We propose to continue a line of research, enabled by an NIMH Merit Award, which has been testing hypotheses about neurobiologic manifestations of schizotaxia (the predisposition to schizophrenia) among schizophrenic patients and the nonpsychotic adult relatives of schizophrenic patients. Our work-showing that schizotaxia is associated with negative symptoms, neuropsychological dysfunction and structural brain abnormalities-converges with data from other centers to show that schizotaxia is a subtle brain disorder affecting about 20 to 50 percent of the nonpsychotic relatives of schizophrenic patients. The data collected during prior funding periods have allowed us to demonstrate a) neuropsychological deficits in schizophrenic patients and their relatives, b) gender differences in the expression of these deficits, c) stability of these deficits over time, d) structural brain abnormalities in patients and relatives, e) functional MRI abnormalities in patients and relatives, and f) how the psychometric features of neuropsychological tests make them useful for assessing phenotypes in genetic linkage studies of schizophrenia. We have decided to pursue three major aims in this continuation proposal that will help us better understand the neural substrates of schizotaxia and how they lead to schizophrenia. First, we will identify predictors of social dysfunction and psychopathology in adolescent children of schizophrenia patients. Second, we will better describe the neural substrate of schizophrenia prior to the onset of psychosis and lay the foundation for work that will examine if neurodegeneration occurs after illness onset. Third, we will establish the infrastructure required to monitor adolescents at risk for psychosis so that future proposals can select adolescents at risk for schizophrenia for prevention protocols. To accomplish these aims, we will assess 300 adolescent children of schizophrenic patients (ACSZ) and 50 normal controls with neuropsychological, psychosis proneness, psychosocial functioning, and family adversity measures. All controls and 150 randomly selected ACSZ will also be evaluated with magnetic resonance imaging. All 350 subjects will be monitored for adverse outcomes at six month intervals. Given the wide age range for the onset of schizophrenia, we plan to follow this sample for many years. Thus, we will also lay the foundation for future proposals that will monitor the incidence of psychosis in this sample through young adulthood. This will eventually allow us to assess 1)the predictive validity of schizotaxia measures and environmental adversity for subsequent psychosis and 2)longitudinal changes in neuro-psychological functioning and brain structure in subjects who do not become psychotic. Achievement of the second goal will help clarify which brain abnormalities in schizophrenic patients can be attributed to neurodevelop-mental events prior to onset and which are due to neurodegeneration after onset.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH043518-13
Application #
6186661
Study Section
Special Emphasis Panel (ZMH1-CRB-B (05))
Program Officer
Heinssen, Robert K
Project Start
1988-04-01
Project End
2004-01-31
Budget Start
2000-08-01
Budget End
2002-01-31
Support Year
13
Fiscal Year
2000
Total Cost
$595,987
Indirect Cost
Name
Harvard University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
Brent, Benjamin K; Rosso, Isabelle M; Thermenos, Heidi W et al. (2016) Alterations of lateral temporal cortical gray matter and facial memory as vulnerability indicators for schizophrenia: An MRI study in youth at familial high-risk for schizophrenia. Schizophr Res 170:123-9
Manschreck, T C; Chun, J; Merrill, A M et al. (2015) Impaired motor performance in adolescents at familial high-risk for schizophrenia. Schizophr Res 168:44-9
Auther, A M; Cadenhead, K S; Carrión, R E et al. (2015) Alcohol confounds relationship between cannabis misuse and psychosis conversion in a high-risk sample. Acta Psychiatr Scand 132:60-8
Seidman, Larry J; Hellemann, Gerhard; Nuechterlein, Keith H et al. (2015) Factor structure and heritability of endophenotypes in schizophrenia: findings from the Consortium on the Genetics of Schizophrenia (COGS-1). Schizophr Res 163:73-9
Seidman, Larry J; Rosso, Isabelle M; Thermenos, Heidi W et al. (2014) Medial temporal lobe default mode functioning and hippocampal structure as vulnerability indicators for schizophrenia: a MRI study of non-psychotic adolescent first-degree relatives. Schizophr Res 159:426-34
Walder, Deborah J; Faraone, Stephen V; Glatt, Stephen J et al. (2014) Genetic liability, prenatal health, stress and family environment: risk factors in the Harvard Adolescent Family High Risk for schizophrenia study. Schizophr Res 157:142-8
Light, Gregory; Greenwood, Tiffany A; Swerdlow, Neal R et al. (2014) Comparison of the heritability of schizophrenia and endophenotypes in the COGS-1 family study. Schizophr Bull 40:1404-11
Scala, Silvia; Pousada, Andrea; Stone, William S et al. (2013) Verbal and visual-spatial memory impairment in youth at familial risk for schizophrenia or affective psychosis: a pilot study. Schizophr Res 144:122-8
Cornblatt, Barbara A; Carrión, Ricardo E; Addington, Jean et al. (2012) Risk factors for psychosis: impaired social and role functioning. Schizophr Bull 38:1247-57
Piskulic, Danijela; Addington, Jean; Cadenhead, Kristin S et al. (2012) Negative symptoms in individuals at clinical high risk of psychosis. Psychiatry Res 196:220-4

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