The primary goal of this five-year training award is to further the candidate's development as an independent and multidisciplinary researcher in aging and neuroscience through structured training and expert mentoring in 1) Alzheimer's disease, Parkinson's disease, and cerebrovascular disease; 2) neurology, neuropathology, neuropsychology, and neuroimaging; and 3) statistical methods and research design of clinical studies (e.g., epidemiological studies and clinical trials). The research project, as an integral part of this training program, aims to understand the neuropathologic pathways through which risk factors affect clinical symptoms such as the decline in cognitive and motor functions. More specifically, the candidate plans to evaluate the contributions of common neuropathologic indices (i.e., amyloid deposition, tangle formation, cerebral infarctions, and Lewy bodies) to the simultaneous rates of decline in cognitive and motor functions over multiple years prior to death. The study will take advantage of clinical pathologic data from two large longitudinal studies: the Religious Orders Study (exploratory cohort) and the Memory and Aging Project (confirmatory cohort).
The specific aims are: 1) Quantify the shared variance (correlation or covariance) between rates of change in cognitive and motor functions; 2) Assess the effect of informative censoring (e.g., death) on correlation (covariance) estimator; 3) Test the hypothesis that these common age-related neuropathologic indices account for the covariance in rates of change in cognitive and motor functions; and 4) Decompose the covariance in decline of cognitive and motor functions into a sum of path weights from three common age-related neuropathologic indices. To achieve these aims, the candidate will develop statistical models and make methodological contributions to longitudinal studies of aging. The longitudinal process and event time data will be modeled jointly to account for the problem of informative missingness. Linear mixed model will be used to capture the longitudinal trajectory whereas conditional Weibull model and conditional piecewise exponential model will be used to model event times. Findings will help us to understand the extent to which these known pathologic conditions account for the decline of cognitive and motor functions and the extent to which other as yet unidentified factors (e.g., oxidative stress, inflammation) must be responsible for decline in both of these abilities. ? ? ?
