNF alpha, C reactive protein, monocyte chemoattractant protein et cetera in the abdominal aorta.

In the brain there’s consistent evidence from animal experts that a range of psychosocial stressors can lead to elevated microglial activity in amygdala, hippocampus, and other brain regions, including the paraventricular nucleus of the hypothalamus.

And I really want to point this out as this could be very important for pathophysiology, because a hypothalamus is not only vulnerable to chronic stress as we see here, but also it sits right behind the lamina terminalis that has fenestrated capillaries where there are osmoreceptors that are located there involved for blood volume regulation.

Of course the hypothalamus is also intimately involved in autonomic function, direct connection to the brain stem areas that regulate blood pressure through the longitudinal fasciculus. It’s the master regulator of stress responses, CRF, and HPA access, and so you could see a situation where the hypothalamus could really essentially have a double hit from both the effects of stress and possibly a direct exposure to the virus through these sorts of fenestrated incomplete blood-brain barrier. So I think it’s really important to think about this.

And the point of this would be twofold. First, I think chronic stress needs to be considered in the pathophysiology of PACT, not just for its psychological effects, but for its physiological effects, and here represented this hypothalamic area which I think could really be at the center of some of this.

And second, stress management is really something that we know that we can do. It can really make a difference in helping the patients recover their neuro-endocrine function, and even perhaps prevent it from occurring in the first place if it was addressed at the acute stage.

So one place to look for evidence supporting stress management for PACT is chronic fatigue syndrome, it’s already been mentioned several times in this symposium, or here’s a 2015 review of treatments for chronic fatigue that found some unique support for counseling therapy and graded exercises, but the trials used these approaches one at a time. In contrast this is an older study that used a multidisciplinary approach using a combination of structural physical exercise, sleep management, careful activity management and involvement of the patient’s family.

And this was an observational study and really needs to be followed by a randomized trial, but the number of patients who were able to return to employment and full function was really encouraging. And so because PASC is also likely to be multifactorial, it would be really important that multidisciplinary approaches should be used from the start, including special attention to sleep and physical activity.

Another piece of evidence in support of a multi-system approach is this review of the effect of tai chi in Gulf War illness. Tai chi is a complex intervention, including some slow, meditative movements, and it has both a psychological and a physical component.

And the benefits of tai chi in Gulf War veterans covered many different areas, including aerobic capacity, exercise self-efficacy, fatigue, and sleep. And the idea here is that improvement in these different domains could become part of a positive feedback loop. Better sleep, reduced daytime fatigue, improved motivation to exercise, which itself could improve sleep.

In fact I would argue that it is really imperative that we study the role of nonpharmacologic interventions for helping with stress, and especially sleep, as part of the primary prevention for reducing the stress burden in patients with acute SARS-CoV-2 infection, and possibly even prevent PASC. So we have some evidence that for example mindfulness-based stress reduction can be as effective as an FDA approved sedative, as you can see here in patients with chronic primary insomnia. You see the mindfulness here on the left, the sedative here on the right.

And in this meta-analysis demonstrated that yoga can be beneficial when compared with nonactive control conditions in terms of managing sleep problems. And NCCIH has so far funded some administrative supplements in this space in response to an FOA specifically addressing stress in COVID-19. We funded three urgent competitive revisions of nonpharmacological interventions to address stress.

We also funded one application, one supplement on mechanisms of resilience as opposed to the trans-NIH social behavioral and economic initiative that got mentioned earlier. But much more needs to be done, and I would argue that incorporating measures of stress and stress management would be really important in these PASC cohorts that we’re just starting that Dr. Koroshetz mentioned.

So in summary, incorporating the effects of stress, stress management in your investigation of the neurological and psychiatric effects of SARS-CoV-2 is important, and I would argue that it’s really an inseparable part of the equation, especially in the context of this pandemic. So it’s now my pleasure, I can introduce the next speaker, Dr. Eliezer Masliah, who is the Director of the Division of Neuroscience at the National Institute on Aging.

DR. MASLIAH: I would like to speak in the next few minutes about the research and the work that we’re supporting trying to understand the relationship between neurodegenerative diseases and SARS-CoV-2 infection of the CNS. This is in the larger context of the research that NIA conducts to understand the pathogenesis of Alzheimer’s disease and related dementias. We of course conduct quite a bit of research on the role of aging, particularly in mechanisms such as protostatic defects, DNA damage, cell senescence.

We also conduct studies about the genetics of AD and ADRD, genes like APOE, presenilin, inflammation genes, endosomal genes, but recently there has been a tremendous interest on environmental factors, including toxins, pollution, heavy metal, trauma, and most recently infectious diseases, and of course of all them SARS-CoV-2 really rose to the top in the last year and a half, and we’ve been funding a number of studies and initiatives looking both at the behavioral social aspects of the aging and aging biology related aspect, but also the neurobiological aspects related to the relationship between AD and SARS-CoV-2.

In this context we’re not only funding initiatives on SARS-CoV-2 on the nervous system, but also in general about the infectious etiology of Alzheimer’s disease, we recently had an RFA where we’re looking at a number of infectious agents, fungal, bacterial, viral, et cetera. Also in collaboration with NIMH and NINDS we’ve been funding for a long-time studies of the pathogenesis of HIV and neurodegeneration of the nervous system, and more recently microbiome and aging and brain and AD/ADRD.

And of course the funding opportunities that are worth mentioning to understand the relationship between AD and COVID-19. I think that here is worth emphasizing, we know this quite well, older individuals are really overrepresenting the risk for SARS-CoV-2 infection as well as PASC and other symptoms related to long COVID. So this is a population that is specifically affected by SARS-CoV-2 and deserves great attention.

We have a number of funding opportunities trying to understand the neuropathogenesis of SARS-CoV-2 in the CNS and elderly individuals, but also we think that it is important, these studies of cohorts and so on, as we have heard before, and we had the opportunity to talk about some of the cohort that we’re funding at our previous talk.

Here what I would like to talk a little bit about is some of the studies that we’re funding in terms of neuropathogenesis, we’re really interested in understanding neurological and neurocognitive syndromes associated in AD/ADRD patients and COVID-19, those mechanisms underlying that neuropathology, and if SARS-CoV-2 actually accelerates or synergizes with the amyloid deposition and the burdenopathy, and inflammation disease disorders, how they are affecting the blood-brain barrier, and if we can develop drugs that get into the brain that might be targeting SARS-CoV-2 that it can be the case.

And then finally computational informatics approaches. And here the idea is SARS-CoV-2 probably might be having effects both at the level of the proteinopathy in the brain in AD/ADRD, but also for example at the vascular level, coagulation, and also at aging mechanisms like cell senescence and DNA damage.

