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Pathology-guided 7T neuroimaging biomarker in FTLD-TDP

FTLD-TDP 中病理学引导的 7T 神经影像生物标志物

基本信息

批准号：
10454272
负责人：
David John Irwin
金额：
$ 24.31万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10454272
关键词：
3-Dimensional 3D Print Affect Aging Alzheimer&apos s Disease Autopsy Biological Markers Biometry Brain Categories Cells Clinical Clinical Trials Complex Custom Data Databases Dementia Development Diagnosis Diffusion Magnetic Resonance Imaging Disease Disease Progression Disease model Fiber Frontotemporal Dementia Frontotemporal Lobar Degenerations Functional Magnetic Resonance Imaging Genetic Goals Gold Graph Heterogeneity Histology Histopathology Human Image Language Length Life Magnetic Resonance Imaging Maps Measures Mediating Methods Microscopic Microtomy Modality Modeling Molds Nerve Degeneration Neurocognitive Pathology Pathway Analysis Pathway interactions Patients Pattern Resolution Sampling Suggestion Symptoms Syndrome Tauopathies Tissues Translating Validation White Matter Disease Work base behavioral variant frontotemporal dementia biomarker development brain tissue cellular pathology cerebral atrophy connectome diagnosis standard digital ex vivo imaging frontotemporal degeneration graph theory gray matter image guided imaging biomarker imaging study in vivo neurodegenerative dementia neuroimaging neuroimaging marker neuropathology novel novel strategies prospective protein TDP-43 recruit targeted treatment tau Proteins tractography white matter

项目摘要

TDP-43 proteinopathy is a common form of neurodegenerative dementia (i.e. frontotemporal dementia, FTD) in patients younger than 65 (i.e. frontotemporal lobar degeneration with TDP-43 proteinopathy, FTLD-TDP) and is a common co-pathology in Alzheimer’s disease and aging. There are currently no biomarker modalities that can accurately identify and track TDP-43 mediated neurodegeneration in living patients, which poses a major obstacle for clinical trials targeting TDP-43 associated mechanisms of disease. Indeed, FTLD-TDP is an incurable condition and cannot be reliably diagnosed and differentiated from clinically similar patients with tauopathy (FTLD-Tau) during life, making autopsy the gold-standard for diagnosis. The overarching goal of this project is to integrate digital histology of human brain tissue with high-resolution ex vivo 7 Tesla (7T) magnetic resonance imaging (MRI) to model TDP-43 disease in the human brain connectome. We aim to first use ex vivo 7T MRI guided sampling of grey matter (GM) regions important for neurocognitive networks that underly FTD clinical symptoms and contrast the distribution of TDP-43 and clinically indistinguishable FTLD-Tau to determine microscopic GM cellular patterns of TDP-43 protienopathy. Next, we will examine TDP-43 pathology in uniquely sampled deep white matter (WM) tracts and contrast the distribution of TDP-43 and tau pathology in WM pathways of neurocognitive networks using graph theoretic analysis. Finally, we will examine GM laminar features of TDP-43 pathology in 7T MRI ex vivo imaging. Successful completion of these aims will provide critically needed autopsy-data to guide development of histopathology-validated markers of progressive microscopic TDP-43 disease in macroscale neurocognitive networks implicated in FTD.

TDP-43蛋白病是神经退行性痴呆（即额颞叶痴呆，FTD）的一种常见形式