Identifying microscopic vasculature within entorhinal cortex in healthy aging and its proximity to pathology profiles in Alzheimer's disease

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Neuron death overwhelms the entorhinal cortex (EC) in Alzheimer’s disease (AD). Neuronal death, whether with or without neurofibrillary tangle formation, is the pathology most strongly correlated with dementia. Poor cerebrovascular health is a known risk factor in AD, but specific vascular territories within EC is not known. The problem is that studies on pathologic biomarkers occur without the context of regional specificity, without knowledge of the local vascular territories where vulnerable neuron populations reside, and clinical biomarkers assess too late in disease progression. Moreover, neurodegeneration (neuronal death), as defined by the NIA- AA framework, is vastly understudied. The field suffers from a disconnection between neuroimaging measures and ground truth validation in the vulnerable entorhinal region. Identifying the microvascular pattern of local penetrators and/or capillary bed for an EC subfield map, with total neuron counts, TDP-43, and tau burden is a vital step to determining the heterogeneity in AD pathogenesis, vulnerability, or potential resilience. Aim 1 is to image postmortem MRI to demonstrate microvascular arterioles, penetrators, and capillary beds in EC. High field MRI at 7T will be used to produce the necessary high resolution with algorithms to enhance vessels. Aim 2 is to validate imaging with histologic vascular staining in EC, cross-referenced with tau, TDP-43, neuron loss. Neuronal loss will be quantified with systematic random sampling stereology counting methods and immunohistochemistry will be used for pathology profiles. Aim 3 is to apply pathology maps, vascular territories map, to large existing in vivo MRI datasets, ADNI, HABS, and HCP. The overall goal is to identify a unique vascular pattern within EC in controls and demonstrate EC subfield vascular territories with neuronal vulnerability. The deliverables in this proposal will be the juxtaposition of vascular, tau, TDP-43, and neuronal loss data validated in human tissue with 3D mapping application to in vivo imaging. The needed work will produce a baseline vascular observation in cognitive controls as well as preclinical AD with pathology profiles. It will identify a vascular biomarker for neuroimaging assessment that will be an indispensable step to developing novel therapies that intervene and halt AD.