We funded a number of both supplements as well as R01s under these initiatives, and just very recently, a couple of weeks ago we had these very exciting symposium where we looked at the research that these investigators were conducting, we had seven different sessions including peripheral neurologic sequalae, dementia care, therapies, resilience and epidemiology, et cetera.

I want to show some of the highlights of some of the research that has been going on, for example, and we heard a lot about this in these two days, about the mapping of SARS-CoV-2 in the brain, and this is in an individual with Alzheimer’s disease and related dementia like Lewy body disease.

And these researchers found that in approximately 20 percent of the cases that they looked at actually they found SARS-CoV-2 RNA in the brain by PCR, and we know that there is a lot of controversy if there is SARS-COV-2 in the brain or not or neuro-invasiveness or not, or if the damage is more neurological or vascular. And of course, there are a number of studies in this regard.

But what I thought was very interesting about these studies is that they show that there was a quite significant axonopathy with APP positive axon swelling, and as you know APP is a precursor of amyloid, and probably the accumulation of amyloid in these individuals might be accentuated, this is something that these investigators are further looking.

Also along the lines of individuals with dementia at a higher risk for COVID-19, a very large study using electronic health records showed that indeed there is a disproportionate increase on SARS-CoV-2 on dementia cases, but even more significant the fact that females were disproportionately affected as well as African Americans. There’s a very large study that continues to be (indiscernible)

Also in terms of studies trying to identify the SARS-CoV-2 mechanisms and the Alzheimer mechanisms interacting, there’s a very recent study that we funded where they looked at transcriptomic, proteomic, and multiomic or even based on CRISPR assays and so on between individuals with COVID-19 cohorts and Alzheimer’s cohort, looking at single cells for RNA, APOE3, APOE4, and then doing network analysis, and in a nutshell these investigators show in these proximity network analyses (indiscernible) between the mechanisms involving Alzheimer’s disease and SARS-CoV-2, in particular as it relates to narrow inflammatory mechanisms including TGF Beta, interferon gamma, and other aspects.

In fact some of the notes involve very close proximity between the two disorders, which really I think tells us that there is some relationship between these two disorders, and one potential point of relationship might be the APOE4 allele, which as we know increased the risk for Alzheimer’s disease.

And in SARS-CoV-2 some very recent studies have shown that for example in neurons and glial cells derived from IPS cells from APOE4 versus APOE3 or APOE2 are at much greater risk for greater SARS-CoV-2 infection, and likewise a study in the UK biobank showed that APOE4 allele individuals are at might higher risk for infection and mortality for SARS-CoV-2, so there is something there between SARS-CoV-2 and APOE and the pathogenesis of Alzheimer’s disease that might be overlapping.

Some of the investigations suggest that maybe reducing expressions of antiviral genes on APOE4 might play a role, but also these individuals with APOE4 have increased expression of receptors for SARS-CoV-2 and endothelial cells, such as the H2, furon, and other markers. Also some genes that regulate amyloid production like IFITM3 and interferon gamma might also be dysregulated both in COVID-19 and Alzheimer’s disease.

Many of the inflammatory pathways I mentioned already, TGF beta, but also NKTR, CXCL10, JAK1, STAT are affected. And also in the endothelium a lot of the blood vessel related markers like BCHEM and genes involving other processes are also equally dysregulated, suggesting synergism in many aspects between COVID-19 and neurodegenerative disorders.

So we really look forward to continuing supporting this type of research and trying to understand better the relationship between Alzheimer’s and NeuroCOVID, and how to hopefully develop therapeutics that would be relevant to both of the disorders. Thank you very much. And with that I will stop sharing and introduce our next speaker, Dr. Alison Cernich, the Deputy Director from the National Institute of Child Health and Human Development. Thank you.

DR. CERNICH: Thank you very much. So I just want to highlight NICHD’s mission and vision with respect to its relevance here. Our role here is to lead research and research and training to understand human development, improve reproductive health, enhance the lives of children and adolescence, and optimize abilities for all.

So as you’ll hear from my presentation, I think the key elements that we have been trying to lead within this and with some of our partners who are on this call are the NIH pediatric research consortium’s efforts, and we have been co-leading that with Dr. Volkow and colleagues. Also we have been working with the community as well as the community of scientists in the NIH on common data elements to help with the standardization of data for populations for whom they do not currently exist.

We have also been leading an effort around return to school and the use of diagnostic testing in that setting that I will cover. And then I will also highlight a few initiatives that we are working on related to child health and rehabilitation.

So with respect to the NIH Pediatric Research Consortium or NPeRC, this is a trans-NIH group that has been capitalizing on pediatric research expertise and resources across the institutes and centers at NIH. And the maternal and child health subgroup has been facilitating supplement funding, including studies that have been evaluating a number of aspects related to the health of moms and children as it relates to the pandemic.

And this includes long-term impact of mental health interventions for adolescents, contributions of parenting interventions on parent adjustment, parent-child relationships, and psychosocial outcomes for children. The effects of the shift to remote learning on child education and development, which obviously will have long-term outcomes with respect to cognition for these children as many of you know.

And then also some of the things that we need to do in well-child care related not only to developmental outcomes, but we are also starting to see some awards that are coming into this group related to, and I think as Dr. Nath even noted there, there are many diseases for which we have vaccines that have neurologic consequences, we are now seeing that vaccines for sort of routine infections are also becoming less well utilized during the pandemic, not just for COVID and in the age groups for where it’s applicable, but also things like the measles vaccine, children are not getting vaccinated at the rates that they used to. And so we are looking very much at some of the preventive health care as it might relate to neurologic impacts.

We have also been working with the community and across the NIH to help to harmonize data, to accelerate COVID research in the areas of pregnancy and pediatrics. So these are being led by experts across the NIH, we’ve convened expert panels of scientific investigators and federal partners to develop recommendations, utilizing a Delphi approach to develop these types of CDEs and the measures associated with them, validated where possible.

This is included biomedical and psychosocial working groups, and they have identified in pregnancy about 64 elements across 13 domains of study, and for pediatric they looked at 111 elements across 21 domains. These common data elements are being used across a number of the NIH-wide initiatives in COVID, and they’re being considered for example in the RADx initiatives as well as being used potentially in the RECOVER initiative, about which you heard from Dr. Koroshetz.

With respect to our efforts through the RADx UP program, so that’s the RADx Underrepresented Populations Program, we have the opportunity to develop a program to develop, evaluate, and implement COVID-19 testing approaches and mitigation strategies to encourage the safe return of children and staff in underserved and vulnerable communities to in-person school settings. To date we have funded 13 projects at 15 institutions across 11 states. And this includes educational settings in early education, in elementary school, middle school, and high school.

We also have projects that are looking at the use of diagnostic testing to return children with intellectual and developmental disabilities to school. Many of you know that for example children with Down Syndrome are about 10 times more likely to have severe consequences or die than many other populations.

