AD-specific changes in the MTL: Novel biomarkers using in vivo / ex vivo imaging

MTL 中的 AD 特异性变化：使用体内/离体成像的新型生物标志物

• 批准号: 9301869
• 负责人: Paul A. Yushkevich
• 金额: $ 77.2万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9301869
• 关键词: Address; Adult; Age; Aging; Algorithms; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Anatomy; Area; Atlases; Autopsy; Biological; Biological Markers; Brain; Brain Pathology; Brain imaging; Brain region; Brodmann' s area; Cerebrovascular Disorders; Clinical Trials; Comorbidity; Computational Technique; Data; Data Set; Dimensions; Disease; Disease Progression; Funding; Goals; Hippocampus (Brain); Histologic; Histology; Hot Spot; Image; Image Analysis; Immunohistochemistry; Individual; Lateral; Link; MRI Scans; Magnetic Resonance Imaging; Maps; Measures; Medial; Methods; Modality; Modernization; Morphology; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuronal Injury; Neurons; Nissl Bodies; Outcome Measure; Participant; Pathologic; Pathology; Pattern; Pharmaceutical Preparations; Phase; Positron-Emission Tomography; Protocols documentation; Recruitment Activity; Research; Resolution; Rest; Scanning; Series; Societies; Spatial Distribution; Specimen; Staining method; Stains; Structure; Techniques; Temporal Lobe; Testing; Thick; Time; Validation; Vascular Diseases; Work; age effect; alpha synuclein; base; computational atlas; cost; density; entorhinal cortex; ex vivo imaging; extracellular; functional MRI scan; gray matter; histological image; imaging biomarker; improved; in vivo; in vivo imaging; longitudinal analysis; magnetic resonance imaging biomarker; molecular pathology; multi-atlas segmentation; neuroimaging; normal aging; novel; novel marker; pre-clinical; relating to nervous system; tau Proteins; treatment effect; ultra high resolution

Alzheimer's disease (AD) is one of the greatest challenges facing our society. Finding a cure will almost certainly require gaining a better understanding of the biological mechanisms that cause AD and distinguishing their effects from aging and commonly comorbid non-AD pathologies. Furthermore, drug trials in AD can benefit from more powerful biomarkers, particularly biomarkers that can better identify individuals who have incipient preclinical AD pathology and are likely to progress to the active neurodegenerative phase of AD in a short timeframe, as well as biomarkers that can act as surrogate measures of outcome by measuring the effects of a drug on subtle changes in the brain's structural integrity. This project will address these challenges by focusing on the medial temporal lobe (MTL), the area of the brain where the earliest AD-related neuronal injury occurs. The project will use a combination of ex vivo and in vivo imaging, including ex vivo and in vivo imaging in the same subjects, to characterize the effects of AD and non-AD pathology on the MTL and to identify “hot spots” in the MTL where changes observable on in vivo MRI are specific to AD pathology. Novel biomarkers of AD that leverage this information will be developed and evaluated using the recently funded Phase 3 of the Alzheimer's Disease Neuroimaging Initiative (ADNI3). Aim 1 will image 80 intact MTL autopsy specimens using ultra high-resolution 9.4 Tesla MRI and serial histological imaging with immunohistochemical staining for tau, beta-amyloid, TDP43, and alpha-synuclein pathologies. Brains from these autopsies will also be assessed for evidence of cerebrovascular disease. Histology data will be co-registered to the MRI, and MRI of all specimens will be co-registered to a novel ex vivo MRI template. Statistical mapping in the template space will be used to describe spatial distributions of AD and non-AD pathologies, to characterize the morphological effects of these pathologies, and to identify regions of the MTL where changes in structural integrity (i.e., gray matter thickness) specifically correlate with AD pathology. Aim 2 will extend prior work on automatic multi-atlas segmentation and quantification of MTL subregions in high-resolution T2-weighted in vivo MRI scans of the MTL with a novel atlas that combines ex vivo and in vivo imaging in the same subjects (n=40). This unique in vivo/ex vivo dataset will allow histological validation of MTL subregion segmentation protocols and algorithms, but will also serve as a conduit for mapping distributions of pathology and other rich information defined in the ex vivo template in Aim 1 into the space of in vivo imaging. Aim 3 will develop in vivo imaging biomarkers based on the cross-sectional and longitudinal analysis of high-resolution T2-weighted in vivo MRI. These biomarkers will incorporate information on the patterns of AD and non-AD pathology in the MTL derived in Aim 1. The proposed biomarkers will be evaluated using high-resolution T2-weighted in vivo MRI in ADNI3 (which is being obtained from over 1000 ADNI3 participants) and compared to current state of the art MRI and PET-based AD biomarkers.

阿尔茨海默病(AD)是我们社会面临的最大挑战之一。找到治愈方法几乎会 当然需要更好地了解导致阿尔茨海默病的生物学机制和区分 它们的影响来自衰老和通常合并的非阿尔茨海默病。此外，AD的药物试验可以 受益于更强大的生物标记物，特别是可以更好地识别具有 早期的阿尔茨海默病的临床前病理，并可能进展到AD的活跃的神经退行性变阶段 短时间框架，以及生物标记物，可以通过测量 药物对大脑结构完整性的细微变化的影响。该项目将解决这些挑战 通过专注于内侧颞叶(MTL)，大脑中最早与AD相关的神经元所在的区域 伤害就会发生。该项目将使用体外和体内成像的组合，包括体外和体内成像 相同受试者的成像，以表征AD和非AD病理对MTL和TO的影响 找出MTL中的“热点”，在活体MRI上可观察到的变化是AD病理特有的。小说 利用这些信息的AD生物标记物将使用最近资助的 阿尔茨海默病神经成像倡议(ADNI3)的第三阶段。 AIM 1将使用超高分辨率9.4特斯拉MRI和连续成像技术对80个完整的MTL尸检标本进行成像 Tau、β-淀粉样蛋白、TDP43和α-突触核蛋白免疫组织化学染色的组织学成像 病理学。这些尸检的大脑也将被评估是否有脑血管疾病的证据。 组织学数据将被共同注册到MRI，所有标本的MRI将被共同注册到一个新的EX 活体核磁共振模板。模板空间中的统计映射将用于描述AD的空间分布 和非AD病理，以表征这些病理的形态效应，并识别区域 结构完整性(即灰质厚度)的变化与AD具体相关的MTL 病理学。Aim 2将扩展先前在多图谱自动分割和MTL量化方面的工作 MTL的高分辨率T2加权在体MRI扫描中的亚区与一种新的图谱相结合 同一受试者的活体和活体成像(n=40)。这一独特的体内/体外数据集将允许组织学 验证MTL次区域分割协议和算法，但也将作为渠道 将目标1中的体外模板中定义的病理和其他丰富信息的分布映射到 活体成像的空间。AIM 3将开发体内成像生物标记物，基于横断面和 体内高分辨率T2加权成像的纵向分析。这些生物标志物将包含信息 关于AIM 1中导出的MTL中AD和非AD的病理模式。建议的生物标志物将是 在ADNI3中使用高分辨率T2加权在体MRI进行评估(从1000多个 ADNI3参与者)，并与目前最先进的磁共振成像和基于PET的AD生物标记物进行比较。