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

识别健康衰老过程中内嗅皮层内的微观脉管系统及其与阿尔茨海默氏病病理特征的接近程度

• 批准号: 10657895
• 负责人: Jean Augustinack
• 金额: $ 212.17万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657895
• 关键词: 3-Dimensional; Affect; Aging; Algorithms; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Amyloid; Anastomosis - action; Anatomy; Architecture; Atlases; Autopsy; Biological Markers; Blood Vessels; Blood capillaries; Brain; Cerebrum; Clinical; Clinical Trials; Cognitive; Data; Data Set; Dementia; Detection; Development; Disease; Disease Progression; Goals; Heterogeneity; Histologic; Histology; Histopathology; Image; Immunohistochemistry; Impaired cognition; Individual; Investigation; Knowledge; Label; Laminin; Magnetic Resonance Imaging; Manuals; Maps; Measures; Medial; Memory; Methods; Microscopic; Modeling; National Institute on Alcohol Abuse and Alcoholism; Nerve Degeneration; Neurons; Optics; Pathogenesis; Pathologic; Pathology; Pattern; Penetration; Perfusion; Periodicity; Population; Resolution; Risk Factors; Sampling; Specificity; Stains; Structure; Tauopathies; Temporal Lobe; Tissues; Validation; Variant; Vascularization; White Matter Hyperintensity; Work; arteriole; capillary bed; cerebrovascular; cerebrovascular health; cerebrovascular lesion; clinical biomarkers; cognitive control; cohort; density; entorhinal cortex; frailty; health record; healthy aging; histological stains; human tissue; in vivo; in vivo imaging; meter; neurofibrillary tangle formation; neuroimaging; neuroimaging marker; neuron loss; novel; novel therapeutics; pre-clinical; protein TDP-43; reconstruction; resilience; systemic inflammatory response; tau Proteins; tau-1

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.

阿尔茨海默病（AD）中神经元死亡损害了内嗅皮层（EC）。神经元死亡，无论 有或没有神经系统缠结形成，是与痴呆最密切相关的病理学。贫困 脑血管健康是AD的一个已知危险因素，但EC内的特定血管区域尚不清楚。的 问题是，对病理生物标志物的研究没有区域特异性， 了解脆弱神经元群体所在的局部血管区域，以及临床生物标志物 在疾病进展中评估太晚。此外，神经变性（神经元死亡），如由NIA- AA框架，还远远没有得到充分研究。该领域遭受神经成像措施之间的脱节 和脆弱的内嗅区的地面真实验证。识别局部微血管模式 渗透器和/或毛细血管床的EC子域图，总神经元计数，TDP-43，和tau负荷是一个 确定AD发病机制、脆弱性或潜在恢复力的异质性的重要步骤。目标1： 死后MRI成像以显示EC中微血管小动脉、穿透器和毛细血管床。高 将使用7 T的场MRI产生必要的高分辨率，并使用算法增强血管。目的 2是用EC中的组织学血管染色验证成像，与tau、TDP-43、神经元损失交叉参考。 将采用系统随机抽样体视学计数方法定量神经元损失， 免疫组织化学将用于病理学特征。目标3是应用病理图、血管区域 映射到现有的大型体内MRI数据集、ADNI、HABS和HCP。总体目标是确定一个独特的 对照组中EC内的血管模式，并显示EC亚区血管区域具有神经元 易损性.本提案中的可交付成果将是血管、tau、TDP-43和神经元的并列 在人体组织中验证的损失数据，3D标测应用于体内成像。所需的工作将 在认知控制以及具有病理学特征的临床前AD中产生基线血管观察结果。 它将为神经影像学评估确定血管生物标志物，这将是不可或缺的一步， 开发干预和阻止AD的新疗法。