Really their morbidity and mortality risk is second only to those with lung cancer at this point, and they do have some specific genetic vulnerability, so not only have we launched some of our projects through the return to school initiative, we’ve also included that in our NIH-wide initiatives around Down Syndrome, the INCLUDE Initiative, where we are specifically studying Down Syndrome.

We’re also studying the impact on children with complex medical conditions who may not be able to be in the school setting, not because of intellectual or developmental disability but because of chronic medical conditions. Those classes of children who have developmental disabilities or chronic medical conditions also may have difficulty with medication. And so they have a higher risk of exposure, as do the staff that work with them.

And so we are not only looking at the ways that we can test and mitigate the impact of COVID-19 in the school setting, because as we know engagement in school actually helps neurologic development and increases access to services and improves mental health, for many children, though not all, we’re also looking within this at the educational development outcomes that are related to in-person learning and what are the impacts when children are in hybrid learning settings or in the fully virtual learning setting. So we hope to really learn quite a bit about this, and we will be having a public workshop if you are interested on August 9th.

We started some of these programs in April so that we can get data from the second semester of schooling, and some of them are continuing in the extended learning programs in some states that are being offered to mitigate learning loss, and so they are continuing to test and study these children, and we will have some initial results and evidence base that we will present in our workshop on August 9th, and that will be available on the NICHD website if you’d like to register.

We also funded two other initiatives that have bearing on the neurologic and psychiatric consequences of COVID-19, so the first is the GRAVID study, which was gestational research assessments for COVID-19, which seeks to understand the effects of the COVID-19 pandemic during and after pregnancy.

This is a registry of approximately 20,000 pregnant persons, and they are focused on maternal, cardiac, neurologic and pulmonary outcomes in pregnant persons who are positive, they also because this is based on our Maternal fetal medicine Unit’s Network have information on some of these pregnancies based on trimester and also pre-pandemic comparative data.

So we are learning from that and looking at pre-term birth, pregnancy outcome, and conditions related to pregnancy. Another overarching initiative that we’re working on with our NIH colleagues is the caring for children with COVID initiative, and this is a collaboration to assess risk and identify long-term outcomes for children with COVID.

This includes efforts to really understand why some children are more likely than others to get infected with SARS-CoV-2 and/or show symptoms of COVID, why do some children who become infected with SARS-CoV-2 have more severe illness, such as the multi-system inflammatory syndrome in children, which can have not only cardiac and pulmonary manifestations but also neurologic manifestations as you’ve heard yesterday.

And then what are the long-term outcomes for children who have become infected with SARS-CoV-2, and this will include not only cardiac and other sort of organ system outcomes, but we are also looking at the neurologic outcomes, the developmental outcomes, and the mental health outcomes of these children.

So that involves studies at NIAD where they are focusing more on the immunologic profile of the children, studies through the National Heart, Lung, and Blood Institute where they are focused primarily on cardiac and pulmonary but also including other systemic outcomes, and then studies through NICHD looking at not only the presentation of these conditions, btu also looking at the potential treatments that we have available for them.

I just want to highlight two notices of special interest. One is a notice that we put out to understand the impact of primary instruction setting disruptions on the mental health, cognitive, social, and emotional development of children ages three to 12. And so that notice is referenced there.

We did this, as Dr. Gordon mentioned, in  collaboration with mental health, so I won’t go over it in detail, but that will expire September 8th 2022, and we really are very interested in what the digital divide may have done to these children or other aspects of the disruption of children as it relates to them not being in a school setting.

The other notice of special interest that I will highlight that comes from our National Center for Medical Rehabilitation Research and which I’m learning more and more about from colleagues across the rehabilitation sector is the notice of special interest looking at applications in three areas related to the intersection of COVID-19 mitigation and rehabilitation. This is encouraging research to address the rehabilitation needs of survivors of COVID-19, especially those who are going to be in rehabilitation services.

We’re also looking at the impact of disruption to rehabilitation services caused by COVID-19 pandemic and associated mitigation, and that really does affect many folks with neurologic conditions, and then also the social, behavioral, economic, and health impact of COVID-19 on people with physical disabilities. This bill expires in May 8th 2023, and we really do encourage you to take advantage of this.

From what we are hearing from our rehabilitation colleagues across the country, there are some very significant impacts, both of COVID-19 on the neurologic, psychiatric, and motor presentation post the initial infection, as well as just the major disruptions that have happened as a result for people with neurologic conditions or other physical disabilities that the services may not be as available to them. So with that I will close and I will turn to introduce Dr. Andria Lerner who is a Medical Officer in the Immediate Office of the Director for the National Institute of Allergy and Infectious Disease. Andrea, to you.

DR. LERNER: Thank you very much Alison. Thanks very much to the organizers of the meeting for the invitation today to share the perspective from the National Institute of Allergy and Infectious Diseases on the neurological and psychiatric effects of SARS-CoV-2. So I’ll just be telling you today about some of our relevant initiatives and projects in this area in the context of our overall research response to the COVID-19 pandemic.

So it’s not news to anyone here that SARS-CoV-2 has multisystem manifestations, both the acute and post-acute phases of disease, including obviously the neurological and psychiatric aspects of disease, in addition to a host of other mutli-system manifestations of acute disease, and also post-COVID conditions.

So in framing how we think of the neurologic and psychiatric effects of SARS-CoV-2 infection from the NIAID perspective, this is a virus that affects many organ systems in the body and exerts multisystemic effects both in the acute and post-acute phases.

So to jump right in to some of our relevant initiatives and projects examining SARS-CoV-2 infection and COVID-19 in the neuro and mental health domains, I’ll allude to the RECOVER Initiative, which NIAID has multiple staff members and SMEs supporting this trans-NIH initiative.

And I won’t go into specifics here because Walter already took us through the initiative, but as he spoke about the long-term effects of COVID include many neurologic and mental health aspects, and there are many questions in these domains that we hope that the RECOVER Initiative will shed light on, and NIAD is working with the other NIH partners to answer some of these questions under this umbrella.

Some of our other observational studies, I’ll walk you through some of our studies here. We have one cohort study that we’re supporting the long-term impact of infection with novel coronavirus cohort, also known as the LIINC Cohort.

This is an observational cohort study of people who have recovered from acute COVID-19 and the link to the ClinicalTrials.Gov reference is there as well, and this study will examine multiple questions with regard to recovery from COVID-19, including not the least of which neurologic and mental health factors.

And the focus here is really on understanding the variability in recovery and also long-term immune responses that may play into the recovery. So this is one study that we’re supporting, an observational study to shed light on some of the neurologic and mental manifestations of COVID-19 in the recovery phase.

The Chasing COVID Cohort is another study that NIAD is supporting, and this is a geographically and socioeconomically diverse cohort, all within the United States, that in this study is designed to understand the spread and impact of COVID-19 on both individuals, households, and whole communities.

