ALZHEIMERS RESEARCH PROJECT: Primate Models of Neurocognitive Aging

National Institute On Aging

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Abstract

Our earlier neuropsychological survey was the largest to date in rhesus macaques, collected from over 100 young adult and aged animals of both sexes, ranging from ~3 to over 30 years of age, assessed in multiple cohorts across several decades. The findings confirmed that, as in rats and humans, marked overall cognitive decline is not an inevitable consequence of advanced age. Indeed, among old monkeys 19 to more than 30 years, chronological age itself is an unreliable predictor of cognitive integrity. In addition, while tests measuring prefrontal cortical and medial temporal lobe function both reveal significant age-related deficits in between-group comparisons, impairments in these domains are independent of each other. Rather than a diffuse process of non-specific deterioration in cognitive aging trajectories, these findings point to striking selectivity in kind and degree, presumably reflecting individual differences in the cell and circuit vulnerabilities that underly these outcomes. Primate research in neurocognitive aging is founded on a rich bacground of clinical and experimental data detailing the consequences of damage involving specific brain regions and circuitry. Normal explicit/declarative memory, for example, is generally understood to require a system of medial temporal lobe (MTL) structures that includes the hippocampus and anatomically related entorhinal, perirhinal and parahippocampal cortex. However, while extensive MTL damage in primates causes robust anterograde amnesia, defining the contribution of the hippocampus itself has proved challenging. The issue is an important one for the study of aging because early detection of compromised functional integrity in vulnerable regions like the hippocampus is a key goal for developing effective interventions. We revisited this long-standing puzzle using a substantial body of archival data directly addressing a number of factors suspected to contribute to conflicting results across earlier studies. Among them, we explored the effects of selective hippocampus damage produced by two common excitotoxin methods. Sample sizes were substantial and all behavioral testing was conducted postoperatively. Performance was assessed on several standard procedures designed for macaques, including multiple variants of the delayed nonmatching-to-sample test of visual object recognition, a series of rapidly acquired two-choice object discriminations, and a delayed response test of spatiotemporal memory. Task-specific parametric manipulations (e.g., increasing retention intervals, and reduced stimulus set size) systematically varied demands on memory, and test/retest analyses enhanced sensitivity for detecting impairment. Despite substantial hippocampal damage, performance failed to differ from that of intact controls on any task, under any test condition, and regardless of data analytic strategy. The findings constrain plausible accounts of discrepancies in the extant literature, and moreover, highlight that research on neurocognitive aging will benefit from developing fresh perspectives on the core operating characteristics of memory mediated by the primate hippocampus.