Alzheimers Disease Project: Primate Models of Neurocognitive Aging

National Institute On Aging

Investigators

Linked publications, trials & patents

Abstract

Research in this project is founded on a long history of investigation on the neural systems organization of memory, executive function and other cognitive capacities. Informed by this neuropsychological framework, we recently aggregated findings from multiple cohorts of young and aged rhesus monkeys tested on a standardized battery of cognitive tasks known to differentially depend on the prefrontal cortex and the hippocampus and related brain regions comprising the medial temporal lobe memory system. The results establish population norms for the largest sample published to date, comprising over 100 young adults (n=34, 4-14 years) and animals aged 20 to over 30 years (n=71). Neuropsychological testing included 3 well-characterized assessments designed for monkeys; a delayed response (DR) test of spatiotemporal working memory, the delayed nonmatching-to-sample visual (DNMS) object recognition task, and a series of object discrimination (OD) and retention tests. Among the key findings, whereas aged subjects scored poorly relative to young on all 3 tasks, there was no relationship between performance measures that reflect prefrontal cortex function, and memory capacities that depend on the medial temporal lobe. The implication is that aging impacts these cognitive capacities independently, rather than as a global aging process that links outcomes across distinct functional domains. In addition, sex and chronological age were generally unreliable predictors of individual differences in cognitive outcome among the aged subjects. Together the results establish normative features of aging important for efforts to probe region and circuit specific alterations in the aged primate brain that mediate cognitive impairment and resilience to decline. Magnetic resonance imaging provides a non-invasive and translation-amenable means of evaluating age-related differences in primate brain structure and functional connectivity associated with individual differences in the cognitive outcome of aging. In one recent analysis, we took advantage of the nonhuman primate model described above in an unbiased, brain-wide survey of regional volumes in young and aged animals, identifying significant regional correlations with object recognition memory performance. For young adults, volumetric correlates of task acquisition and forgetting rates prominently involved precisely the medial temporal lobe regions known to be critical for memory, i.e., the hippocampus and laterally adjacent rhinal cortical areas. Less expected, the cerebellum was also a significant correlate of task performance. Memory in aged subjects, by comparison, was coupled with prefrontal cortex and striatal structure. Our results suggest the possibility that the regional distribution of regional volumes coupled with memory is reorganized over the lifespan, consistent with the perspective that the capacity for structural reorganization in the primate brain persists into old age. Prompted by our findings, a recently published study tested the translational validity of our observations in monkeys using data from the Baltimore Longitudinal Study of Aging. In that analysis linear mixed models and partial correlations were used to test for associations between changes in cerebellum volume and memory during aging. Together the findings suggest that the relationship between cerebellum volume and memory decline is age-dependent and regionally selective. An important future direction is to explore the possibility that the cerebellum mediates the prominent link between decline in physical function and cognitive aging reported in clinical research.