So in this cohort recent symptoms and trends in symptoms will be assessed, how messaging from the clinicians and public health providers is taken up, and changes behavior, and also we’ll look at the effects of COVID-19 on general health, including mental health. Also healthcare access and employment.

Another relevant cohort study that I wanted to highlight is one referenced in the third bullet here, the evaluation of the interplay between HIV and COVID-19. This is a study being conducted in a large urban HIV clinic, and this is really looking at the interplay of SARS-CoV-2 infection, both risk of infection and the effect of infection on clinical outcomes among people with HIV.

And also looking at the immune responses against COVID-19 in people with and without HIV after SARS-CoV-2 infection, and also looking at the disruption to healthcare systems, social support, HIV services, that the pandemic has had among people who are living with HIV.

So those were three observational studies that I wanted to highlight that are occurring extramurally. And then there are two that I wanted to highlight that actually involve people being seen at the NIH clinical center. So one, the first bullet here, is Dr. Mike (name indiscernible) study, a Longitudinal Study of COVID-19 Sequelae and Immunity.

And in this observational study of individuals who have recovered from COVID-19, they are brought to the NIH clinical center to monitor complications, assess their ongoing symptoms and immune responses, and really undergo a very comprehensive assessment, which includes neurological tests and assessment of mental health. And this study will follow people over three years.

Another study involving our NIH clinical center as a site is the Pediatric SARS CoV-2 MIS-C Long-term Follow-up. This is another NIAD intramural study that partners with Children’s National Medical Center to really examine the recovery and sequalae of children from age zero up to young adulthood who have recovered from COVID-19 as well as their household contacts.

As I mentioned this study is going to look at the incidence and prevalence of sequalae, risk factors for developing such sequelae, including neurologic and psychiatric sequalae, and also looking at quality of life, social impact, the incidence and prevalence of reinfection, and this study will also establish a biorepository. So just highlighting two additional observational studies that are on the intramural side of things.

And then I also wanted to highlight some interesting laboratory-based studies in the domain of neurology and mental health. One is a proteomic analysis of the olfactory cleft region, looking at the region where the olfactory neuroepithelium is located, and this analysis will aim to identify COVID-19 specific protein signatures that might be relevant to the loss of taste and smell that we all know can be a consequence of COVID-19 infection.

Our DIR is also conducting an analysis of autopsy brain tissue from COVID-19 patients as well as controls. This will aim to look at the levels of CNS virus, capillary endothelial cell activation, and also up-regulation of adhesion molecules to look at how SARS-CoV-2 is affecting the integrity of the blood-brain barrier.

And there are also some interesting brain imaging studies on two animal models, SARS-CoV-2 infected hamsters and non-human primates, where the aim is to characterize the changes in brain metabolic activity with disease progression and look at how that relates to the immune responses.

So I think that is my last slide here, I will stop sharing. But I hope I’ve given you a snapshot of NIAD’s perspective on activities in the neurologic and psychiatric mental health domains of SARS-CoV-2 infection, which I think we’ve seen as this pandemic has gone on has been one of the most impactful and serious ways that people are affected by this virus. So I think now I will turn it over to Dr. Susan Sullivan, Program Director at the National Institute on Deafness and Other Communication Disorders. Thanks very much.

DR. SULLIVAN: Thank you so much. NIDCD’s mission is to support research in several areas, including hearing, balance, taste, smell, voice, speech, and language. And we are supporting COVID related research in all these areas through NIDCD issued administrative supplements, and notices of special interests, as well as participating in various NIH programs. To date though one of the major focuses of our institute with respect to COVID has been on the olfactory system and the loss of smell associated with COVID.

So as Andrea mentioned it’s known that early on that the sudden loss of smell was recognized as a common symptom of COVID, and many studies using objective smell tests have been done, and it’s estimated that approximately 80 percent of patients with COVID lose their sense of smell, either partially or completely. Fortunately, this smell lose generally resolves itself in a few weeks, but in about five to ten percent of these individuals the smell loss persists for months.

So to better understand the relationship between COVID and smell, we’re funding several projects that are aimed at identifying genetic variations associated with smell loss and individuals with COVID, characterizing the expression of ACE2 and TMPRSS2 and related viral entry genes throughout the olfactory system. We’re interested and have projects examining the mechanisms underlying persistent smell loss in some individuals.

We have ongoing projects looking to determine if COVID related smell loss is predictive of disease severity or persistence. We’re looking at post mortal tissue from patients to evaluate COVID related changes in the olfactory system. And finally, we have projects that are developing cheap, quick, at home, objective chemosensory tests to screen for COVID.

So in the next few slides I’ll just highlight some progress that has been made in some of these areas. To understand how COVID might alter the olfactory systems, studies were performed to determine which cells might be target for infection. And an obvious first place to start was through olfactory epithelium, given that it is peripheral and exposed to the environment.

And the olfactory epithelium real quickly consists of a variety of cell types, including the olfactory sensory neurons, and these are the cells that detect odorants and then project back to the olfactory bulb of the brain. There’s also, but they die throughout your life, and are replenished by stem cells shown here in purple, and also another major cell type in the olfactory epithelium are the supporting cells, and they are critical for sensory function.

And so early studies doing immunostaining with either ACE2 or TMPRSS2 show that in fact these genes are expressed in the supporting cells and in the basal stem cells, but not in the olfactory sensory neurons themselves. So it seems that the supporting cells are a good candidate for being the initial target of infection.

And similar studies with the olfactory bulb, again the ACE2 and TRP22 proteins were not found in the neurons but in cells of the blood vessel. So we’re interested in further studies and funding projects to determine the mechanisms by which the supporting cells and the olfactory epithelium or the blood vessel cells in the olfactory bulb affect olfactory function.

In an unrelated study, Barnham et al examined how bitter taste receptor phenotypes might be associated with clinical outcomes in individuals with COVID. And the T2R family of bitter receptors are known to be expressed in taste cells in the tongue, and they respond or detect incoming bitter tastants.

But they’re also expressed in the upper airway. And these cells in the upper airway, the receptors recognize microbial pathogens and upon activation initiate an immune response. So this led to the question are individuals with nonfunctional T2R38 receptors, which are the ones that are expressed in the airway, more susceptible to COVID-19 infections.

And just briefly there are two major haplotypes for the T2R38 receptors, PAV which is functional, and AVI which are nonfunctional. So people with two functional alleles of the T2R38 receptor are supertasters with respect to the bitter taste of probe. Whereas individuals with two nonfunctional alleles are non-tasters with respect to the bitter tastant probe. And heterozygotes fall in the middle.

So what’s interesting about this study is that they followed 1935 healthcare workers, and what they found was that the non-tasters were more susceptible to getting COVID, and also more likely to have severe cases that required hospitalization. So of the 55 subjects that had to be hospitalized, 85 percent were non-tasters.

