Post-stroke normal appearing white matter diffusion properties and cognitive trajectories across age

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PROJECT SUMMARY Post-stroke cognitive impairment is common, particularly in older individuals. Existing knowledge gaps about mechanisms underpinning poor outcome, particularly in the aged, have been the most significant barriers to developing novel therapeutic targets and approaches to prevent cognitive decline and progression to Alzheimer’s disease and related dementias (ADRD). This is especially relevant to health disparity populations, specifically women and Black demographics. Previous studies of Alzheimer’s disease and mild cognitive impairment, suggest that the morphological changes of the corpus callosum are related to cognitive measures. Existing data show that classical neuroimaging biomarkers such as acute infarct volume, location, and white matter hyperintensity burden have modest prognostic predictive utility in models of post-stroke cognitive function. We have recently used diffusion tensor imaging in acute stroke patients to show that decreased fractional anisotropy of the ipsi- and contra-lateral hemispheric normal appearing white matter, as well as the corpus callosum, are associated with higher stroke scale impairment severity. Additionally, we have also used advanced diffusion imaging to examine white matter microstructure in midlife individuals with significant vascular risk factors, as well as Black and women demographics at risk for stroke and cognitive impairment. Our preliminary results suggest that the corpus callosum and other white matter structures involved in cognition manifest specific diffusion changes that not only relate to vascular risk factor burden exposure, but also to post-stroke outcome. Our laboratory has pioneered diffusion MRI acquisition and modeling approaches that are sensitive to not only white matter anisotropy, but also white matter complexity. As such, we are well poised to comprehensively characterize the diffusion properties of normal appearing white matter across time and age, in acute stroke patients and their post-stroke cognitive trajectories. Our established expertise in diffusion imaging and modeling that is sensitive to white matter complexity in relation to the presence of age-related vascular risk profiles, allows us to longitudinally examine the unique microstructural properties of the corpus callosum, infarcted and non-infarcted tissue, and more remote structures on the contralateral non-lesioned hemisphere and their relationship to post- stroke recovery. It is therefore possible that a deeper understanding of white matter microstructure in the acute stage after ischemic stroke and its change over time, will enhance prediction models of post-stroke cognitive recovery and identify novel target for therapeutic interventions. This knowledge will also help our clinicians provide much needed bed-side prognosis to patients and their families. Our central hypothesis is that after unilateral ischemic stroke, temporal changes in the diffusion properties of normal appearing white matter of the corpus callosum specifically, and the white matter across both hemispheres in general, are associated with the differential patterns of post-stroke age-related cognitive trajectories.