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Age-related TDP-43 neuropathology: using disease-driving mechanisms to guide classification

年龄相关的 TDP-43 神经病理学：利用疾病驱动机制指导分类

基本信息

批准号：
10056816
负责人：
MATTHEW DANIEL CYKOWSKI
金额：
$ 317.9万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10056816
关键词：
ABCC9 gene Address Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Amnestic Disorder Amygdaloid structure Amyloid Amyloid beta-Protein Anatomy Area Arteriosclerosis Automobile Driving Autopsy Biological Assay Biometry Blood Vessels Brain Brain Pathology Brain region Cells Classification Classification Scheme Clinical Clinics and Hospitals Communities Complex Data Detergents Disease Elderly Future Genetic Polymorphism Genomics Goals Hospitals Human Immunoblotting Immunohistochemistry Impaired cognition Individual Institution Kentucky Knowledge Location Mass Spectrum Analysis Methodist Church Methods Nerve Degeneration Pathologic Pathology Patients Persons Phase Process Proteins Proteome Proteomics Research Research Design Resistance Resources Risk Factors Sampling Structure Testing Universities Work age related aging brain aging population alpha synuclein base biomarker development cohort comorbidity density disorder subtype frontotemporal lobar dementia-amyotrophic lateral sclerosis genetic risk factor genetic variant improved insight limbic-predominant age-related TDP-43 encephalopathy misfolded protein multidisciplinary multimodal data multimodality neuropathology novel programs protein TDP-43 tau Proteins therapeutic development vascular injury white matter

项目摘要

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a common pathology of aging, associated with an amnestic syndrome mimicking Alzheimer’s disease (AD). The co- morbid pathologic and genetic risk factors of LATE-NC remain incompletely understood. The goals of this proposal are to clarify the mechanisms underlying LATE-NC, to determine how these mechanisms interact and affect subregions of human amygdalae, and to generate a practical classification scheme of LATE-NC that is necessary to guide future studies. The amygdala is the first brain region affected in LATE-NC and therefore represents the best anatomic region to understand LATE-NC in its earliest phase(s). A major challenge has been to reconcile mechanisms underlying TDP-43 proteinopathy in community-based autopsy cohorts of older adults (which show a spectrum of complex age-related diseases such as LATE-NC, and mixed pathologies), with results in hospital/clinic-based cohorts that tend to include autopsy patients with less common but “pure” TDP-43 proteinopathies, such as FTLD-TDP and ALS. Therefore, we will combine results from a high quality community-based autopsy cohort (U. Kentucky) with an excellent hospital-based cohort (Houston Methodist Hospital) to analyze common disease-driving mechanisms. The study will incorporate well-characterized human brains (N>1400 total) of patients with ALS-FTD spectrum disorders, and AD neuropathologic changes (ADNC), with and without comorbid LATE-NC. We will characterize the comorbid proteinopathies and vascular pathologies associated with the earliest foci of TDP-43 pathology, including co-localization of TDP-43 and other misfolded proteins, such as Tau. We hypothesize that the initiation of LATE-NC in human amygdalae results from a selective cellular vulnerability that varies in association with specific genetic risk factors. We will examine and contrast the proteomic profiles of susceptible and resistant subregions of human amygdalae, both within individuals and across disease states (e.g., LATE-NC versus ADNC, LATE-NC versus ALS-FTD spectrum, including FTLD-TDP cases. We also hypothesize that pathologically and genetically distinct forms of age-related TDP-43 proteinopathy exist in human brains, including: (a) an ADNC-related subtype influenced by APOE, (b) a FTLD-related subtype affected by GRN and TMEM106B, and (c) an arteriosclerosis-related subtype associated with ABCC9 gene variant. We will test methods of disease delineation - areas of overlap and points of difference - and evaluate how these hypothesized mechanism-classified subtypes synergize or negate each other when they are comorbid, and how the disease subtypes manifest clinically. The multimodal data may indicate a practical classification scheme. The two-institution study design enables us to evaluate inter-rater reliability and to emphasize replicability. Overall, the project will clarify mechanisms contributing to age-related TDP-43 pathology, and provide an optimized and useful framework to guide future mechanistic studies, therapeutic development, and biomarker development.

边缘显性年龄相关性TDP-43脑病神经病理改变（LATE-NC）是一种常见的脑病