And in addition, they found that they also had longer duration of disease. So whereas the super tasters, the disease lasted maybe five days, the symptoms in the non-tasters lasted 23-24 days. So this raises the possibility that taste phenotyping might be a useful tool in predicting disease susceptibility, severity, and duration.

And finally, I just want to mention one other study through the RADx rad program, NIDCD is supporting four awards that aim to develop chemosensory tests to use as COVID screening tools, perhaps to supplement temperature taking.

And we hope with these projects and others like them to develop inexpensive, objective chemosensory tests to screen for COVID that will be fast, give instant results, will be disposable and self-administered, highly scalable, with multiple versions so that a person could take the test day after day after day. And finally, that they would be stabile and be able to be globally deployed.

So that’s kind of what I wanted to highlight from NIDCD’s side of things, and I’ll pass the mic on to Lillian Shum, the Division of Extramural Research at the National Institute of Dental and Craniofacial Research.

DR. SHUM: Thank you Susan. Good afternoon everyone. It has been really good to have heard from many of you in the last day and a half coming together to address the topic of significant impact to those affected by SARS-CoV-2 infection, and from different research perspectives. So I’m Lillian Shum, the Director of the Division of Extramural Research at the National Institute of Dental and Craniofacial Research or NIDCR in short, and thanks for having me on this panel.

NIDCR supports research and research training to advance fundamental knowledge about dental, oral, and craniofacial tissues in health and disease, and also to translate these findings into prevention, early diagnosis, and treatment strategies to improve the health of all individuals and communities across the lifespan.

Shown here are some of the tissues of interest to us in the head and neck region, and that would include the trigeminal system and other cranial nerves, the skeletal system including the temporomandibular joint, salivary glands, and tissues in the oral cavity including teeth, tongue, and oral mucosa.

Now studies have shown that SARS-CoV-2 can infect the salivary glands, and oral mucosa, and can replicate in those cells. And as we’ve been wearing masks for over a year now, it really speaks to the importance of the oral cavity and saliva as the primary route of transmission.

So last year NIDCR provided support for COVID-19 and SARS-CoV-2 research, and some in collaboration with other ICs, and I’ve summarized a few items here. So Susan already mentioned earlier that the two institutes collaborated to develop this initiative on chemosensory testing, and we also collaborated with NCATS on another initiative on novel biosensing from skin and oral cavity to detect SARS-CoV-2.

NIDCR also provided urgent support for research of high priority and immediate impact, and a few are highlighted here, including a registry of dental practitioners within the National Dental Practice Based Research Network to capture data on their approaches they used to reduce transmission risk in their practices and associated costs, as well as the comfort level using these methods, and also about reopening the practice.

We supported a few studies on aerosols in the dental settings and infection controls, also coronavirus vaccine acceptance and readiness among dentists to administer the vaccine. Also the impact of delayed care, oral health behaviors and mental health in low-income urban families. Also the impact of delayed care in high-risk oral cancer patients and survivors, and finally SARS-CoV-2 in the oral microbiome.

And in January of this year, we released a notice of special interest to encourage more research on the physiological involvement of the oral cavity in COVID-19. And there are several focus areas, on the basic biology of SARS-CoV-2 infection and transmission in the oral cavity, including the microbiota, oral gut axis and dysbiosis, effects of ACE2 expression and distributions in function, salivary gland as the reservoir for SARS-CoV-2, oral mucosal immunity and differential interactions between the virus, the mutants, or the variants with oral and nasal cells.

Also the pathophysiological mechanisms of oral manifestation of COVID-19, including post-acute sequelae of the disease, interactions of between the SARS-CoV-2 and oral and nasal microbiota and potential therapeutics to limit infectivity and transmission, and also finally tools and technologies for studying these areas, for example animal models, ex vivo models including oral and nasal tissue chip platforms, as well as computational modeling of the virus receptor interactions.

Now, in the literature we are seeing case reports and other observational studies on comorbidities and complexities of SARS-CoV-2 infection and COVID-19 that relate to dental, oral, and craniofacial health. So for example there is a study here reporting a surge in temporomandibular disorders and bruxism and associated pain during the pandemic. Also the impact of COVID-19 on psychosocial aspect and pain experience in patients already affected by temporomandibular joint disorders.

Another one on the clinical outcome of patients with Sjogren’s syndrome infected with SARS-CoV-2, and then a hypothesis that there’s a potential relationship between SARS-CoV-2 infection and risk for oral cancers. Now theses are really small studies, observational, and merely correlational. So we don’t really know if pain and distress or other comorbidities are direct or indirect results of neurological disturbances, let alone any mechanisms of action.

Which really leads to various research opportunities to unravel the underpinnings of these health outcomes. So for example we continue to be interested in the pathophysiology of smell and taste disorders, the role of the craniofacial sensory innovations and potential contributions of the oral and nasal microbiome.

Oral complications from neurovascular disturbances, presentation of mucosal lesions and salivary gland dysfunctions and exacerbation of orofacial pain and autoimmune Sjogren’s syndrome from neuroinflammation and neuroimmune disturbances, the impact of dental care delivery delays on oral health needs and access to care, particularly in vulnerable special needs and underserved populations, and impact on dental practitioners, including the mental health as they face unique challenges during the pandemic and uncertainties in the near future. And lastly, and certainly not least, we look forward to seeing dental, oral, and craniofacial health outcome data from the RECOVER initiative.

So thank you, and now I will pass the stage to the next presenter, Dr. Yolanda Vallejo with NCATS.

DR. VALLEJO: Thank you Lillian. So, good afternoon everyone. I’m Yolanda Vallejo from the National Center for Advancing Translational Sciences, better known as NCATS, where I am a Program Director for The Clinical and Translational Science Awards and Trial Innovation Network. And I am here to tell you about how NCATS has been using a translational approach to address the COVID-19 pandemic and its neurologic effects.

So at NCATS our mission is to catalyze the generation of innovative methods and technologies that will enhance the development, testing, and implementation of diagnostics and therapeutics across human diseases and conditions, including those brought about by the COVID-19 pandemic.

As such, NCATS has been uniquely positioned throughout the pandemic to rapidly pivot efforts to support SARS-CoV-2 and COVID-19 research across the translational spectrum. We’ve done so by pivoting our robust preclinical platforms and technologies, developing research tools and resources, leveraging cross-cutting collaborations and partnerships, and using our networks to draw together experts with necessary and complementary skills and experience to enable projects to cut through operational roadblocks.

I’d like to tell you a bit about what our division of preclinical innovation, together with external collaborators, has been working on. They’ve been busy developing 3D tissue models, including human pluripotent stem cell derived brain organoids, indicating SARS-CoV-2 neurotropism in choroid plexus epithelium, and 3D lung tissue models to speed virus drug testing, as well as using new approaches like biological activity-based modeling to look at potential anti-SARS-CoV-2 agents whose activity profiles, not structures, predict activity against biological targets.

