White Matter Abnormalities in Schizophrenia

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DESCRIPTION (provided by applicant): The proposed Mt. Sinai Conte Center for the Neuroscience of Mental Disorders (CCNMD) is designed to be a highly focused effort to elucidate the role of white matter, oligodendrocytes and myelin in schizophrenia. This proposal is informed by increasing evidence of white matter abnormalities in schizophrenia in a variety of areas of scientific exploration. A failure in connectivity has been demonstrated to have a role in schizophrenia. Myelination and those factors that affect myelination, such as the function of oligodendroglia, are critical processes that could profoundly affect neuronal connectivity, especially given the diffuse distribution of oligodendrocytes and the widespread distribution of brain regions that have been implicated in schizophrenia. Multiple lines of evidence now converge to implicate oligodendroglia and myelin in schizophrenia. Imaging and neurocytochemical evidence, similarities with demyelinating diseases, age-related changes in white matter, myelin-related gene abnormalities, and morphological abnormalities in the oligodendroglia demonstrated in schizophrenic brains, all contribute to a hypothesis that oligodendroglial dysfunction and even death, with subsequent abnormalities in myelin maintenance and repair, contribute to the schizophrenic syndrome (see overview and specific projects for detailed references). A broad set of methodologies and expertise will be brought to bear on the questions the CCNMD will pursue, including neuroanatomy, neuroimaging, molecular biology, molecular genetics, neuropsychology, phenomenology, statistics, and data management. The CCNMD is comprised of 4 Cores: Core A: Administrative; Core B: Clinical; Core C: Brain Bank; Core D: Data Management and Statistics. The projects of the CCNMD include: Project 1 which will quantify alterations in both numbers of and spatial distribution of oligodendroglia in the brains of schizophrenic patients, focusing on cortical, thalamic, and predominantly white matter areas. Project 2 is based on microarray findings by the laboratory of Dr. Buxbaum of decreased expression of 6 myelin-related genes in the dorsolateral prefrontal cortex of a subgroup of relatively treatment refractory patients. Project 3 examines genes involved in myelination for DNA sequence variation affecting protein sequence and expression in order to assess the possibility that some of these variants are involved in determining susceptibility to schizophrenia. Project 4 brings powerful neuroimaging techniques- diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI)- to the study of white matter in schizophrenia. Project 5 applies proton magnetic resonance spectroscopy (1 MRS) to white matter areas in the brains of schizophrenic patients.