Muli-scale Structural Imaging of Alzheimer's Disease Neuropathology and Neurodegeneration

项目概要/摘要。 先进的生物标志物图谱已经导致目前的理解，即阿尔茨海默病（AD）是一种 非常复杂的神经退行性疾病，在时间和空间上具有实质性异质性 患者中典型淀粉样蛋白和tau蛋白病理学的特征以及由此产生的神经变性 (as由淀粉样蛋白-tau-神经变性，“A-T-N”生物学框架描述，该框架是 表征AD的神经病理学）。这种复杂性是临床护理的主要障碍， 开发有效的治疗方法，强调综合生物标志物神经映射的重要性， 了解AD然而，在患者的神经病理学表征方面仍然存在重大挑战。 目前用于标测AD的神经退行性成分（N）的程序在对早期AD的敏感性方面是有限的。 病理此外，基于淀粉样蛋白和tau蛋白的原发性AD神经病理学的特异性生物标志物 仅可通过相对侵入性和/或昂贵的正电子发射断层扫描（PET）获得， 在专业实验室和诊所进行腰椎穿刺（LP）脑脊液（CSF）检查。我们瞄准这里 为了在多个层面上推进AD神经病理学映射：1）我们将实施一种新的多尺度结构， 磁共振成像（MSSM）程序，用于AD的神经变性成分的灵敏定量; 2）我们 将使用MSSM程序来差异性预测有症状和无症状患者中的淀粉样蛋白和/或tau蛋白阳性， 无症状的个体，提供了一种高度可及的病理检测方法， 生物标志物不可用; 3）我们将通过整合生物标志物来创建个性化的“A-T-N”脑图。 MSSM指标与现有的PET淀粉样蛋白和tau数据;以及4）我们将使用MSSM特征用于区域 预测淀粉样蛋白和tau病理学，用于PET数据不可用时。我们的目标是：目标 1.为了测试一种新的MSSM程序的准确性， 无症状的个体为淀粉样蛋白“阳性”或tau“阳性”。假设1a（H1 a）。我们 假设MSSM“N”度量可以以高灵敏度水平用于预测个体是否 使用标准阈值通过PET测量的A+和/或使用标准阈值通过PET测量的T+，或 两者H1b。MSSM将比传统的基于MRI的方法更好地分离N+与N-个体。 萎缩测量，通过与分子病理学和临床进展的一致性进行验证。目标2. 利用新的MSSM特征合成AD神经病理改变的PET样图。H2a。 MSSM特征将提供特定区域神经病理变化的准确空间预测。预测 将根据独立的体内数据集（包括尸检确认的子集）测量准确度 以及斑块、缠结和神经元损失的区域定量。成功实施MSSM将 大大提高了筛查早期和复杂AD神经病理学的能力。成功的MSSM 实施将大大提高筛选AD神经病理学的能力。

Project Summary/Abstract. Advanced biomarker mapping has led to the current understanding that Alzheimer’s disease (AD) is an extremely complex neurodegenerative disorder, with substantial heterogeneity in temporal and spatial characteristics of the classical amyloid and tau pathologies and resultant neurodegeneration among patients (as described by the amyloid-tau-neurodegeneration, ‘A-T-N’ biological framework that is the new standard for characterizing the neuropathology of AD). This complexity is a major barrier to clinical care and to the development of effective therapies, highlighting the importance of integrated biomarker neuromapping for understanding AD. However, substantial challenges remain in the neuropathologic characterization of patients. Current procedures for mapping the neurodegenerative component (N) of AD are limited in sensitivity to early pathology. Additionally, the specific biomarkers of the amyloid- and tau-based primary AD neuropathologies are only available through relatively invasive and/or expensive positron emission tomography (PET) and lumbar puncture (LP) cerebrospinal fluid (CSF) procedures in specialized laboratories and clinics. We aim here to advance AD neuropathology mapping on multiple levels: 1) we will implement a novel multi-scale structural mapping (MSSM) MRI procedure for sensitive quantification of the neurodegeneration component of AD; 2) we will use the MSSM procedure to differentially predict amyloid and/or tau positivity in symptomatic and asymptomatic individuals, providing a highly accessible method for pathology detection when advanced biomarkers are not available; 3) we will create individualized ‘A-T-N’ brainmaps through the integration of the MSSM metrics with existing PET amyloid and tau data; and 4) we will use MSSM features for the regional prediction of amyloid and tau pathology for use when PET data are not available. Our Specific Aims are: Aim 1. To test the accuracy of a novel MSSM procedure for probabilistic classification of symptomatic and asymptomatic individuals as being amyloid “positive” or tau “positive.” Hypothesis 1a (H1a). We hypothesize that MSSM ‘N’ metric can be used with a high level of sensitivity to predict whether an individual is A+ measured via PET using standard thresholds and/or T+ measured via PET using standard thresholds, or both. H1b. MSSM will provide better separation of individuals as N+ vs. N- than conventional MRI-based atrophy measures, validated through concordance with molecular pathology and clinical progression. Aim 2. To utilize the novel MSSM features for synthesis of PET-like maps of AD neuropathologic change. H2a. MSSM features will provide accurate spatial prediction of specific regional neuropathologic changes. Prediction accuracy will be measured against independent in vivo datasets including a subset with autopsy confirmation and regional quantification of plaques, tangles, and neuronal loss. Successful MSSM implementation would greatly advance the ability to screen for early and complex AD neuropathology. Successful MSSM implementation would greatly advance the ability to screen for AD neuropathology.