Our investigators have generated antiviral leads by tapping into the vast pool of data generated by hundreds of quantitative high throughput screening analyses run on NCAS’ in-house collection of more than 500,000 compounds and drugs.

And because one of NCATS’ objectives is to speed translation of effective therapies against the virus and disease it causes, we’ve developed a site in collaboration with active and industry partners called the Open Data Portal, to openly and quickly share COVID-19 related drug repurposing data and experiments for approved drugs. Users can sort by compounds or mechanisms, sort for activity in a particular assay or can download complete annotated datasets to run their own analyses.

Users can also access and download validated SARS-CoV-2 assay protocols to adapt or run experiments in their own labs. There’s a wealth of COVID-19 research information built into this site, so we encourage everyone to browse the open data portal or read more about the effort to determine how it might be able to help or enhance or guide your own research.

NCATS has also been leveraging existing resources such as the clinical and translational science awards program, better known as the CTSAs, and its trial innovation network. The CTSAs are a national network of approximately 60 medical research institutions that we call hubs that have local and regional partners and collaborators.

NCATS and many of the CTSA hubs have rapidly mobilized to address the pandemic in a multitude of ways, including managing COVID-19 multi-site trials run through the CTSA hubs focused on identifying treatments, including two of the NIH’s accelerating COVID-19 therapeutic interventions and vaccines, better known as the ACTIV Studies, as well as the convalescent plasma clinical trials.

NCATS and the CTSAs have also been leveraging our national presence in community engagement activities to expand the reach of NIH’s Rapid Acceleration of Diagnostics in Underserved Populations Program, and the Community Engagement Alliance Against COVID-19 Disparities Effort, better known as CEAL, as well as in deploying CTSA supported community engagement tools through NCATS’s Trial Innovation Network.

While the CTSAs have been central to many of the efforts I just mentions, NCATS has also harnessed their resources together with NIGMS’s institutional development award networks for clinical and translational research and the National Center for Data to Health to create the National COVID Cohort Collaborative, better known as NC3, to generate a secure national resource of the electronic medical record data from COVID-19 tested patients and make this real world data available to speed COVID-19 research, identify potential treatments and improve patient care.

Thus far over 60 institutions covering 49 out of 50 states have worked together to build this database and generate over 6.6 billion rows of data for more than 6.1 million patients with greater than two million of those being COVID positive patients.

The others are COVID negative and include COVID possible. Currently there are more than 200 projects using the enclave data underway, and access to the N3Cs is open to researchers, clinicians, and citizen scientists through data use agreements.

So some of you may be wondering how can data from so many sites be useful given the variation in common data models, such as those shown on the left, that are used across institutions. N3C has a comprehensive data ingestion and harmonization pipeline that includes data quality checks and transformation of different data models into a harmonized OMOP N3C dataset.

Examples of the types of EHR data that can be found within the N3C include but are not limited to demographics, lab results and vital, vaccine and medication data, comorbidities including neurological condition, and social determinants of health.

By integrating data from multiple sites, N3C enables researchers to explore questions with vastly more statistical power than is achievable at individual sites and apply machine learning methods. For example, N3C researchers examine data about patients, tests, and vitals on the first day they visited the hospital to identify factors that predict clinical severity. The top ten predictors are shown here. N3C researchers have also begun to generate an empirical definition of long COVID by mapping literature and patient reported outcomes to human phenotype ontology.

N3C also enables researchers with shared interests to analyze data within the data enclave and collaborate more efficiently through domain teams. Users can join or start an N3C domain team. I’ve highlighted two existing domain teams here in red that are focused on long COVID and neurology that may be of interest to folks in attendance today.

This slide simply highlighted some recent N3C related publications on COVID. If you’d like more information or would like to join the N3C please visit these sites. And lastly, I will mention that NCATS also participates with the NIH’s Researching COVID to Enhance Recovery initiative that recently published these two research opportunity announcements on mobile health and data repositories. Thank you for your attention, and I will now I believe pass it over to my colleague Sean from NHLBI.

DR. COADY: Thank you. It is an honor to speak here today on NHLBI’s interest in resources with respect to neurological and psychiatric effects of COVID-19. And I’d like to just start off with the NHLBI mission, and although as you could probably expect it’s rather heavily focused on prevention and treatment of heart, lung, and blood diseases, I do believe that there is an implicit recognition of the whole, and that in order to enhance the health of all that we really need to look beyond just the heart, lung, and blood domain. And to kind of emphasize that point I’d like to highlight a few critical questions from a couple of NHLBI strategic objectives.

So under normal biological function and resilience one of the clinical questions has to do with mechanisms and normal physiologic responses to environmental and neuropsychiatric social and other stimuli that predict homeostatic resilience and transition, and under objective two, newly discovered pathobiological mechanisms, the pathology that underlies vascular causes of cognitive decline, as well as mechanisms whereby social conditions and psychosocial stress contribute to the onset, progression, and morbidity of ischemic heart disease and peripheral arterial disease.

So what these examples are really suggesting is that neurologic and mental health conditions can act as risk factors or mediators for heart, lung, blood, and sleep disorders, or as outcomes as well. So there’s clearly a range of shared interest across neurologic and mental health spectrum that extend out to SARS-CoV-2.

So with that in mind I’d like to briefly highlight a few resources beginning with the MACS and WIHS combined cohort study. So just as a way of brief background, the MACS study, which is the Men’s AIDS Cohort Study, was initiated in 1984 enrolling HIV positive and HIV negative men reporting sex with men.

And then similarly the WIHS Study, the Women’s Interagency HIV Study, enrolled HIV positive and HIVE negative high-risk women beginning in 1993. So both of these studies were initiated by NIAID and under NIAID stewardship for several decades before being very recently shifted to NHLBI as HIV transition from an acute infectious disease to really kind of a chronic condition. And under NHLBI management the two separate studies have been combined, and thus you see the combined cohort study.

So four MACS and WIHS combined cohort study after a pause due to COVID in terms of examinations, those examinations are now restarting, and as part of this current wave there’s going to be an ongoing enrollment to enrich the cohort, with particular attention to southern black and Hispanic men. And the MACS/WIHS combined cohort study is a true trans-NIH project with 14 NIH ICs contributing to the project.

So as long ongoing prospective cohort studies, there’s a wealth of pre-pandemic phenotyping across the neurocognitive and the mental health domains, and I’ve listed out some of them here, I won’t go to reading them all. And then in terms of COVID, what MACS and WIHS combined cohort study has done is to deploy three waves of a questionnaire, focused both on COVID, but also on pandemic effects as well. And just some of the initial findings from the questionnaire waves.

