Mapping the perivascular reticular network in health, aging, and AD

绘制健康、衰老和 AD 中的血管周围网状网络图

• 批准号: 10739104
• 负责人: Rupal I. Mehta
• 金额: $ 124.64万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739104
• 关键词: Adult; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Amyloid beta-Protein; Anatomy; Antigens; Apolipoprotein E; Area; Biological; Biological Markers; Blood Vessels; Brain; Cell Density; Cells; Cerebral Amyloid Angiopathy; Cerebrospinal Fluid; Cerebrum; Clinical; Cognition; Communities; Complex; Data; Dementia; Diagnosis; Diagnostic Factor; Disease; Education; Encephalitis; Epidemiology; Excision; Future; Genotype; Health; Heterogeneity; Histology; Homeostasis; Human; Immune; Impaired cognition; Individual; Inflammation; Intercellular Fluid; Intervention; Investigation; Knowledge; Liquid substance; Literature; Lymphatic; Lymphatic clearance; Magnetic Resonance Imaging; Maps; Measures; Membrane; Memory; Meningeal; Microscopic; Microscopy; Morphology; Movement; Mus; National Institute on Alcohol Abuse and Alcoholism; Nature; Nerve Degeneration; Nervous System; Neuroimmune; Neuroimmunomodulation; Neurologic; Neurology; Pathologic; Peripheral; Pia Mater; Play; Porosity; Process; Prognostic Factor; Property; Qualifying; Research; Resolution; Resources; Role; Senile Plaques; Severities; Site; Structure; Surface; Techniques; Testing; Therapeutic; Time; Tissues; Ultrafine; United States; Universities; Work; abeta accumulation; age related; brain tissue; cerebrovascular; cohort; comorbidity; cytokine; density; glymphatic system; human disease; imaging study; insight; lymphatic circulation; lymphatic vessel; nervous system disorder; neuropathology; novel; novel diagnostics; prognostic; protein aggregation; proteostasis; religious order study; resilience; response; scaffold; senescence; sex; statistics; β-amyloid burden

PROJECT SUMMARY/ABSTRACT Perivascular space (PVS) pia is a unique tissue composite within the mammalian nervous system and is traversed by cerebrospinal fluid (CSF) during CSF-interstitial fluid exchange. PVS are known to become more complex with aging. Accumulating evidence suggests that PVS subserve specialized roles in glymphatic- lymphatic transport and may be a critical factor in brain resilience and diseases, including Alzheimer’s disease. In spite of this, the basic structure of brain pia is minimally investigated across species. Historically, pia has been perceived to play passive roles as an ultrafine membrane that restricts fluid movement at the brain surface. Substantial gaps in knowledge remain regarding the specific morphology and constituents of this meningeal layer and its associations with disease, due in large part to lack of systematic and high-resolution microscopic analyses. To advance the field, better characterization of pia structure is needed. In this project, high-resolution microscopy techniques will be used to elucidate the morphology of human pia mater and its morphological and compositional changes with aging. Pial anatomy will be mapped using immunohistochemical techniques and its properties will be correlated with established neuropathological and neurological measures of disease. For this work, we will leverage a rich resource of clinical and pathologic material available from the Rush Religious Orders Study and Memory and Aging Project (ROSMAP) and will collect and analyze novel data pertaining to the unique structure of PVS pia. The hypothesis is that PVS pia functions as a critical neuroimmune tissue and that pial senescence is associated with Alzheimer’s disease (AD). In Aim 1, we will examine the associations of pial morphology with intracranial beta-amyloid (βA) accumulation and pathology of AD. In Aim 2, we will examine the associations of pial morphology with cognitive decline and resilience. In Aim 3, we will explore the associations of pial morphology with PVS and brain inflammation. In each aim, we will investigate how relationships differ by age, sex, and comorbid diseases. Overall, these studies have the potential to uncover new knowledge regarding the function of pia mater in aging and AD as well as novel insights into its heterogeneity in aging. The proposed investigations will advance the field and may reveal mechanistic, diagnostic and prognostic factors for AD while laying a framework for studying this meningeal layer in the setting of other age-related neurological diseases.

项目概要/摘要 血管周围间隙 (PVS) 软脑膜是哺乳动物神经系统内独特的组织复合物， 在脑脊液-间质液交换过程中，由脑脊液 (CSF) 穿过。众所周知，PVS 会变得更加 与衰老复杂。越来越多的证据表明 PVS 在类淋巴系统中发挥特殊作用 淋巴运输，可能是大脑恢复能力和疾病（包括阿尔茨海默病）的关键因素。 尽管如此，对不同物种的软脑膜基本结构的研究却很少。从历史上看，pia 一直是 人们认为它作为限制大脑表面液体运动的超细膜发挥着被动作用。 关于这种脑膜的具体形态和成分的知识仍然存在巨大差距 层及其与疾病的关联，很大程度上是由于缺乏系统和高分辨率的显微镜 分析。为了推进该领域的发展，需要更好地表征 pia 结构。在这个项目中，高分辨率 显微镜技术将用于阐明人类软脑膜的形态及其形态和结构 成分随老化而变化。将使用免疫组织化学技术及其方法绘制软脑膜解剖结构图 特性将与疾病的既定神经病理学和神经学测量相关。为了这 工作中，我们将利用 Rush Religious Orders 提供的丰富的临床和病理材料资源 研究、记忆和衰老项目（ROSMAP）将收集和分析有关独特的新数据 PVS pia 的结构。假设PVS软脑膜作为一种关键的神经免疫组织发挥作用，并且软脑膜 衰老与阿尔茨海默病（AD）有关。在目标 1 中，我们将检查 pial 的关联 AD 颅内 β-淀粉样蛋白 (βA) 积累的形态学和病理学。在目标 2 中，我们将检查 软脑膜形态与认知能力下降和恢复能力的关联。在目标 3 中，我们将探索关联 软脑膜形态与 PVS 和脑炎症的关系。在每个目标中，我们将通过以下方式研究关系有何不同： 年龄、性别和合并症。总体而言，这些研究有可能发现有关以下方面的新知识： 软脑膜在衰老和 AD 中的功能以及对其在衰老过程中异质性的新见解。拟议的 研究将推动该领域的发展，并可能揭示 AD 的机制、诊断和预后因素，同时 为研究其他与年龄相关的神经系统疾病中的脑膜层奠定了框架。