January 14, 2011
Pathophysiology of HIV-Associated Neurodegeneration in Aging Populations on Long-term Anti-Retroviral Therapy
NAMHC Concept Clearance
Dianne Rausch, Ph.D.
Deputy Director, Center for Mental Health Research on AIDS
Division of AIDS Research (DAR)
This initiative will support research on elucidating mechanisms of neuropathogenesis of HIV-Associated Neurocognitive Disorders (HAND) in the aging population, in the setting of long-term treatment and associated neurodegenerative diseases and co-morbid conditions.
Over the past few decades, there has been a dramatic increase in the number of older persons living with HIV infection and/or AIDS. This increase derives from two sources: (1) a growing number of cases newly diagnosed in older persons; and (2) recent improvements in antiretroviral therapy (ARV), with individuals diagnosed at younger ages surviving into older age. From 2000 to 2004, the Centers for Disease Control and Prevention (CDC) report that the proportion of AIDS patients 50 years of age and older rose from 19 percent to 27 percent, and the number of older adults 50 years of age and older living with HIV infection and/or AIDS more than doubled. Thus the number of older people with HIV/AIDS is expected to increase even further during the next decade, as this younger group survives with current treatment and moves into the older age group. It is projected that by 2015, more than half of all HIV-infected individuals in the United States will be over the age of 50.
Despite the widespread use of ARV, the prevalence of HAND remains high. The pathophysiology of HAND may be distinct in aging HIV-infected populations because of potential interaction between aging-associated events, HIV-associated neurodegenerative processes and long term anti-retroviral treatment. It is possible that chronic HIV infection and inflammation may accelerate aging and associated neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Long-term ARV treatment also exacerbates aging-associated co-morbid conditions, such as cerebrovascular disease resulting from hypercholesterolemia and diabetes. These vascular events could have significant impact on cognitive decline seen in HAND. This initiative will support research on elucidating mechanisms of neuropathogenesis of HAND in the aging population in long term-treatment and associated neurodegenerative diseases and co-morbid conditions.
Expected Outcomes/Indicators of Success
The ultimate goal is to define novel mechanisms of pathogenesis driving neurocognitive decline at the intersection of HIV-associated neurodegenerative processes, aging associated CNS disease, chronic ARV treatment effects and host susceptibility factors. Examples include:
- Elucidate the pathways leading to dysregulated expression of amyloid-beta, amyloid precursor protein, tau and synuclein as a result of chronic HIV infection/inflammation and long term anti-retroviral therapy;
- Study the impact of HIV on autophagy and clearance of misfolded proteins in neurodegenerative processes;
- Develop novel animal models to study the effects of HIV and aging related factors in neurodegenerative processes;
- Study the mechanism of action associated with HIV and treatment effects and aging-related co-morbid conditions (diabetes, hypercholesterolemia) on cerebrovascular factors that cause neurocognitive impairment; and,
- Define host genetic factors that alter susceptibility to accelerated HIV-associated aging events that have an impact on neurocognitive outcomes.