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.

项目摘要/摘要 血管周围间隙(PVS)pia是哺乳动物神经系统内的一种独特的组织复合体，是 在脑脊液-间质液交换过程中被脑脊液(CSF)穿过。已知的PVS变得更多 随着年龄增长而变得复杂。越来越多的证据表明，PVS在淋巴组织中起着特殊的作用。 淋巴运输，可能是大脑韧性和包括阿尔茨海默病在内的疾病的关键因素。 尽管如此，跨物种对大脑pia的基本结构进行了最低限度的研究。从历史上看，pia一直是 被认为扮演着被动角色，如限制大脑表面液体运动的超细薄膜。 关于这种脑膜的具体形态和成分，人们的认识仍然存在很大差距。 地层及其与疾病的联系，主要是由于缺乏系统和高分辨率的显微镜 分析。为了推动这一领域的发展，需要更好地表征PIA结构。在这个项目中，高分辨率 显微技术将被用来阐明人类软膜的形态及其形态和 成分随着年龄的增长而变化。将使用免疫组织化学技术绘制硬膜解剖图，并 这些特性将与既定的神经病理学和神经学疾病测量方法相关联。为了这个 在工作中，我们将利用拉什宗教教团提供的丰富的临床和病理材料资源 研究、记忆和老龄化项目(ROSMAP)，并将收集和分析与独特的 PVS Pia的结构。假设PVS Pia作为一种重要的神经免疫组织发挥作用，而Pial 衰老与阿尔茨海默病(AD)有关。在目标1中，我们将研究pial的关联。 阿尔茨海默病的形态与颅内β-淀粉样蛋白(βA)积聚及病理。在目标2中，我们将研究 软膜形态与认知衰退和恢复力的关系。在目标3中，我们将探索 软膜形态与PVS和脑部炎症的关系。在每个目标中，我们将调查关系在以下方面的不同 年龄、性别和并存疾病。总体而言，这些研究有可能揭示以下方面的新知识 软骨膜在衰老和阿尔茨海默病中的作用以及对其在衰老中的异质性的新见解。建议数 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 为在其他与年龄相关的神经疾病的背景下研究这一脑膜层奠定了框架。