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：
10431908
负责人：
John Fonda Crary
金额：
$ 81.77万
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 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10431908
关键词：
Address Affect Aggressive behavior Aging Agitation Alzheimer disease prevention Alzheimer&apos s Disease Amygdaloid structure Anxiety Argyrophilic Grain Disease Biological Markers Blood Vessels Boston Brain Brain Diseases Brain region Clinic Clinical Cognition Cognitive Consensus Data Data Set Databases Dementia Deposition Detection Development Diagnosis Diagnostic Diagnostic Errors Disease Elderly Episodic memory Frequencies Goals Health Hippocampus (Brain)Impaired cognition Impairment Individual International Investigation Knowledge Lead Lewy Body Disease Memory Disorders Mental Depression Mission Molecular Neurodegenerative Disorders Pathologic Pathology Patients Pattern Personal Satisfaction Prefrontal Cortex Protocols documentation Public Health Reproducibility Research Research Personnel Sampling Severities Sleep disturbances Standardization Subgroup Tauopathies Therapeutic Tissues United States National Institutes of Health Universities age discrimination age related aged base chronic traumatic encephalopathy clinical diagnosis comorbidity diagnostic strategy diagnostic tool diagnostic value end of life improved inflammatory marker insight mild cognitive impairment neuroinflammation neuropathology neuropsychiatric symptom neuropsychiatry novel novel diagnostics protein TDP-43 symposium tau Proteins tau mutation

项目摘要

Establishing an accurate neuropathological diagnosis is a critical function of the Alzheimer's Disease Center (ADC) Neuropathology Cores and is a prerequisite to all tissue-based research. Although chronic traumatic encephalopathy (CTE), primary age-related tauopathy (PART), argyrophilic grain disease (AGD) and aging- related tau astrogliopathy (ARTAG) are all age-related tauopathies, each has distinctive patterns of abnormal tau deposition. Additionally, each has specific, but overlapping, effects on cognitive and neuropsychiatric function. Neuropathological criteria to diagnose CTE, PART, AGD and ARTAG have been recently proposed, yet no modules exist to capture these disorders in the National Alzheimer's Coordinating Center (NACC) database. Without rigorous, reproducible protocols for the diagnosis of age-related tauopathies, their disease- specific contributors to late life cognitive and neuropsychiatric impairment may be overlooked and obscured. This proposal will draw on the neuropathological expertise of Drs. Ann McKee, Dennis Dickson, and John Crary, who have pioneered investigations of CTE, AGD and PART. We will use 250 cases of AD and age- related tauopathies from the Boston University, Mayo Clinic Jacksonville and Mount Sinai ADCs to identiify novel tau and inflammatory markers that accurately detect and distinguish the age-related tauopathies. After re-examining tissue from the NACC-Neuropathology Data Set (NDS), we will establish the frequency of CTE, PART, AGD and ARTAG among individuals who had ante-mortem clinical diagnoses of normal cognition, mild cognitive impairment, or dementia. We will determine the unique contribution of these disorders to clinical diagnosis and to cognitive and neuropsychiatric impairment. We will also determine whether examining under- studied brain regions, namely the prefrontal cortex, uncal gyrus and amygdala identifies new cases of age- related tauopathies and whether pathology in these regions contributes to neuropsychiatric impairment. Lastly, we will apply knowledge gained from this project to develop CTE, PART, AGD and ARTAG assessment and diagnostic modules that we will use to organize an international NIH consensus conference to harmonize the neuropathological diagnoses of the age-related tauopathies for general use. Overall, this proposal will address critical, yet still unknown issues related to CTE, PART, AGD and ARTAG: 1) Identification of novel tau and neuroinflammatory biomarkers to aid in detection and discrimination of the age-related tauopathies, 2) Determination of age-related tauopathy frequency among memory disorder clinic patients; 3) Determination of age-related tauopathy contribution to cognitive and neuropsychiatric impairment; and 4) Development of harmonized criteria for age-related tauopathy neuropathological diagnosis. This project will also enrich the existing NACC-NDS, making data on age-related tauopathies available to other researchers. Overall, the successful completion of this proposal will transform the way we conceptualize the tauopathies and will facilitate future research on the diagnosis, treatment, and prevention of AD and related disorders.

建立准确的神经病理学诊断是阿尔茨海默病中心的一项重要职能 (ADC) 神经病理学核心，是所有基于组织的研究的先决条件。虽然是慢性创伤脑病 (CTE)、原发性年龄相关 tau 蛋白病 (PART)、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 蛋白病，每种都有独特的异常模式 tau 沉积。此外，每种因素对认知和神经精神都有特定但重叠的影响功能。最近提出了诊断 CTE、PART、AGD 和 ARTAG 的神经病理学标准，但国家阿尔茨海默病协调中心 (NACC) 不存在捕获这些疾病的模块数据库。如果没有严格的、可重复的方案来诊断与年龄相关的 tau蛋白病，他们的疾病- 导致晚年认知和神经精神障碍的具体因素可能被忽视和掩盖。该提案将利用 Drs 的神经病理学专业知识。安·麦基、丹尼斯·迪克森和约翰 Crary 是 CTE、AGD 和 PART 研究的先驱。我们将使用 250 例 AD 和年龄- 来自波士顿大学、杰克逊维尔梅奥诊所和西奈山 ADC 的相关 tau蛋白病，以识别新型 tau 蛋白和炎症标记物可准确检测和区分与年龄相关的 tau 蛋白病。后重新检查 NACC-神经病理学数据集 (NDS) 中的组织，我们将确定 CTE 的频率，生前临床诊断为正常认知、轻度认知障碍的个体的 PART、AGD 和 ARTAG 认知障碍，或痴呆。我们将确定这些疾病对临床的独特贡献诊断以及认知和神经精神障碍。我们还将确定是否审查不足研究大脑区域，即前额皮质、钩回和杏仁核，发现了新的年龄相关病例相关的tau蛋白病以及这些区域的病理是否会导致神经精神损伤。最后，我们将运用从该项目中获得的知识来开发 CTE、PART、AGD 和 ARTAG 评估，我们将使用该诊断模块来组织国际 NIH 共识会议，以协调与年龄相关的 tau蛋白病的神经病理学诊断，通用。总体而言，该提案将解决与 CTE、PART、AGD 和 ARTAG 相关的关键但仍未知的问题：1) 新型 tau 和神经炎症生物标志物有助于检测和区分与年龄相关的 tau蛋白病，2) 确定记忆障碍门诊患者中与年龄相关的 tau 蛋白病频率； 3) 测定年龄相关的 tau 蛋白病对认知和神经精神障碍的影响； 4) 开发年龄相关 tau 蛋白病神经病理学诊断的统一标准。该项目也将丰富现有的 NACC-NDS，为其他研究人员提供与年龄相关的 tau蛋白病的数据。总体而言，该提案的成功完成将改变我们对 tau蛋白病的概念化方式，并将促进未来关于 AD 及相关疾病的诊断、治疗和预防的研究。