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技术在神经影像学方式中是独一无二的，因为它们探测组织使用其他方法看不见的微米量表的特征。因此，这类MRI方法是有望满足阿尔茨海默氏病（AD）和相关神经影像的未满足需求痴呆症：1。早期检测细微的细胞和蛋白质改变以及2。合并症的描述 AD中的病理。特别是，扩散MRI（DMRI）对细胞的改变敏感形态学以及其他微结构变化和松弛计MRI（RMRI）对大分子含量。这两种微观结构MRI技术都与检测AD有关病理学，即β-淀粉样蛋白（AB）斑块和tau缠结，以及合并症等病理路易疾病（LBD），海马硬化症（HS）和TDP-43蛋白质病。在人类的研究时已经开始使用其中一些方法，需要了解放射科学 MRI的对应与潜在的组织病理变化，并确定哪些更先进的DMRI和RMRI方法是翻译为人类研究的最有希望的方法。为了为了应对这些挑战，我们提出了使用MRI显微镜图像验尸的“自下而上”研究有或没有生命中AD临床诊断的人类的临时叶和脑干组织。我们的第一个目的是识别AD病理的DMRI和RMRI标记，我们将在其中优化和应用验收后组织的获取，加工和分析策略进行扩散张量MRI（DTI），平均表观繁殖器MRI（MAP-MRI），Q-Space轨迹成像（QTI），绑定池馏分（BPF）和髓鞘水分（MWF）映射。然后将组织染色以用于磷酸化的tau（PTAU） AB并接受神经病理学的综述和评分以及定量组织学。相关性将在MRI指标和神经病理学结果之间进行统计数据，以鉴定放射线学 - 病理关系。在我们的第二个目标中，我们将通过附加的病理研究 A-核蛋白和TDP-43的染色和评分。类似的相关分析将用于确定 DMRI和RMRI度量谱与LBD和TDP-43蛋白质病有关。然后我们的最终目标将比较不同临时叶结构中的这些放射科学特征（例如，海马，杏仁核，皮质和白质）以及脑干区域（座位层，背raphe核和白质区）。总体而言，我们的目标是建立有关最有前途的MRI的初步发现用于进一步开发和翻译AD研究和诊断的MRI标记的方法。