Endophenotypic markers provide a crucial link to the underlying genetic makeup of an individual. Many studies have now reported findings in family members of schizophrenics consistent with the strongly suspected genetic basis of this disease process. While we know that markers for schizophrenia occur in relatives, we do not have a clear grasp of why some subjects with certain traits develop schizophrenia, while others with the same traits do not. By looking at the differences between schizophrenics and close relatives who express certain endophenotypes, but who do not develop the disease, we may be able to identify processes that differentiate the two populations. Our long-range goal is to be able to reliably detect those at risk for development of schizophrenia, so that proper treatment can be targeted at those who need it. The objective of this application is to study a population of schizophrenics and their first-degree relatives, and correlate abnormal measures on ratings scales and neuropsychological tests with changes in cerebral structural changes, as well as activity during functional MRI scanning of a working memory test. We hypothesize that there will be a range of frequency of deficits on clinical ratings and cognitive tests that correlates with abnormalities in brain structure and function. Relatives with significant clinical symptoms and cognitive deficits will have similar but less numerous deficits in brain structure and function than their schizophrenic probands, but more so than first-degree relatives with no such deficits, who will be similar to normal control subjects.
Our first aim i s to determine the degree of changes in cognitive deficits and clinical symptoms in our subjects. We expect that about 30-66% of first-degree relatives will have specific deficits in working memory, attention, and visuomotor processing that are similar to but less severe and less numerous than schizophrenics. We will also determine the cerebral structural correlates of clinical symptoms and cognitive tests. We expect that first-degree relatives with poorer cognitive performance will have more structural brain abnormalities as measured with voxel-based morphometry.
A final aim examines the functional cerebral correlates of a cognitive test of working memory. We predict that the degree of poor performance will be related to the amount of abnormal brain activity in the patients and affected relatives, and that regional connectivity will be proportionately disturbed as well. ? ?
