Microstructural MRI Microscopy of Post-mortem Specimens to Identify and Improve Markers of Alzheimer's Disease Pathology

尸检标本的微结构 MRI 显微镜可识别和改善阿尔茨海默病病理学标志物

基本信息

批准号：
10190347
负责人：
ELIZABETH B HUTCHINSON
金额：
$ 16.15万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10190347
关键词：
Address Affect Alzheimer disease detection Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease diagnosis Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Amygdaloid structure Amyloid beta-Protein Anatomy Arizona Atrophic Autopsy Basic Science Biochemical Brain Brain Stem Brain region Cells Cellular Morphology Cellularity Clinical Consequentialism Data Detection Development Diagnosis Diffusion Diffusion Magnetic Resonance Imaging Early Diagnosis Ensure Environment Equipment Foundations Future Goals Hippocampus (Brain)Histology Hour Human Image Imaging Device Imaging Techniques Imaging technology Immunohistochemistry Lewy Body Disease Life Magnetic Resonance Imaging Methodology Methods Microscopy Modality Myelin Neurites Neurobiology Neurofibrillary Tangles Outcome Pathologic Pathology Patients Peptides Procedures Process Proteins Radiology Specialty Recovery Research Research Personnel Research Proposals Resolution Resources Science Senile Plaques Sensitivity and Specificity Severities Specificity Specimen Stains Structure Techniques Temporal Lobe Time Tissues Translations Universities Vision Water Work alpha synuclein analysis pipeline base beta amyloid pathology bioimaging brain health brain tissue clinical Diagnosis comorbidity density dorsal raphe nucleus hippocampal sclerosis human disease human tissue imaging biomarker imaging facilities imaging modality improved locus ceruleus structure macromolecule microscopic imaging neuroimaging neuropathology novel novel strategies protein TDP-43 recruit response statistics targeted imaging tau Proteins tau aggregation tau-1 tissue processing tool translation to humans white matter

项目摘要

Summary Microstructural MRI techniques are unique among neuroimaging modalities because they probe tissue features at the micron scale that are invisible using other methods. This class of MRI methods is therefore promising to address the unmet needs for neuroimaging in Alzheimer’s disease (AD) and related dementias: 1. early detection of subtle cellular and protein alterations and 2. delineation of comorbid pathologies in AD. In particular, diffusion MRI (dMRI) is sensitive to alterations in cellularity, cell morphology, and other microstructural changes and relaxometery MRI (rMRI) is sensitive to macromolecular content. Both of these microstructural MRI techniques are relevant for detecting AD pathology, namely beta-amyloid (Ab) plaques and Tau tangles, as well as comorbid pathologies such as Lewy body disease (LBD), hippocampal sclerosis (HS) and TDP-43 proteinopathy. While studies in humans have begun to use some of these approaches, there is a need to understand the radiologic-pathologic correspondence of MRI changes with the underlying tissue pathology and also to determine which of the more advanced dMRI and rMRI methods are the most promising for translation to human studies. In order to meet these challenges, we propose a “bottom-up” study using MRI microscopy to image post-mortem temporal lobe and brainstem tissue from humans with and without a clinical diagnosis of AD in life. Our first aim is the identification of dMRI and rMRI markers of AD pathology in which we will optimize and apply acquisition, processing and analysis strategies for post-mortem tissue for diffusion tensor MRI (DTI), mean apparent propagator MRI (MAP-MRI), q-space trajectory imaging (QTI), bound pool fraction (BPF) and myelin water fraction (MWF) mapping. Then the tissue will be stained for phosphorylated Tau (pTau) and Ab and undergo neuropathologic review and scoring as well as quantitative histology. Correlation statistics will be performed between MRI metrics and neuropathologic outcomes to identify radiologic- pathologic relationships. In our second aim, we will investigate comorbid pathologies by the additional staining and scoring of a-synuclein and TDP-43. Similar correlation analysis will be used to determine the dMRI and rMRI metric profiles associated with LBD and TDP-43 proteinopathy. Our final aim will then compare these radiologic-pathologic signatures in different temporal lobe structures (e.g. hippocampus, amygdala, cortex and white matter) and in brainstem regions (locus coeruleus, dorsal raphe nucleus and white matter tracts). Overall, our goal is to establish initial findings about the most promising MRI methods for further development and translation of improved MRI markers for AD research and diagnosis.

概括微观结构 MRI 技术在神经影像学模式中是独一无二的，因为它们探测组织因此，使用其他方法无法看到的微米级特征。有望解决阿尔茨海默病 (AD) 及相关疾病的神经影像学未满足的需求痴呆症：1. 早期发现细微的细胞和蛋白质变化，2. 描述共病尤其是 AD 的病理学，扩散 MRI (dMRI) 对细胞结构、细胞的变化很敏感。形态学和其他微观结构变化以及弛豫 MRI (rMRI) 对这两种微观结构 MRI 技术都与检测 AD 相关。病理学，即 β-淀粉样蛋白 (Ab) 斑块和 Tau 缠结，以及共病病理学，例如路易体病 (LBD)、海马硬化症 (HS) 和 TDP-43 蛋白病在人类中进行的研究。已经开始使用其中一些方法，有必要了解放射学病理学 MRI 变化与潜在组织病理学的对应关系，并确定哪些更先进的 dMRI 和 rMRI 方法最有希望转化为人类研究。为了应对这些挑战，我们提出了一项“自下而上”的研究，使用 MRI 显微镜对尸检进行成像来自生活中患有或未患有 AD 临床诊断的人类的颞叶和脑干组织。第一个目标是识别 AD 病理学的 dMRI 和 rMRI 标志物，我们将在其中优化和应用弥散张量 MRI (DTI) 死后组织的采集、处理和分析策略，平均表观传播 MRI (MAP-MRI)、q 空间轨迹成像 (QTI)、结合池分数 (BPF) 然后对组织进行磷酸化 Tau (pTau) 染色。和 Ab 并进行神经病理学检查和评分以及定量组织学。将在 MRI 指标和神经病理结果之间进行统计，以确定放射学- 在我们的第二个目标中，我们将通过额外的方法来研究共病病理。类似的相关性分析将用于确定α-突触核蛋白和TDP-43的染色和评分。我们的最终目标是与 LBD 和 TDP-43 蛋白病相关的 dMRI 和 rMRI 指标。比较不同颞叶结构（例如海马、杏仁核、皮质和白质）和脑干区域（蓝斑、中缝背核和总体而言，我们的目标是确定最有前途的 MRI 的初步发现进一步开发和转化用于 AD 研究和诊断的改进 MRI 标记的方法。