MRI biomarkers of glial-specific metabolites and microstructure in aging

项目摘要 阿尔茨海默病（AD）的个体表现可能是由多种病理过程引起的。最近 有证据表明炎症的关键作用，由神经胶质细胞（星形胶质细胞，小胶质细胞）驱动， 我们的脑组织。当面对急性损伤（疾病、创伤）时，神经胶质细胞呈现出防御性的、活跃的表型 通过增殖和膨胀。这种保护性神经胶质反应在正常衰老和AD中可能被淹没， 导致慢性炎症，破坏神经胶质支持神经结构的能力， 认知.然而，在人脑中很少有体内炎症测量。常用外设 血液和脑脊液中的标记物不能提供有关受影响脑区的信息 通过炎症。正电子发射断层扫描克服了这一限制，但它涉及注射昂贵的 可能对神经胶质及其表型（静息、活化）不敏感和特异的配体。磁 磁共振成像和磁共振波谱（MRI/S）包括同样有前途的和非侵入性的 测量神经炎症的方法已经在动物模型中得到验证，但最近才被 用于人类，尽管很少用于衰老研究。其中一种研究不足的方法是扩散加权 MRS（DW-MRS），其通过选择性地量化 神经胶质细胞内常见的代谢物（细胞内代谢物浓度）。DW-MRS还提供了 每种代谢物的扩散测量（代谢物扩散系数），可以区分 静息（在非肿胀细胞中的低扩散）和活化（在肿胀细胞中的高扩散）神经胶质表型。 而神经胶质特异性代谢物可以选择性地使用DW-MRS，多室扩散- 加权MRI（DWI）测量脑组织的结构特性，这些特性不是胶质细胞特有的，但可能 然而对神经胶质增生和肿胀敏感。证明这些DW之间的关系- MRS和DWI指标将对其他对神经炎症感兴趣的研究小组有价值， 现有的和大规模的数据集已经获得了多室DWI，但没有DW-MRS。本项目旨在 测试这些MRI/S方法对衰老中神经炎症的敏感性及其与记忆的关系 在认知正常的年轻人和老年人中获得DW-MRS和DWI扫描， 还要完成一系列神经心理测试我们将测试年龄较大是否伴随着较高的DW- 海马中的MRS神经胶质特异性代谢物度量（浓度、扩散系数）（特定目标 1），这与该区域在衰老中易受胶质细胞激活的证据一致。然后我们将测试 DW-MRS神经胶质特异性代谢物指标与DWI测量的分子水扩散有关， （细胞内扩散）和（扩散的分散）细胞之间（具体目标2），如预期的，如果 DWI指标对胶质细胞的增殖和肿胀也很敏感。在这两个目标中，更高的DW-MRS神经胶质细胞- 海马体中的特定代谢物指标和DWI扩散指标预计与更差的 老年人的记忆表现，但不是在年轻人，因为他们将有最小的神经炎症。 总的来说，这个项目将提供一个更详细的特征，年龄相关的神经炎症， 人类体内研究并揭示了与记忆功能障碍相关的重要炎症途径的新型生物标志物 在正常的衰老过程中。

PROJECT SUMMARY Individual manifestations of Alzheimer’s disease (AD) likely result from multiple pathological processes. Recent evidence indicates a critical role for inflammation, driven by glial cells (astrocytes, microglia) that comprise half of our brain tissue. When faced with an acute insult (illness, trauma), glia assume a defensive, active phenotype by proliferating and swelling. This protective glial response can be overwhelmed in normal aging and AD, resulting in chronic inflammation that disrupts the ability of glia to support neural structures and ultimately impacts cognition. Yet, there are few in vivo measures of inflammation in the human brain. Commonly used peripheral markers from blood and cerebrospinal fluid do not provide information about the brain regions that are impacted by inflammation. Positron emission tomography overcomes this limitation, but it involves injections of expensive ligands that may not be sensitive and specific to glia and their phenotypes (resting, activated). Magnetic resonance imaging and magnetic resonance spectroscopy (MRI/S) include equally promising and non-invasive approaches to measure neuroinflammation that have been validated in animal models but are only recently being used in humans, although rarely in studies of aging. One such under-studied approach is diffusion-weighted MRS (DW-MRS), which greatly improves on traditional MRS by selectively quantifying concentrations of metabolites commonly found within glial cells (intracellular metabolite concentration). DW-MRS also provides a measure of diffusion for each metabolite (metabolite diffusion coefficient), which may distinguish between the resting (low diffusion in non-swollen cells) and activated (high diffusion in swollen cells) glial phenotypes. Whereas glial-specific metabolites can be selectively targeted using DW-MRS, multi-compartment diffusion- weighted MRI (DWI) measures structural properties of brain tissue that are not specific to glia but may nonetheless be sensitive to glial proliferation and swelling. Demonstrating a relationship between these DW- MRS and DWI metrics will be valuable for other research groups interested in neuroinflammation as many existing and large-scale datasets have acquired multi-compartment DWI, but not DW-MRS. This project aims to test the sensitivity of these MRI/S approaches to neuroinflammation in aging and their relation to memory performance by acquiring both DW-MRS and DWI scans in cognitively normal younger and older adults who also complete a neuropsychological test battery. We will test whether older age is accompanied by higher DW- MRS glial-specific metabolite metrics (concentrations, diffusion coefficients) in the hippocampus (Specific Aim 1), consistent with evidence that this region in vulnerable to glial activation in aging. We will then test whether the DW-MRS glial-specific metabolite metrics are related to DWI measures of diffusion of molecular water within (intracellular diffusion) and between (dispersion of diffusion) cells (Specific Aim 2), as would be expected if the DWI metrics are also sensitive to proliferation and swelling of glia. Across both aims, higher DW-MRS glial- specific metabolite metrics and DWI diffusion metrics in the hippocampus are expected to relate to worse memory performance in older adults, but not in younger adults as they will have minimal neuroinflammation. Taken together, this project will provide a more detailed characterization of age-related neuroinflammation in humans in vivo and reveal novel biomarkers of an important inflammatory pathway linked to memory dysfunction in normal aging.