So among the percent testing positive for COVID-19, there was a tendency for people living with HIV to have a higher positive test rate compared to those who were seronegative, and both women and men, with men reaching statistical significance. Another resource is the collaborative cohort of cohorts for COVID-19 research or C4R, which was much more eloquently presented by Lizzy Elsner than I could ever do, so I’ll just try to very briefly kind of refresh some memories.

So C4R is a collaborative of 14 cohort studies with a very racially and ethnically diverse sample, among more than 43,000 questionnaires that have been completed. And a major component of C4R is the harmonization of previously collected neurocognitive assessments.

And again, just extremely quickly, so what C4R is doing is they’re deploying two waves of questionnaires with a uniform adjudication of COVID-19 events, and then there’s also a sero survey for SARS-CoV-2 antibodies, primarily through home collection of dried blood spots.

And I’d be severely remiss if I didn’t both mention and thank our cofounding partners on this effort, NINDS and NIA, not only for the cofounding, but for the expertise amongst the program officials in managing this whole effort. So among the questionnaire domains within NC4R there’s what you’d expect in terms of COVID related questions that one would ask, but there’s also questions related to psychosocial factors from the pandemic itself and how those can be impacted by either pre-pandemic characteristics or COVID.

So similar to MACS and WIHS, these being long running observational cohort studies, there’s been very deep phenotyping within both the cognitive and mental health space, and you can see here that in terms of cognitive measures some of the cohorts that have done say lighter touches on cognitive measures as well as very deep touches on neuro psych measures, and five of our cohorts adjudicate mild cognitive impairment and dementia, and then with respect to psychosocial measures, several of our cohorts have conducted assessments within trait anger coping, loneliness, stress, and depression.

And finally, I’d like to conclude with TOPMed, which is NHLBI’s transnomics for precision medicine initiate. The goal of TOPMed is to integrate whole genome sequencing and other omics with molecular behavioral imaging, environmental and clinical data, to improve our fundamental understanding of biological processes that underlie heart, lung, and blood disorders.

And as you see here in terms of funded samples, there’s been more than 193 samples funded for whole genome sequencing and nearly 125,000 for other omics. And you can see here on the righthand panel the breakdown of the other omics that have been done in TOPMed.

And finally, to wrap things up this is the racial and ethnic diversity of ancestry within the whole genome sequencing, with Hispanic Latinos making up around 15 percent, African ancestry nearly over 30 percent, Asian ancestry nine percent, and then over here on the pie on the right the diversity within the RNA sequencing data including African Americans at nearly 20 percent and Hispanic Latinos at around 40 percent. And with that I thank you, and I will stop sharing now.

DR. GORDON: Thank you very much to all the institute representatives and directors on the call, on the zoom today, for their explication. We have a number of questions that folks have posted to the Q&A, and please feel free to post more, we have about 15 minutes in which to answer some of them. So if the panelists could turn on their videos and respond to the questions, just raise your hand if you want to answer one, but some of them are directed to specific people. This first one is not, although I suspect Walter you might be in a good position to answer it. There may be others as well.

In terms of research that would be focused on a treatment, is some of the issue, is there an issue about the lack of definition of the disease, and I assume by the disease we’re talking about the post-acute sequelae of COVID, there are so many heterogeneous symptoms, and you think it’s almost too soon to start looking at treatments until we understand what the disease is. Walter, do you want to take a stab at that?

DR. KOROSHETZ: I would say it is true that if you consider it as a disease, we don’t have a standard enough to develop a treatment. But on the other hand, that’s true about a lot of diseases, and what we try to do is to help the patient the best we can by working on developing symptomatic therapies, so I think that one thing we don’t know is what symptomatic therapies will be helpful in this population. If you just take exercise for instance, in people with MECFS there’s a concern that you exercise, you make them worse.

In this condition you would like to see if you could exercise people gradually, but we don’t know the answer. So that might be something that we could do right away. There may be other things, how do you help the sleep, how do you help the pain, and it would be symptomatic targeted therapies though at this point.

DR. GORDON: Here is a question for Dr. Langevin. You spoke today about the effects of emotional and mental stress on physiology and implications for long COVID. Could you please speak to whether physical stress, whether of a viral infection or otherwise, can have these same results, noting that many long haulers were not experiencing high levels of emotional and mental stress and yet have these symptoms. Can you talk about that Dr. Langevin?

DR. LANGEVIN: That is an interesting question. How do we think about stress? So if you think about stress as the stress response, it can be in response to a variety of different stressors, but there’s a common sort of denominator to this, activation of the HPA axis, there’s sympathetic response in acute stress and response to chronic stress.

So whatever the trigger is is probably a mixture of mental and physical, and physical aspects of stress can cause mental symptoms and vice versa. So you can’t really draw a line as to whether it’s a physical stress or a mental stress, it’s a common sort of pathway of response that is the stress response, which we understand a fair amount about. So I think it’s good to think about it that way as almost a mind and body type of thing.

DR. GORDON: Here is a question for Dr. Shum. Can you please speak to the common serious dental problems that COVID long haulers are experiencing for the first time in their lives, cracked teeth, teeth falling out, these are puzzling to patients but are also historically comment in the MECFS patient population.

DR. SHUM: These are anecdotal case reports, there have not been large observational studies to look at dental issues. We do read in the news about tooth loss, one could hypothesize, and it’s testable, whether there are neurological and vascular disturbances in the dental pulp that might lead to compromised dental health. So we really look forward to seeing data from the RECOVER initiative and oral health components so that we can gather data and build hypotheses and test those hypotheses and design interventions if needed.

DR. GORDON: Thank you. Dr. Koroshetz, there are a couple of questions that might be best addressed to you. I don’t know if you want to look them over and answer the one that you’d like to do before I choose someone else.

DR. KOROSHETZ: I see one here about antiviral clinical trials, Andrea might chime in.

DR. GORDON: The question is whether antiviral clinical trials could be useful for long COVID.

DR. KOROSHETZ: So I think there are two things that are on my mind. One is is there COVID still present in the body and would antiviral against COVID be helpful. I think the autopsy studies hopefully will get us an answer to that. There is this interesting anecdotal thing about people getting vaccinated and feeling better, and whether that’s pointing to the fact that there’s still virus around is a good question, although we don’t know for sure.

And the other one that’s out there in the public is the question of reactivation of EBV, Epstein Barr Virus, which occurs very commonly after viral infections, but since this looks a lot like infectious mononucleosis the question is is it the activation of EBV that is causing the symptoms, and again I think we need more data, but if that’s the case then an antiviral might be something to try. Angela, do you want to pipe in there?

DR. LERNER: I think it just speaks to the question of the underlying pathophysiology for long COVID and other post-acute sequelae. From my perspective I think we need to know more about the underlying biology before thinking would an antiviral against SARS-CoV-2 or any other virus be a logical approach.

DR. GORDON: The question is about vitamin D and whether vitamin D might be playing a role, and whether vitamin D levels are going to be considered as one of the things to measure as we go forward with these studies. Would anyone care to answer that?

