Michigan Alzheimer’s Disease Research Center-Supplement

密歇根阿尔茨海默病研究中心增刊

• 批准号: 10599387
• 负责人: Henry L Paulson
• 金额: $ 50.02万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599387
• 关键词: Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease related dementia; Amyloid; Amyloid deposition; Animal Model; Automobile Driving; Autopsy; Axon; Blood Vessels; Brain; Brain region; Cell membrane; Characteristics; Cholesterol; Clinical; Clinical Research; Cognitive deficits; Data; Dementia; Demyelinations; Diagnosis; Diffusion; Disease; Disease Pathway; Education and Outreach; Elderly; Freezing; Future; Gliosis; Goals; Health; Histologic; Image; Impaired cognition; Infiltration; Iron; Lead; Lesion; Link; Lipids; Magnetic Resonance Imaging; Maps; Measures; Mediating; Membrane; Membrane Fluidity; Membrane Lipids; Methods; Michigan; Microglia; Monitor; Myelin; Neurologic; Oligodendroglia; Pathologic; Pathologic Processes; Pathology; Patients; Pattern; Process; Property; Radiology Specialty; Research; Resources; Role; Sampling; Signal Transduction; Specificity; Stains; Study models; T2 weighted imaging; Techniques; Thick; Tissue Fixation; Tissues; United States; Universities; Variant; Vascular Dementia; Water; Work; base; brain dysfunction; clinically significant; density; fluidity; histological studies; imaging study; improved; in vivo; indexing; light microscopy; multimodality; neuroimaging; neuropathology; repository; skills; tau-1; white matter

ABSTRACT – SUPPLEMENT We seek to define the MR correlates of white matter histopathological features in Alzheimer’s disease and related disorders (ADRD) by combining the resources at MADRC Neuropathology core, with its repository of post-mortem frozen tissue with a wealth of accompanying pre-mortem MR studies, with the resources of MADRC Neuroimaging core and its advanced MR facility comprised of experts in the fields of MR acquisition, post-processing, and parameterization. Post-mortem histological studies and pre-mortem imaging studies indicate that multiple pathologies often co-exist and that single pathologies are often the exception, as demonstrated by the frequent presence of brain lesions of presumed vascular origin, such as white matter (WM) lesions, microbleeds, and microinfarcts. The clinical significance and the degree to which such lesions contribute to clinical decline is unclear, partly because routine MRI techniques such as T1 and T2 weighted imaging lack the specificity to further characterize their pathological underpinnings such as demyelination, gliosis, or axonal loss. Guided by pre-mortem MR studies of donors with a diagnosis of vascular dementia (VD), Alzheimer’s disease (AD), and neurologically intact donors (ND), we will analyze frozen post-mortem tissue both from brain regions surrounding LPVO’s and brain regions without any T2 abnormalities. We will obtain advanced MR (MWF, ihMT, and multi-shell, multi-directional diffusion) parameters from these tissue blocks as well as conventional T1-weighted and T2-weighted MRI’s at 7T. Tissue fixation, histological/immunohistochemical techniques, and light-microscopy will be used to classify and quantify the presence of various pathological parameters, including myelin density, microglia proliferation, oligodendrocyte density, phosphorylated tau, tissue iron content, vessel wall thickness, and amyloid deposition. Our goal is to characterize the MR signature patterns that correlated with various pathological features in white matter abnormalities. Defining the multi-modal MR signatures that correlate with ominous histopathological features, and the relationship between pathological diagnosis and MR signal in the normal-appearing white matter will allow us to disentangle MR features that reflect pathological changes driving cognitive decline from those that are related to other factors such as aging. Establishing this histo-radiological link will sharpen the focus of in- vivo MR methods and allow their incorporation in future studies to more precisely monitor and predict cognitive decline in ADRD. In addition to its non-amyloid approach, this proposal brings together resources of multiple cores at MADRC and involves the expertise from three major universities in Michigan, each with its own set of skill sets to drive the project forwards. In addition, the raw data from these efforts will be shared among other centers to allow for future collaborative work in the field.

摘要-补充 我们试图确定阿尔茨海默病中白色物质组织病理学特征的MR相关性， 相关疾病（ADRD），通过结合MADRC神经病理学核心的资源， 死后冷冻组织以及大量伴随的死前MR研究，资源包括 MADRC神经成像核心及其先进的MR设施，由MR采集领域的专家组成， 后处理和参数化。死后组织学研究和死后成像研究 表明多种病理常常共存，而单一病理常常是例外， 通过经常出现假定为血管来源的脑部病变（如白色物质）证实 (WM)病变、微出血和微梗塞。这种病变的临床意义和程度 导致临床下降的原因尚不清楚，部分原因是常规MRI技术，如T1和T2加权 成像缺乏进一步表征其病理基础如脱髓鞘的特异性， 神经胶质增生或轴突缺失。以诊断为血管性痴呆的供体的死前MR研究为指导 (VD)，阿尔茨海默病（AD）和神经系统完整的供体（ND），我们将分析冷冻尸检 LPVO周围脑区和无任何T2异常的脑区的组织。我们将 从这些组织获得高级MR（MWF、ihMT和多壳、多向扩散）参数 块以及7 T下的常规T1加权和T2加权MRI。组织固定， 组织学/免疫组织化学技术和光学显微镜将用于分类和定量 存在各种病理参数，包括髓鞘密度、小胶质细胞增殖、少突胶质细胞 密度、磷酸化tau、组织铁含量、血管壁厚度和淀粉样蛋白沉积。我们的目标是 表征与白色物质中各种病理特征相关的MR特征模式 异常定义与不祥的组织病理学特征相关的多模态MR特征， 病理诊断与正常白色物质MR信号的关系 使我们能够将反映导致认知能力下降的病理变化的MR特征与那些 与其他因素有关，如老化。建立这种组织-放射学联系将使重点更加突出， 体内MR方法，并允许其纳入未来的研究，以更精确地监测和预测认知 ADRD下降。除了其非淀粉样蛋白的方法，这项建议汇集了多种资源， 核心是MADRC，涉及密歇根州三所主要大学的专业知识，每一所大学都有自己的一套 推动项目向前发展的技能。此外，这些工作的原始数据将与其他机构共享。 中心，以便在该领域的未来合作工作。