Neural substrates of diffusion imaging in cognitively aging rhesus monkeys

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7. Abstract. The ability to identify and follow-up neurobiological changes that occur during brain maturation and aging is not only fundamental to our understanding of cognition, but is also crucial for clinical studies that focus on either neurodevelopmental or neurodegenerative disorders, including clinical trials. While post-mortem studies provide data that are well characterized in terms of localized histological changes, these data can be limited due to their cross sectional nature and small samples sizes. In contrast, non-invasive in vivo imaging allows for the collection of longitudinal data in much larger populations, and is a more powerful tool to investigate life span trajectories of brain maturation and aging. Recent developments in neuroimaging have provided evidence for the relationship between imaging changes and cognitive aging in monkeys, and humans. Unfortunately, the cellular underpinnings of cognitive age are a subject of debate and hence the biological specificity of available imaging measures is not well established. More alarming, while older imaging measures still lack thorough validation, newer “more specific” measures that are being constantly introduced into clinical research are even further from validation. Over the past funding period, we have worked with a large repository of histological, cognitive and imaging legacy data from cognitively aging rhesus monkeys, testing the hypothesis that neuroinflammation and myelin degeneration play crucial roles in cognitive aging, and that neuroimaging biomarkers can reflect those biological processes. We propose to further our work in this direction, by proposing translational experiments that will include 1). acquiring new, high resolution “Human Connectome Project (HCP)” compatible imaging data, 2). Expand our neuroimaging by adding neuroinflammation- and myelin-specific PET radioligands, 3). Develop neuroimaging white matter-specific biomarkers of mild cognitive impairment- a risk factor for Alzheimer’s disease, and 4). Investigate biological underpinnings of sex differences in aging. This is enabled by a collaboration of three PIs, with unique and complementary expertise in MRI imaging, morphometry, neuroanatomy, immunohistochemistry and cognitive aging, and will be further facilitated by acquiring and analyzing behavioral, imaging, blood and post mortem data from a cohort of 24 rhesus monkeys of both sexes, 8 young adults (4 males and 4 females) and 16 old adults (8 males and 8 females, half diagnosed with mild cognitive impairment (MCI)). The results of this proposed study will greatly impact our understanding of aging processes and their mechanisms and provide tissue validated understanding of imaging measures that can be applied to studies of normal human aging as well as many neurodevelopmental and neurodegenerative diseases of the central nervous system.