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

在阿尔茨海默病(AD)中，神经元死亡淹没了内嗅皮层(EC)。神经元死亡，无论是 无论有无神经原纤维缠绕形成，都是与痴呆症最相关的病理。穷 脑血管健康是AD的已知危险因素，但EC内特定的血管区域尚不清楚。这个 问题是，对病理生物标记物的研究没有区域特异性的背景，也没有 易损神经元群体所在的局部血管区域和临床生物标记物的知识 在疾病进展中评估为时已晚。此外，根据NIA的定义，神经变性(神经元死亡)- AA框架，但对它的研究还远远不够。这一领域受到神经成像测量之间的脱节之苦 并在脆弱的内脏区域进行地面真理验证。确定局部的微血管类型 EC子场图的穿透器和/或毛细血管床，神经元总数，TDP-43和tau负荷是 确定AD发病机制、脆弱性或潜在恢复力的异质性的关键步骤。目标1是 死后MRI成像显示EC的微血管、穿透器和毛细血管床。高 将使用7T的现场MRI来产生必要的高分辨率，并使用算法来增强血管。目标 2是通过组织学血管染色与tau、TDP-43、神经元丢失对照，验证EC的影像表现。 神经元丢失将用系统的随机抽样体视学计数方法和 病理切片将采用免疫组织化学方法。目标3是应用病理图，血管区域 映射到现有的大型活体MRI数据集，ADNI、HABS和HCP。总体目标是确定唯一的 对照组EC内的血管模式和EC亚区血管区域的神经元显示 脆弱性。这项提案中的成果将是血管、tau、tdp-43和神经元的并列。 丢失的数据在人体组织中得到验证，3D映射应用于活体成像。所需的工作将 对认知控制组和临床前AD患者进行基线血管观察，观察其病理特征。 它将确定用于神经成像评估的血管生物标记物，这将是 开发干预和阻止阿尔茨海默病的新疗法。

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.