Influence of Age-related Neuropathology on Functional Brain Networks

Massachusetts General Hospital, Boston MA

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Abstract

DESCRIPTION (provided by applicant): The proposed research examines the potential role of three age-related neuropathological processes, namely dopamine dysfunction, amyloid accumulation, and white matter disruption, in understanding declines in a frontostriatal brain network. The proposal builds upon a theoretical orientation that many effects on cognition and underlying brain networks often attributed to developmental processes of advanced aging may be associated with neuropathological processes; a long-term goal of the research program is thorough testing of this theoretical orientation using multiple methods. The first aim is to characterize the frontostriatal network and examine its relationship to behavior during aging. Training for this aim will build on the candidate's previous experience and will provide a foundation for the later aims. The second aim is to test whether specific neuropathologies are associated with disruption of the frontostriatal network. Training for this aim will develop the candidate's expertise in molecular imaging techniques using positron emission tomography (PET). Short- term goals include obtaining expertise in PET techniques and characterizing the cross-sectional relationship between these three age-related neuropathologies. The third aim is to test whether neuropathology predicts longitudinal change in the frontostriatal network. Training for this aim will develop the candidate's expertise in longitudinal analytic methods and will further the candidate's long-term goal of identifying mechanistic pathways involved in cognitive and neural change observed during aging. Markers of three brain pathologies will be obtained by leveraging data collected in conjunction with already funded projects and by adding new data to be collected in the proposed project. Dopaminergic function, which declines during aging to an extent not as severe as that observed in Parkinson's disease, will be measured with PET imaging of dopamine transport. Amyloid accumulation will be measured with PET imaging of amyloid plaques, a hallmark pathology of Alzheimer's disease. White matter integrity, commonly disrupted in vascular dementia, will be measured using structural magnetic resonance imaging (MRI). Training available at Massachusetts General Hospital allows access to resources and mentors in the many techniques necessary to the aims of the candidate's training and career goals. The relationship of each neuropathological process to disruption in a frontostriatal brain network will be examined to determine if age-related reductions in this network's integrity can be traced to specific influences of neuropathology. Using longitudinal data, the influence of each neuropathology on change in frontostriatal network integrity over time will be assessed. Completion of the aims will enhance understanding of the role of sub-clinical neuropathology in age-related declines of brain network integrity and associated cognitive abilities. This research holds relevance for potential screening for undiagnosed neuropathology and disruption of brain networks that may aid in early diagnosis of age-related neurodegeneration and allow development of biomarkers for evaluating interventional therapies.