The Contribution of Age-Related Tauopathies to Alzheimer's Disease

年龄相关的 Tau蛋白病对阿尔茨海默病的影响

基本信息

批准号：
10740116
负责人：
John Fonda Crary
金额：
$ 243.07万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10740116
关键词：
Age Aging Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Amyloid beta-Protein Argyrophilic Grain Disease Astrocytes Biological Markers Brain Classification Clinical Cognition Cognitive Consensus Data Set Databases Dementia Deposition Detection Diagnosis Digital Libraries Disease Elderly Epitopes Evaluation Foundations Frequencies Funding Gene Expression Goals Health Hippocampus Impaired cognition Individual Leadership Life Machine Learning Manuscripts Mission Molecular Molecular Profiling Nerve Degeneration Neurobehavioral Manifestations Oligodendroglia Pathology Pattern Personal Satisfaction Persons Phosphorylation Progressive Supranuclear Palsy Proteins Protocols documentation Public Health Publishing Random Allocation Research Resources Role Scheme Staging Stains Symptoms Tauopathies Therapeutic Tissues Underrepresented Populations Update age related alpha synuclein cell type chronic traumatic encephalopathy clinical diagnosis deep learning algorithm diagnostic tool digital image archival system improved indexing insight mild cognitive impairment neuroinflammation neuropathology neuropsychiatric symptom neuropsychiatry novel novel diagnostics novel marker protein TDP-43 sex single nucleus RNA-sequencing single-cell RNA sequencing tau Proteins tau mutation tau-1 therapeutic target whole slide imaging

项目摘要

Project Abstract Establishing an accurate neuropathological diagnosis is a critical function of Alzheimer’s Disease Research Centers and a prerequisite to tissue-based research. Alzheimer’s disease (AD), chronic traumatic encephalopathy (CTE), primary age-related tauopathy (PART), progressive supranuclear palsy (PSP), argyrophilic grain disease (AGD), and aging-related tau astrogliopathy (ARTAG) are all age-related tauopathies. Each has distinctive patterns of abnormal tau deposition and clinical manifestations. While AD is the most common pathology, the other tauopathies are present in as many as 20% of brains. We recently spearheaded consensus panels to update criteria to diagnose CTE, PART, PSP, and ARTAG, yet these disorders are not captured well in the National Alzheimer’s Coordinating Center (NACC) database. During our first funding cycle, we published 29 manuscripts, showed that 4R immunostaining improves recognition of CTE in early cases and in young people, and established the roles of 4R and 3R tau, different phosphorylation epitopes, different cell types, and the utility of our staging scheme in CTE. We identified JADE1 in 4R tauopathies, the distinctive hippocampal p-tau pathology of CTE, PART vs. AD and uncovered unique neuroinflammatory proteins that distinguish CTE, PSP and AD. In addition, we showed that deep machine learning-based approaches allow recognition and quantification of tau and other pathologies and can identify novel regional and cellular features that predict dementia. We performed single nucleus RNA sequencing of oligodendrocytes and astrocytes in CTE, established a digital whole slide image (WSI) library of 150 index cases of AD, CTE, PART and AGD and developed a novel REDcap assessment protocol for tauopathies. Our long-term goal is to advance our understanding of the neuropathological signatures of the tauopathies to build a foundation for mechanistic studies that will enable new biomarkers and therapeutic targets. The objective of this proposal is to continue to identify novel markers for CTE, PART, AGD, and ARTAG, and to expand the scope to include PSP and cases from underrepresented groups. We will continue to build a digital library of WSI from 600 randomly selected, age and sex-matched NACC brain donors, including 200 people with normal cognition, 200 with mild cognitive impairment and 200 with dementia to determine if re-assessment yields previously undetected cases of the age- related tauopathies. We will examine the contribution of those pathologies to cognitive and neuropsychiatric symptoms (NPS). In addition, we will determine whether prediction of cognitive impairment and NPS is improved using supervised and unsupervised deep learning algorithms. We will also use single nucleus RNA sequencing to examine alterations in gene expression in astrocytes and oligodendrocytes in CTE, PART, PSP, vs. AGD. This proposal is significant because it will answer a critically unmet need in the study of neurodegeneration, it will establish the frequency of the age-related tauopathies in the NACC database and determine whether these tauopathies contribute to the clinical expression of cognitive and neuropsychiatric decline.

项目摘要建立准确的神经病理学诊断是阿尔茨海默病研究的关键功能阿尔茨海默病（AD）、慢性创伤性研究的中心和先决条件。脑病 (CTE)、原发性年龄相关 tau 蛋白病 (PART)、进行性核上性麻痹 (PSP)、嗜银颗粒病 (AGD) 和衰老相关 tau 星形胶质细胞病 (ARTAG) 都是与年龄相关的 tau 病。每种疾病都有独特的异常 tau 沉积模式和临床表现，其中 AD 最为常见。除了常见的病理学之外，其他 tau蛋白病也存在于多达 20% 的大脑中，我们最近率先提出了这一点。共识小组更新了 CTE、PART、PSP 和 ARTAG 的诊断标准，但这些疾病并未在我们的第一个资助周期中，国家阿尔茨海默病协调中心 (NACC) 数据库中充分记录了这一情况。我们发表了 29 篇手稿，表明 4R 免疫染色提高了对早期病例中 CTE 的识别，并且在年轻人中，并建立了 4R 和 3R tau、不同磷酸化表位、不同细胞的作用类型，以及我们的分期方案在 CTE 中的效用，我们在 4R tau蛋白病（独特的 4R tau蛋白病）中发现了 JADE1。 CTE、PART 与 AD 的海马 p-tau 病理学并发现了独特的神经炎症蛋白区分 CTE、PSP 和 AD 此外，我们还表明基于深度机器学习的方法允许。识别和量化 tau 蛋白和其他病理，并能识别新的区域和细胞特征我们对 CTE 中的少突胶质细胞和星形胶质细胞进行了单核 RNA 测序，建立了包含 AD、CTE、PART 和 AGD 150 个索引案例的数字全玻片图像 (WSI) 库，开发了一种针对 tau蛋白病的新型 REDcap 评估方案。我们的长期目标是推进我们的研究。了解 tau 病的神经病理学特征，为机制奠定基础该提案的目标是继续进行新的生物标志物和治疗靶点的研究。识别 CTE、PART、AGD 和 ARTAG 的新标记，并将范围扩大到包括 PSP 和病例我们将继续从 600 个随机选择的年龄群体中建立一个 WSI 数字图书馆。和性别匹配的 NACC 大脑捐赠者，其中 200 名认知正常的人，200 名轻度认知的人损伤和 200 患有痴呆症，以确定重新评估是否产生以前未发现的年龄- 我们将研究这些病理学对认知和神经精神的贡献。此外，我们将确定认知障碍和 NPS 的预测是否得到改善。使用监督和无监督深度学习算法我们还将使用单核 RNA 测序。 CTE、PART、PSP 与 AGD 中星形胶质细胞和少突胶质细胞基因表达的变化。该提案意义重大，因为它将满足神经退行性研究中一个严重未满足的需求，它将确定 NACC 数据库中与年龄相关的 tau蛋白病的频率，并确定这些是否 tau蛋白病导致认知和神经精神下降的临床表现。