NAMHC Concept Clearance •
Stacia Friedman-Hill, Ph.D.
Chief, Mechanisms of Cognitive Dysfunction Program and Trajectories of Neurocognitive Functioning Program
Division of Developmental Translational Research
This initiative aims to support a collaborative, multi-site, prospective longitudinal study to track neurodevelopmental trajectories and to collect biomarkers in children and adolescents at high risk for psychosis by virtue of having 22q11.2 deletion syndrome (DS).
It is widely accepted that schizophrenia involves pathological neurodevelopment, possibly due to prenatal abnormalities combined with dramatic changes in adolescence and early adulthood. Elucidating the interplay of genetic and environmental risk and characterizing early neurodevelopmental trajectories of psychosis has been challenging. Familial risk for schizophrenia results in psychosis in a very small proportion of offspring and siblings. 22q11.2 DS provides an opportunity to investigate trajectories of risk, because approximately 30% of patients with this genetic syndrome experience psychosis. NIMH has supported several longitudinal imaging studies of brain and behavioral development in individuals with 22q11.2 DS. These studies are uncovering significant differences in cortical structure and function between individuals with 22q11.2 DS and age-matched typically developing adolescents. Additionally, changes in neuroimaging measures over time have been correlated with changes in neurocognition in individuals with 22q11.2 DS. However, because 22q11.2 DS is a rare disorder, each individual neuroimaging study lacks sufficient power to compare neurodevelopmental trajectories of patients who eventually convert to psychosis with those who do not. Another limitation due to constraints on recruitment has been that study groups have tended to include wide age bands. The proposed coordinated multi-site study would be designed to ensure a well-powered, prospective, multi-modal (involving a variety of imaging technologies), longitudinal study. Starting in preadolescence, the study would determine neurocognitive and neurodevelopmental trajectories and how these are shaped by potential moderators and mediators, such as stress, puberty, social and emotional support, and genomic factors of risk (high penetrance within the deleted region) and resilience (modifiers outside the deleted region).
The proposed initiative would complement other NIMH efforts and would be in a position to leverage genomic findings. The proposed initiative would also be informed by NIMH investments in non-22q11.2 DS individuals with psychosis or in the prodromal stage; working hypotheses would include investigation of whether predictive biomarkers identified in the North American Prodrome Longitudinal Study (NAPLS II) or the Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) are also associated with future clinical symptoms when assessed in pre-prodromal individuals with 22q11.2 DS.
A successful initiative would result in a cooperative award with multiple research groups joining forces to characterize neurodevelopmental trajectories of risk and resilience in a large sample of subjects with high genetic vulnerability for psychosis, due to 22q11.2 DS. The large sample size would allow investigators to examine sensitive periods, identify biosignatures for risk and disease onset or progression, compare biomarkers in individuals with 22q11.2 DS to those found in individuals with schizophrenia and other neuropsychiatric disorders, and uncover factors such as stress or family environment which may interact with genomic risk. An additional goal would be harmonization of clinical assessments, neurocognitive measures, and neuroimaging protocols across 22q11.2 DS and the non-22q psychosis spectrum. Through coordination with existing data repositories, this initiative would also strive to establish a widely shared, open-access dataset of neurocognitive and neuroimaging measures from individuals who represent the entire psychosis spectrum (22q and non-22q), including those at risk and in the early stages of pathology.