Objective: To assess the contribution of dementia-related neuropathologic lesions to age-related and disease-related change in cognitive function. Methods:A total of 354 Catholic nuns, priests, and brothers had annual clinical evaluations for up to 13 years, died, and underwent brain autopsy. The clinical evaluations included detailed testing of cognitive function from which previously established composite measures of global cognition and specific cognitive functions were derived. As part of a uniform neuropathologic evaluation, the density of neurofibrillary tangles was summarized in a composite measure and the presence of Lewy bodies and gross and microscopic cerebral infarction was noted.Results: During follow-up, rate of global cognitive decline was gradual at first and then more than quadrupled in the last 4 to 5 years of life consistent with the onset of progressive dementia. Neurofibrillary tangles, cerebral infarction, and neocortical Lewy bodies all contributed to gradual age-related cognitive decline and little age-related decline was evident in the absence of these lesions. Neurofibrillary tangles and neocortical Lewy bodies contributed to precipitous diseaserelated cognitive decline, but substantial disease-related decline was evident even in the absence of these lesions. Conclusion:Mild age-related decline in cognitive function is mainly due to the neuropathologic lesions traditionally associated with dementia. Neurology Much cognitive loss in old age is limited to very subtle decline evolving slowly over a period of years. The neurobiologic mechanisms underlying these changes are not known. Traditionally, this gradual age-related decline has been attributed to normative developmental processes and distinguished from the precipitous cognitive decline attributed to pathologic processes such as those underlying Alzheimer disease (AD) and other common dementias. However, few clinical-pathologic studies have examined the relation of pathologic indices to change in cognitive function over time, 1,2 and none of these has separated slowly progressive age-related change from more rapid disease-related decline. Thus, knowledge about the contribution of common neurodegenerative lesions to cognitive aging is limited.In the present study, we test the hypothesis that the neurodegenerative lesions associated with late-life dementia, including AD pathology, cerebrovascular disease, and Lewy bodies, contribute to age-related cognitive decline. The hypothesis is based on the observations that these neuropathologic lesions are commonly observed in the brains of old people who die with no or mild cognitive impairment 3-8 and their cross-sectional correlation with level of cognitive function in persons without dementia is comparable to the correlation seen in persons with e-Pub ahead of print on September 15, 2010, at www.neurology.org.

Numerous reports have linked extremity muscle strength with mortality but the mechanism underlying this association is not known. We used data from 960 older persons without dementia participating in the Rush Memory and Aging Project to test two sequential hypotheses: first, that extremity muscle strength is a surrogate for respiratory muscle strength, and second, that the association of respiratory muscle strength with mortality is mediated by pulmonary function. In a series of proportional hazards models, we first demonstrated that the association of extremity muscle strength with mortality was no longer significant after including a term for respiratory muscle strength, controlling for age, sex, education, and body mass index. Next, the association of respiratory muscle strength with mortality was attenuated by more than 50% and no longer significant after including a term for pulmonary function. The findings were unchanged after controlling for cognitive function, parkinsonian signs, physical frailty, balance, physical activity, possible COPD, use of pulmonary medications, vascular risk factors including smoking, chronic vascular diseases, musculoskeletal joint pain, and history of falls. Overall, these findings suggest that pulmonary function may partially account for the association of muscle strength and mortality.

We tested the hypothesis that physical activity modifies the course of age-related motor decline. More than 850 older participants of the Rush Memory and Aging Project underwent baseline assessment of physical activity and annual motor testing for up to 8 years. Nine strength measures and nine motor performance measures were summarized into composite measures of motor function. In generalized estimating equation models, global motor function declined during follow-up (estimate, -0.072; SE, 0.008; P < 0.001). Each additional hour of physical activity at baseline was associated with about a 5% decrease in the rate of global motor function decline (estimate, 0.004; SE, 0.001; P = 0.007). Secondary analyses suggested that the association of physical activity with motor decline was mostly due to the effect of physical activity on the rate of motor performance decline. Thus, higher levels of physical activity are associated with a slower rate of motor decline in older persons.

No abstract