DR. KOROSHETZ: There were some data in the beginning that low vitamin D levels were associated with poor recovery, but I think that there were supplement studies that showed no effect afterwards. But I think it’s probably something that could be looked at for sure.

DR. GORDON: What about migraine and neck pain, are they going to be studied? Apparently there is some evidence to suggest that these are common amongst long COVID patients. Are there going to be studies looking specifically at that, especially as they relate to theories of neurovascular inflammation?

DR. KOROSHETZ: I think that’s again in the cohort studies they may pick a certain area, I think headache is a big one that we have to answer what type of headaches. Sleep disorder is another one. Pain. But I think also there will be research around the world which is going to be going after these particular features of long COVID. So there are a lot of questions and mysteries out there, we need a lot of shots on goal to try to open up the door to treatments that work.

DR. GORDON: This one is more about the grant process. Is there a plan for NeuroCOVID specific RFAs or review sections with NeuroCOVID expertise, such as has been for NeuroHIV? OF course, the long COVID studies will be general, although a lot of focus on the nervous system and on neurological and psychiatric sequelae. But I don’t know if anyone would want to speak to, whether it would be Dr. Masliah or Dr. Koroshetz about whether there is some thought to specific RFAs in the area of neurological consequences.

DR. MASLIAH: I think definitely a number of RFAs in that regard, both in NINDS and NIA collaborating with NHLBI. I have not heard, and I don’t think there are any plans from CSR. The movement needs to have narrow COVID specific study sections similar to what we have for HIV. I mean at least for now the applications that are coming are being reviewed by the different already established neuro study sections.  I agree that maybe in the future as the number of applications grow and they become more complex there might be a need for that.

DR. KORALNIK: So Dr. Gordon, if I may since I asked a question, I’m Dr. Koralnik and I’m a neurologist heavily involved in NeuroCOVID research as you know, I want to applaud all the panelists and I really learned a lot this afternoon and yesterday as well. And I learned from Dr. Masliah that there’s a notice currently, the AG21016 to do neuro PASC research in older adults.

However as we learned today and yesterday the bulk of the non-hospitalized neuro PASC patients are between 20 and 60 years old, average age 40, and currently there is no specific mechanism to study those mechanisms or to fund research on those patients. We had the exchange in the chat with Dr. Koroshetz at that level as well. And so this is also echoing the question from Dr. Spudich who asked that at the previous session as well.

So this is a plea really for NIH to consider putting out RFAs that are neuropsychiatric specific, especially in this younger population of patient which is sorely needed, and also to have review section with expertise in the topic, which is nonexistent at this point. This is not revolutionary because it has been done for NeuroHIV in the past as well.

And as you know the PASC ROA is funding large cohorts of preexisting cohort, which are led mainly by epidemiologists, symptomologists and cardiologists, and I have the highest respect for those people, but do we want those cardiologists and pulmonologists to decide what type of neurological evaluation needs to be done in those patients, or do we want to involve neurologists who have an existing cohort of neuro PASC patients at least to have a seat at the table?

DR. GORDON: I think we appreciate the input. Just to clarify one thing regard to the expectations, because of the authority under which the PASC studies are being setup, the expectations for monitoring and for measuring neurologic and psychiatric consequences are not being left up to the applicants and are being negotiated in a collaborative way with NIH and with the appropriate expertise. But I think it’s still a good question for Dr. Koroshetz if you want to respond in some way about the need for targeted studies in the neurologic and psychiatric realm, I think we’ve all spoken to you about the institute specific efforts we have in that way.

DR. KOROSHETZ: Yes, as I started off I think that it is not entirely clear how much RECOVER will cover, but my suspicion now is that it’s not something that we can depend upon to solve all our questions, and that the institutes are going to have to fund the pieces that they’re most interested in, and with RECOVER we have the flexibility of moving things in and out, but as Igor said they do have people who have neurologic expertise in each of the teams, but to push for neuro and psychiatric components of RECOVER, since it’s a negotiation, so I recently put my foot down when they didn’t have spinal fluid as one of the things that they’re going to collect, I said you’ve got to have spinal fluid, and they went back and they put it in. But it’s that kind of negotiation that’s going on now.

DR. GORDON: So I thank everyone for their questions and all the panelists for their patient responses and for presenting on each institute’s interest in these areas. I think we’re out of time now. Someone did ask when the reporting of the two-day conference will be available, so I’m hoping one of the organizers can post that information into the chat so that everyone can see it. And I’m going to turn it over to I believe Dr. Diane Rausch who is going to close it out.

Agenda Item: Closing Remarks

DR. RAUSCH: Thanks everyone. First, I want to also thank all the speakers and panelists and the NIH leadership and meeting organizers for putting this really important informative two-day meeting together. So Serena, Avi, Eliezer, and Jeymohan, great job. Sigmund, I had a few comments just to wrap up, a significant amount of data presented today targeting all aspects of the long-term effects of SARS-CoV-2 infection, including pathophysiology and psychopathology, so just a few comments to summarize.

So we heard a lot about the virus and immune mediated pathophysiologic mechanisms that were addressed using state of the art technologies that are potentially involved in driving neurologic and psychiatric effects of SARS-CoV-2 infections.

We also heard about some other comorbidities such as MS and HIV infection, as well as some other noroviruses that were discussed comparing some common and unique symptomatology and underlying biological mechanisms. Several resources were identified, including cohorts, registries, and biobanks, and we encourage everyone to take advantage of these and establish collaborations.

We heard about global efforts relating to NeuroCOVID ID from the WHO, as well as on the ground events in India where the pandemic has had a devastating impact. It was really interesting to hear the patients’ perspectives, the description of the range and extent of the impact on daily life and function was very powerful.

The news media reports on their experience with long-haul NeuroCOVID symptoms really highlighted the continued need for research in this area. Issues of racial disparity and increased risk for NeuroCOVID and access to care were highlighted, and this is extremely important and timely, and more work needs to be done to address this issue.

Because all the presentations provided by NIH leadership outline the priorities, resources, and initiatives of the 12 institutes, we particularly want to thank Dr. Gordon and Dr. Koroshetz for leading this discussion, and we thank all the participants. We encourage you to reach out to the individual ICs for more information on your specific interests.

The panel discussions identified key gaps and priorities that emerged from these two days of meetings, and we will be preparing a meeting report to summarize these discussions and important next steps. The timing of that publishing is a little unclear, but we will keep putting information out on the website as we get it.

And just a final note, the complexity of this disease as we have seen over the past two days really enforces the need for communication and collaboration across all disciplines, including populations affected, to continue to share data and findings in a timely manner and to collaborate. And from the NIH perspective we’re always eager to foster collaborations whenever we can. So on that note gain I’d like to thank everybody and have a good night.