Effects of PER3 clock gene polymorphisms on aging-related changes of the cerebral cortex

Considerable evidence suggests that circadian rhythmicity is progressively disrupted in senescence. Among clock genes, Period3 (PER3) has been associated with circadian phenotypes, homeostatic regulation of sleep, and cognitive performance in young adults. However, the effects of PER3 genotype on aging-related changes in both cognitive function and cortical integrity remain largely unknown. To shed light into this issue, we have investigated differences in cognitive performance, patterns of cortical thickness, and cortical glucose consumption in normal elderly subjects homozygous carriers of the short (PER3^4/4, n = 32) and long repeat alleles (PER3^5/5, n = 32). Relationships between cognitive performance and cortical thickness/metabolism were further explored for each PER3 genotype. We found that PER3^5/5 carriers had poorer cognitive performance (attention, executive function, semantic memory, and verbal fluency) and lower cortical integrity (structural and functional) than PER3^4/4. PER3^5/5 further showed thinning of temporo-parietal areas, and reductions of glucose consumption in fronto-temporo-parietal regions bilaterally. Moreover, PER3^5/5 subjects exhibited significant correlations between decreased glucose metabolism in fronto-parietal regions and poorer cognitive flexibility, though only correlations with lower glucose consumption of the supramarginal gyrus distinguished PER3^5/5 from PER3^4/4 groups. Overall, these findings enhance our understanding on the gene-brain interaction in aging, and may have further implications for the detection of subclinical cognitive decline associated with PER3 genotypes in late life.