NEUROIMAGING SIGNATURE OF DOPAMINE SYSTEM COMT GENOTYPE IN OLDER ADULTS

Abstract

Robust dopaminergic signaling is key for proper function in several brain regions susceptible to degeneration in Alzheimer's disease (AD). Dopamine is catabolized by the enzyme catechol-O-methyltransferase (COMT), which is coded by the COMT gene. It would be expected that val allele homozygotes of the COMT gene, indicating lower dopamine levels, would have steeper declines in cognitive performance with aging than met allele carriers. However, results to date are conflicting, and therefore we aimed to investigate the neuroimaging mechanisms of this association. Gray matter volumes (GMV) were obtained from T1 weighted MRIs carried out at the University of Pittsburgh Magnetic Resonance Research Center. Intracranial volume was defined as the total volume inside the skull. Mediotemporal and frontostriatal regions of interest (ROIs) were selected for analysis based on the importance of dopaminergic signaling in those areas and their implications in AD. Using ANCOVA we evaluated the relationship of COMT genotype with GMV in the ROIs of interest in older adults in the Health, Aging, and Body Composition Healthy Brain sub-study (N=314; median age =82.0; 57.6% female, 40.5% Black, 85.7% at least high school education). In sex-stratified ANCOVA models adjusted for race and intracranial volume, met/met genotype was associated with greater gray matter volume in males, but not females, in left and right parahippocampi (p=0.025 and p=0.045 respectively). Other associations were ns (p>.05). The COMT genotype may indicate subgroups with varying levels of protection against brain atrophy in brain regions implicated in Alzheimer's disease. Future sex-stratified longitudinal assessments of neuroimaging markers are needed to evaluate longitudinal changes in brain volume in relationship to COMT genotype.