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

阿尔茨海默病神经病理学和神经变性的多尺度结构成像

基本信息

批准号：
10207104
负责人：
BRADFORD C DICKERSON
金额：
$ 46.11万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2021-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10207104
关键词：
Alzheimer disease screening Alzheimer&apos s Disease Alzheimer&apos s disease therapeutic Amyloid Area Atrophic Autopsy Biological Biological Markers Brain Cerebrospinal Fluid Characteristics Classification Clinic Clinical Clinical Research Clinical Trials Complex Computer Models Data Data Set Databases Dementia Detection Development Enrollment Heterogeneity Histopathology Image Individual Label Laboratories Magnetic Resonance Imaging Maps Massachusetts Measurement Measures Methods Molecular Disease Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Pathology Patients Phenotype Positron-Emission Tomography Procedures Property Research Resolution Spinal Puncture Structure Symptoms Testing Thick Tissues Validation Work base clinical care clinical diagnostics clinical trial participant cost effective early screening effective therapy in vivo mild cognitive impairment molecular marker molecular pathology morphometry neuron loss neuropathology novel patient subsets pre-clinical screening specific biomarkers support vector machine tau Proteins three dimensional structure

项目摘要

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.

项目摘要/摘要。高级生物标志物映射已导致当前的理解，即阿尔茨海默氏病（AD）是极其复杂的神经退行性疾病，临时和空间中具有很大的异质性经典淀粉样蛋白和TAU病理的特征以及患者导致的神经退行性的特征（如淀粉样蛋白-tau-神经变性，“ A-T-N”生物学框架，是新标准表征AD的神经病理学）。这种复杂性是临床护理和临床护理的主要障碍开发有效的疗法，强调综合生物标志物神经膜的重要性了解广告。但是，患者的神经病理学表征仍然存在重大挑战。绘制AD神经退行性成分（N）的当前程序在对早期的敏感性方面受到限制病理。此外，基于淀粉样蛋白和TAU的原发性AD神经病理学的特定生物标志物仅通过相对侵入性和/或昂贵的正电子发射断层扫描（PET）和专业实验室和诊所中的腰椎穿刺（LP）脑脊液（CSF）程序。我们在这里为了在多个层面上推进AD神经病理学映射：1）我们将实施一种新型的多尺度结构映射（MSSM）MRI程序，用于对AD神经退行性成分的敏感定量； 2）我们将使用MSSM程序在有症状和/或无症状的个体，提供高度可访问的病理检测方法生物标志物不可用； 3）我们将通过集成来创建个性化的“ A-T-N”脑图具有现有PET淀粉样蛋白和TAU数据的MSSM指标； 4）我们将为该地区使用MSSM功能淀粉样蛋白和tau病理的预测在没有宠物数据时使用。我们的具体目标是：目标 1。测试新型MSSM程序的准确性，以示意症状和概率分类无症状的个体为淀粉样蛋白“阳性”或tau“阳性”。假设1a（H1a）。我们假设MSSM“ N”度量可以具有高度的灵敏度来预测个人是否是通过使用标准阈值和/或使用标准阈值测量的A+通过PET测量的A+ 两个都。 H1b。 MSSM将比常规MRI提供更好的个体分离为N+ N- 通过与分子病理和临床进展一致的一致性来验证萎缩量。目标2。利用新颖的MSSM特征来合成AD神经病理学变化的宠物样图。 H2A。 MSSM特征将对特定区域神经病理学变化提供准确的空间预测。预言将针对独立的体内数据集测量精度，包括带有尸检确认的子集以及斑块，缠结和神经元损失的区域定量。成功的MSSM实施将大大提高了筛查早期和复杂的AD神经病理学的能力。成功的MSSM 实施将大大提高筛查AD神经病理学的能力。