ADRC Consortium for Clarity in ADRD Research Through Imaging

ADRC 联盟通过成像来明确 ADRD 研究

• 批准号: 10803806
• 负责人: BRADFORD C DICKERSON
• 金额: $ 3080万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10803806
• 关键词: Accounting; Address; Age of Onset; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Autopsy; Biological Assay; Biological Markers; Blood Vessels; Brain; Classification; Clinical; Clinical Data; Cognitive; Cohort Studies; Collection; Consensus; Data Collection; Data Set; Dementia; Diagnosis; Diagnostic; Disclosure; Disease; Ecosystem; Enrollment; Ensure; Etiology; Foundations; Functional disorder; Future; Genetic; Glial Fibrillary Acidic Protein; Heterogeneity; Image; Impaired cognition; Impairment; Individual; Infrastructure; Investigational Therapies; Ischemia; Joints; Label; Lewy Bodies; Link; Literature; Longitudinal Studies; MRI Scans; Magnetic Resonance Imaging; Measures; Metabolic; Methods; Microvascular Dysfunction; Modeling; Morphology; Motion; Nerve Degeneration; Outcome; Participant; Pathology; Patients; Pattern; Perfusion; Phenotype; Plasma; Positioning Attribute; Positron-Emission Tomography; Predisposition; Process; Protocols documentation; Research; Resource Sharing; Resources; Severities; Site; Source; Standardization; Symptoms; Syndrome; System; Techniques; Time; Underrepresented Populations; Validation; Vascular Diseases; Visual; Work; adjudication; aging brain; alpha synuclein; astrogliosis; burden of illness; clinical heterogeneity; cognitive change; cohort; data sharing; design; diagnostic accuracy; fluorodeoxyglucose positron emission tomography; imaging biomarker; imaging study; improved; in vivo; in vivo imaging; ischemic lesion; mild cognitive impairment; mixed dementia; neurobehavioral; neuropathology; patient engagement; programs; prospective; protein TDP-43; recruit; response; serial imaging; shared repository; success; tau Proteins; therapeutic development; tool; treatment trial

PROJECT SUMMARY Alzheimer’s disease (AD) pathophysiology seldom occurs in isolation, and it is widely established from the neuropathology literature that the majority of individuals with dementia have multiple etiology dementia (MED). MED is common but undetected in extant major cohort studies and treatment trials for AD; many studies intentionally restrict clinical heterogeneity to an assumed single etiology by using narrowly defined clinical enrollment criteria. A major gap in our field is the lack of validated tools to detect MED in-vivo. The next era of large-scale imaging biomarker studies for AD and related disorders (ADRD) will require strategies commensurate with the known but largely unaddressed problem of etiologic heterogeneity. The Alzheimer’s Disease Research Centers (ADRCs) are uniquely positioned to meet this need. Collectively the 37 ADRCs follow ~14,000 active enrollees with high brain donor and autopsy rates (>60%). The ADRCs recruit across the clinical severity continuum and amply represent the several diseases comprising ADRD. Now, as a consortium, the centers will conduct a uniform imaging protocol capable of elucidating individualized etiological profiles including foundational PET imaging for AD proteinopathy (Amyloid and Tau), vascular burden with MRI and additional structural MRI and FDG PET for assessing the several patterns of morphologic and metabolic Neurodegeneration signatures of both AD and non-AD proteinopathies on deeply phenotyped patients. Design: This is a longitudinal imaging study at 2-year intervals that is superimposed on and fully integrated with the ongoing uniform cognitive and clinical data collection the 37 ADRCs already do. We will study 2,000 ethnoculturally diverse ADRC participants that are either clinically unimpaired (CU; N=800) or impaired (N=1,200) where AD is a considered, though need not be the primary suspected etiology. Aim 1 creates the ATN cohort through prospective imaging and plasma collection and establishes the foundational shared resource in conjunction with the National Alzheimer’s Coordinating Center (NACC) with linkage to the vast clinical, cognitive, and genetic datasets on these same participants. In Aim 2 we examine the temporal progression of the two most common etiologies—AD and vascular disease. We examine onset ages and duration of each and their joint effect on cognitive decline. Aim 3 focuses on other common proteinopathies. Classification and joint modelling methods will be applied to estimate etiologic composition and the effect of multi-proteinopathy on clinical and cognitive change. ATN imaging–a critical foundation for characterizing likely dementia etiologies—is needed on this expertly-diagnosed, uniformly evaluated MED ADRD cohort where neuropathology can inform clinicopathologic correlation, mechanistic underpinnings, and strategic diagnostic and therapeutic development. The consortium of ADRCs have the expertise and capacity to conduct this study and will work together to ensure its success and its impact on the field.

项目概要 阿尔茨海默病 (AD) 的病理生理学很少单独发生，它是从 神经病理学文献表明，大多数痴呆症患者患有多病因痴呆症（MED）。 MED 很常见，但在现有的主要队列研究和许多 AD 治疗试验中未被发现； 通过使用狭隘定义的临床，有意将临床异质性限制为假定的单一病因 我们领域的一个主要差距是缺乏有效的体内检测 MED 的工具。 AD 及相关疾病 (ADRD) 的大规模成像生物标志物研究需要相应的策略 阿尔茨海默病研究中存在已知但很大程度上尚未解决的病因异质性问题。 中心 (ADRC) 具有独特的优势，可以满足这一需求，37 个 ADRC 总共关注约 14,000 个活跃的中心。 ADRC 招募了具有高脑供体率和尸检率（>60%）的参与者。 现在，作为一个联盟，这些中心将连续并充分代表构成 ADRD 的几种疾病。 进行统一的成像方案，能够阐明个体化的病因学特征，包括 AD 蛋白病（淀粉样蛋白和 Tau）的基础 PET 成像、MRI 血管负荷和其他 结构 MRI 和 FDG PET 用于评估形态和代谢的多种模式 深度表型患者的 AD 和非 AD 蛋白病的神经退行性特征设计： 这是一项以 2 年为间隔的纵向成像研究，与 37 个 ADRC 已经在进行统一的认知和临床数据收集，我们将研究 2,000 个。 临床上未受损（CU；N=800）或受损的民族文化多样化 ADRC 参与者 (N=1,200) 其中 AD 被考虑，但不一定是主要的可疑病因，目标 1 创建了 ATN。 通过前瞻性成像和血浆采集进行队列研究，并建立基础共享资源 与国家阿尔茨海默病协调中心 (NACC) 合作，与广泛的临床、认知、 在目标 2 中，我们检查了两个最重要的参与者的时间进程。 我们检查了常见病因——AD 和血管疾病及其关节的发病年龄和持续时间。 目标 3 关注其他常见蛋白质病的分类和联合建模。 将应用方法来估计病因组成以及多蛋白病对临床和治疗的影响 认知改变是需要 ATN 成像——描述痴呆可能病因的关键基础。 这个经过专业诊断、统一评估的 MED ADRD 队列，神经病理学可以为该队列提供信息 临床病理相关性、机制基础以及战略诊断和治疗发展。 ADRC 联盟拥有开展这项研究的专业知识和能力，并将共同努力确保 它的成功及其对该领域的影响。