Up to 50% of all individuals over age 85 have a measurable decline in cognitive function. Cognitive decline reliably predicts the imminent development of functional cognitive impairment, and therefore its early detection provides an opportunity for cost-effective proactive planning and therapeutic intervention. As the US population rapidly ages, the need for more accurate early diagnostic and prognostic measures becomes an increasingly compelling issue. Our clinical collaborators at OHSU have recently shown that it may be possible to predict functional cognitive impairment by monitoring changes in motor function as well as declining cognitive function. Indeed, they have found that simple motor measures provide one of the best predictors of progression to dementia. Currently, the mechanisms linking motor decline and cognitive loss are poorly understood, in part due to the lack of appropriate experimental animal models. To help overcome this problem, we propose to conduct a series of experiments using the rhesus monkey (Macaca mulatta). Like humans, this primate shows cognitive decline during aging and, equally important, it can be maintained under carefully controlled environmental conditions (e.g., diet, temperature, photoperiod, medication, and sex-steroid exposure). In the proposed pilot study, we will assess cognitive function using the delayed response test of spatial working memory, the delayed non-matching-to-sample test of recognition memory, and complex reaction time; we will assess motor speed with a simple reaction time task, fine motor function with food retrieval tasks, locomotor function with videotracking analysis of spontaneous and motivated locomotion, and circadian activity and sleep quality indices with continuous home cage monitoring. These measures will allow us to test the hypotheses that age-associated motor decline and circadian rhythm disruption are closely correlated with concurrent age-associated cognitive decline. Furthermore, experiments will be repeated several times across the two-year testing period to provide preliminary data on longitudinal changes and predictive relationships. The proposed pilot study represents a rapid and cost-effective way of establishing whether the rhesus monkey can act as a pragmatic animal model for future mechanistic studies and development of treatment strategies. Moreover, the data will be of immediate relevance and value to clinical collaborators at OHSU, who are planning the development and implementation of related human studies, as well as others studying human cognitive aging. ? ? ?
