Imaging and Genetics Investigations in Schizophrenia and Aging: A Focus on White Matter

Schizophrenia has long been considered a disorder of impaired brain connectivity, and such disconnectivity might be due to disruption of white matter tracts that connect brain regions. This thesis investigates the oligodendrocyte/myelin/white matter pathway in schizophrenia in vivo, and also considers aging effects, as similar substrates are affected during the healthy aging process. In study one, association of oligodendrocyte/myelin genes is examined with schizophrenia, and in study two association of a myelin gene is examined with basic MRI volumetric phenotypes. Then, in study three, diffusion tensor tractography, a technique that can visualize and measure white matter is applied, and is shown to be reliable in healthy controls and schizophrenia patients using a novel clustering segmentation method. In study four, this method is then used to examine interaction of schizophrenia and aging with respect to white matter, where fronto-temporal disconnectivity is demonstrated in younger chronic schizophrenia patients, but not in elderly community dwelling schizophrenia patients compared to age-matched controls. In study five, relationships among age, white matter tract integrity, and cognitive decline in healthy aging are demonstrated using diffusion tensor tractography and structural equation modeling. Genetics and neuroimaging are then combined using the intermediate phenotype approach in study six to demonstrate a key role for the BDNF gene across adult life in healthy aging. In these individuals, the BDNF val66met variant influenced neural structures and cognitive functions in a pathological aging risk pattern. Finally, in study seven, complex relationships are then demonstrated among oligodendrocyte gene variants, white matter tract integrity and cognitive performance in both healthy controls and schizophrenia patients. The combination of genetics and neuroimaging can parse out heterogeneity of disease phenotypes, and characterize the effects of gene variants on at-risk neural structures and cognitive functions in healthy and disease populations.Ph