PROGRESSIVE BRAIN TISSUE LOSS IN MONOZYGOTIC AND DIZYGOTIC TWIN PAIRS DISCORDANT FOR SCHIZOPHRENIA

Abstract

Structural neuroimaging studies in COS show profound parietofrontal cortical GM loss during adolescence in a pattern that appears exaggeration of the normal GM maturation. At longer term follow up the GM loss slows with age and gets circumscribed to prefrontal and superior temporal cortices(n=84,197 scans vs controls n=86, 220 scans; age range 8-28 yrs), mimicking a pattern seen in adult onset schizophrenia. Longitudinal analyses on healthy COS siblings (n=85,170 scans) also show prefrontal and temporal GM deficits in early ages, which normalize by age 20, suggesting that the GM trajectory itself could be a trait marker. Candidate gene analyses support these observations. For example, initial analyses comparing GM development in 75 COS subjects (176 scans), 44 healthy siblings (92 scans) and 166 healthy controls(402 scans) showed that COS subjects and their healthy siblings with val-COMT allele had accelerated GM loss across prefrontal, cingulated and temporal cortices compared to matched healthy controls who in contrast showed negative GM slow with the met-COMT genotype, suggesting the influence of individual risk genes or cortical GM development in schizophrenia. Sub regional cerebellar maps in 85 COS subjects (206 scans), 78 healthy siblings, and 95 matched healthy controls (225 scans) show significant 'sub regional' decline in volume with age, while the vermal regions showed fixed deficits. The volume loss is shared by healthy COS siblings in the posterior inferior cerebellar regions (compared to the same set of controls) suggesting the trait nature of these changes at sub regional level. Finally, it is important to understand the progressive nature GM changes in the context of underlying white matter (WM) development. Our recent 3-Dmaps of localWMgrowth rates in 12COSpatients and 12 healthy controlsmatched for age, gender and scan interval, over a 5-year period, showup to 2.2% slowerWMgrowth per year in COS(P=0.02, all P-values corrected). The deficits appear early in the frontal regions and later in the parietal regions suggesting a progressive abnormality that follows thenormal front to backWMdevelopmental pattern. In addition tohighlighting significantWMgrowthdeficits inCOS, these findings also suggest that the cortical GM loss in schizophrenia is unlikely to be the result of WM encroachment.