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

• 批准号: 10199918
• 负责人: John Fonda Crary
• 金额: $ 81.82万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10199918
• 关键词: Address; Affect; Aggressive behavior; Aging; Agitation; Alzheimer disease prevention; Alzheimer' 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; 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; tool

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氏病中心的关键功能 （ADC）神经病理学核心，是所有基于组织研究的先决条件。虽然慢性创伤 脑病（CTE），初级与年龄相关的双胞胎病（部分），杂粒谷物疾病（AGD）和衰老 相关的tau星形胶质病（ARTAG）都是与年龄相关的aopathies，每种都有独特的异常模式 tau沉积。此外，每个人都有对认知和神经精神病学的特定但重叠的影响 功能。最近提出了诊断CTE，部分，AGD和ARTAG的神经病理学标准，最近提出了 然而，在国家阿尔茨海默氏症协调中心（NACC）中，没有任何模块来捕获这些疾病 数据库。没有严格的可再现方案来诊断与年龄相关的tauopathies，他们的疾病 - 对晚期生活认知和神经精神障碍的特定贡献可能会被忽视和掩盖。 该建议将借鉴Drs的神经病理学专业知识。 Ann McKee，Dennis Dickson和John 克雷尔（Crary）率先对CTE，AGD和Part进行了调查。我们将使用250例AD和年龄案例 来自波士顿大学，梅奥诊所杰克逊维尔和西奈山ADC的相关tauopathies识别 精确检测和区分与年龄相关的tauopathies的新型TAU和炎症标记。后 从NACC神经病理学数据集（NDS）重新检查组织，我们将确定CTE的频率， 一部分，有正常认知临床诊断的个体中的AGD和ARTAG 认知障碍或痴呆症。我们将确定这些疾病对临床的独特贡献 诊断和认知和神经精神障碍。我们还将确定是否检查不足 研究了大脑区域，即前额叶皮层，无效的回和杏仁核，确定了新的年龄病例 相关的扭曲病以及这些地区的病理是否有助于神经精神障碍。最后， 我们将应用该项目获得的知识来开发CTE，部分，AGD和ARTAG评估以及 我们将用来组织国际NIH共识会议的诊断模块来协调 与年龄相关的tauopathies的神经病理学诊断。总体而言，该建议将解决 与CTE，部分，AGD和ARTAG有关的批判性但仍然未知的问题：1）识别新颖的Tau和 神经炎性生物标志物有助于检测和歧视年龄相关的tauopathies，2） 确定记忆障碍诊所患者中与年龄相关的扭曲频率； 3）确定 与年龄相关的tauopathy对认知和神经精神障碍的贡献； 4）发展 与年龄相关的双病神经病理学诊断的统一标准。这个项目还将丰富 现有的NACC-ND，对其他研究人员可用的与年龄相关的Tauopathies的数据进行数据。总体而言， 该提案的成功完成将改变我们概念化tauopathies的方式，并将 促进对AD和相关疾病的诊断，治疗和预防的未来研究。