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.

项目概要 阿尔茨海默病 (AD) 的个体表现可能是由多种近期病理过程引起的。 有证据表明，炎症在炎症中发挥着关键作用，由神经胶质细胞（星形胶质细胞、小胶质细胞）驱动，神经胶质细胞占一半 当我们的脑组织面临急性损伤（疾病、创伤）时，神经胶质细胞会呈现出防御性、活跃的表型。 通过增殖和肿胀，这种保护性神经胶质反应可能会在正常衰老和 AD 中被淹没， 导致慢性炎症，破坏神经胶质细胞支持神经结构的能力，并最终影响 然而，常用的外周炎症的体内测量方法却很少。 血液和脑脊液中的标记物不能提供有关受影响的大脑区域的信息 通过炎症进行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药物。 配体可能对神经胶质细胞及其表型（静止的、激活的）不敏感和特异。 磁共振成像和磁共振波谱 (MRI/S) 包括同样有前景的非侵入性技术 测量神经炎症的方法已在动物模型中得到验证，但最近才被采用 尽管在衰老研究中很少使用，但一种尚未得到充分研究的方法是扩散加权。 MRS (DW-MRS)，通过选择性量化浓度，大大改进了传统 MRS 神经胶质细胞内常见的代谢物（细胞内代谢物浓度）也提供了一个。 每种代谢物的扩散测量（代谢物扩散系数），可以区分 静息（非肿胀细胞中低扩散）和激活（肿胀细胞中高扩散）神经胶质表型。 虽然使用 DW-MRS 可以选择性地靶向神经胶质特异性代谢物，但多室扩散- 加权 MRI (DWI) 测量脑组织的结构特性，这些特性不是神经胶质细胞特有的，但可能 然而，要对神经胶质增殖和肿胀敏感，证明这些 DW- 之间的关系。 MRS 和 DWI 指标对于其他对神经炎症感兴趣的研究小组来说很有价值 现有的大规模数据集已经获得了多室DWI，但没有获得DW-MRS。该项目的目的是。 测试这些 MRI/S 方法对衰老过程中神经炎症的敏感性及其与记忆的关系 通过对认知正常的年轻人和老年人进行 DW-MRS 和 DWI 扫描来评估他们的表现 还完成了一组神经心理学测试，我们将测试年龄较大是否伴随着较高的 DW-。 海马区 MRS 胶质细胞特异性代谢物指标（浓度、扩散系数）（具体目标 1），与该区域在衰老过程中容易受到神经胶质激活的证据一致，然后我们将测试是否如此。 DW-MRS 胶质细胞特异性代谢物指标与 DWI 内分子水扩散测量值相关 （细胞内扩散）和（扩散分散）细胞之间（具体目标 2），正如预期的那样，如果 DWI 指标对神经胶质细胞的增殖和肿胀也很敏感，在这两个目标中，较高的 DW-MRS 神经胶质细胞。 海马体中的特定代谢指标和 DWI 扩散指标预计与更差的情况相关 老年人的记忆力下降，但年轻人的记忆力下降，因为他们的神经炎症很少。 总而言之，该项目将提供与年龄相关的神经炎症的更详细的特征 人类体内并揭示了与记忆功能障碍相关的重要炎症途径的新生物标志物 在正常的衰老过程中。