MRI biomarkers of glial-specific metabolites and microstructure in aging

衰老过程中神经胶质特异性代谢物和微观结构的 MRI 生物标志物

• 批准号: 10742593
• 负责人: Ilana Jacqueline Bennett
• 金额: $ 43.31万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 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 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10742593
• 关键词: Acute; Address; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Animal Model; Animals; Astrocytes; Blood; Brain; Brain region; Cells; Cerebrospinal Fluid; Choline; Chronic; Cognition; Cognitive; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Dissociation; Elderly; Ethnic Origin; Future; Goals; Hippocampus; Human; Impaired cognition; Individual; Inflammation; Inflammatory; Injections; Interest Group; Intervention; Iron; Ligands; Link; MRI Scans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Maps; Measures; Mediating; Memory; Memory impairment; Microglia; Molecular; N-acetylaspartate; Nerve Degeneration; Neuroglia; Neurons; Neurophysiology - biologic function; Neuropsychological Tests; Oxidative Stress; Participant; Pathologic Processes; Pathway interactions; Performance; Peripheral; Phenotype; Positron-Emission Tomography; Proliferating; Property; Research; Rest; Role; Sensitivity and Specificity; Spectrum Analysis; Stress; Structure; Swelling; Techniques; Testing; Thalamic structure; Tissues; Trauma; Water; Work; age effect; age group; age related neuroinflammation; aging brain; brain tissue; cell type; cognitive performance; diffusion weighted; glial activation; human old age (65+); improved; in vivo; inflammatory marker; large scale data; magnetic resonance imaging biomarker; neural; neuroimaging; neuroinflammation; neuromechanism; neuronal cell body; normal aging; novel; novel marker; pre-clinical; response; young adult

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.

项目摘要 阿尔茨海默氏病（AD）的个体表现可能是由多种病理过程引起的。最近的 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，完成了一半 我们的脑组织。当面对急性损伤（疾病，创伤）时，GLIA假定防御性，主动表型 通过增殖和肿胀。这种受保护的神经胶质反应在正常衰老和AD中不知所措， 导致慢性感染破坏了神经胶质支持神经元结构的能力并最终影响 认识。然而，人脑中炎症的体内测量很少。通常使用的外围 血液和脑脊液的标记不提供有关受影响的大脑区域的信息 通过注射。正电子排放层析成像克服了这一限制，但涉及昂贵的注射 可能对神经胶质及其表型不敏感且特异的配体（静止，激活）。磁的 共振成像和磁共振光谱（MRI/S）包括同样有希望的和无创的 测量在动物模型中已验证的神经炎症的方法，但直到最近才 用于人类，尽管很少用于衰老研究。一种这种研究不足的方法是扩散加权 MRS（DW-MRS），通过选择性量化的浓度大大改善了传统MRS 代谢物通常在神经胶质细胞中发现（细胞内代谢产物浓度）。 DW-MR也提供了 每种代谢物（代谢物扩散系数）扩散的度量，这可能会区分 静止（在非毛状细胞中的低扩散）和激活（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产物可以选择性地靶向DW-MR，而多室扩散 - 加权MRI（DWI）测量非特定于神经胶质的脑组织的结构特性 但是，对神经胶质增殖和肿胀保持敏感。证明这些dw-之间的关系 MRS和DWI指标将对对神经炎症感兴趣的其他研究小组很有价值 现有和大规模数据集获得了多室DWI，但没有获得DW-MRS。这个项目旨在 测试这些MRI/S对衰老中神经炎症的敏感性及其与记忆的关系 通过在认知正常和老年人中获得DW-MRS和DWI扫描的表现 还要完成神经心理测试电池。我们将测试年龄是否伴随着较高的DW- 海马中的神经胶质特异性代谢产物指标（浓度，扩散系数）（特定目的 1），与证据相一致，表明该区域在衰老中容易受到神经胶质激活的影响。然后我们将测试是否 DW-MRS神经胶质特异性代谢产物指标与DWI分子水扩散有关 （细胞内扩散）和（扩散的分散）细胞（特定目标2），如预期的那样 DWI指标也对神经胶质的增殖和肿胀也很敏感。在这两个目标中，较高的dw-mrs glial- 预计海马中的特定代谢物指标和DWI扩散指标有望与更糟 老年人的记忆力表现，但在年轻人中不具有最小的神经炎症。 综上 人类在体内并揭示了与记忆功能障碍有关的重要炎症途径的新型生物标志物 在正常衰老中。