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

项目总结/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CSF-间质液交换期间，脑脊液（CSF）穿过。众所周知，PVS变得更加 复杂的老化。越来越多的证据表明，PVS在胶质淋巴细胞中起着特殊的作用。 淋巴运输，可能是大脑恢复力和疾病，包括阿尔茨海默病的关键因素。 尽管如此，大脑软脑膜的基本结构在物种间的研究很少。从历史上看， 被认为是作为一种限制大脑表面流体运动的超细膜而发挥被动作用。 关于这种脑膜炎的具体形态和成分， 层及其与疾病的联系，在很大程度上是由于缺乏系统的和高分辨率的显微镜， 分析。为了推进这一领域，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学及其形态学和 随着年龄的增长而变化。软脑膜解剖将使用免疫组织化学技术绘制， 性质将与疾病的已建立的神经病理学和神经学测量相关。为此 工作，我们将利用丰富的资源，临床和病理材料可从拉什宗教秩序 研究和记忆与衰老项目（ROSMAP），并将收集和分析有关的独特的新数据， PVS软脑膜结构假设PVS软脑膜作为一种重要的神经免疫组织起作用， 衰老与阿尔茨海默病（AD）有关。在目标1中，我们将研究软膜的关联 颅内β-淀粉样蛋白（βA）积聚的形态学和AD的病理学。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力的关系。在目标3中，我们将探讨 软脑膜形态与PVS和脑炎症的关系。在每一个目标中，我们将通过以下方式研究关系的不同之处： 年龄、性别和共病。总的来说，这些研究有可能揭示有关 软脑膜在衰老和AD中的功能以及对其在衰老中的异质性的新见解。拟议 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系统疾病中研究脑膜层奠定了框架。

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.