ADRC Consortium for Clarity in ADRD Research Through Imaging

项目总结 阿尔茨海默病(AD)的病理生理学很少孤立发生，它广泛地建立在 神经病理学文献表明，大多数痴呆症患者患有多病因痴呆(MED)。 在现有的主要AD队列研究和治疗试验中，MED很常见，但未被发现；许多研究 通过使用狭义的临床定义，有意将临床异质性限制在假定的单一病因上 注册标准。我们领域的一个主要空白是缺乏有效的工具来检测体内的MED。下一个时代 AD及相关疾病(ADRD)的大规模成像生物标记物研究将需要相应的策略 已知但在很大程度上没有解决的病原学异质性问题。阿尔茨海默病的研究进展 中心(ADRC)具有满足这一需求的独特定位。37个ADRC总共跟踪了14,000个活跃的ADRC 脑捐赠者和尸检率高的参与者(&gt；60%)。ADRC在临床严重程度上招募人员 连续和充分地代表了构成ADRD的几种疾病。现在，作为一个联合体，这些中心将 实施统一的成像方案，能够阐明个性化的病因学特征，包括 AD蛋白病(淀粉样蛋白和Tau)的基础PET成像、血管负荷的MRI和其他 结构MRI和FDGPET评价几种形态和代谢模式 深表型患者的AD和非AD蛋白病变的神经退行性变特征。设计： 这是一项每隔两年进行一次的纵向成像研究，该研究叠加并完全整合了 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 种族文化多样性的ADRC参与者，要么临床上没有受损(CU；N=800)，要么受损 (n=1,200)，其中AD是被考虑的，尽管不一定是主要的可疑病因。AIM 1创建ATN 通过前瞻性成像和血浆收集进行队列，并建立基础共享资源 与国家阿尔茨海默氏症协调中心(NACC)合作，与广泛的临床、认知、 以及这些参与者的基因数据集。在目标2中，我们考察了这两个最重要的 常见病因--阿尔茨海默病和血管疾病。我们检查了每种疾病及其关节的发病年龄和持续时间。 对认知功能下降的影响。目标3侧重于其他常见的蛋白质病。分类和联合建模 方法将用于评估病因组成和多蛋白病对临床和临床的影响 认知变化。ATN成像-表征可能的痴呆症病因的关键基础-需要 这一经过专业诊断、统一评估的MED ADRD队列可以从神经病理中获得信息 临床病理相关性，机制基础，以及战略性诊断和治疗发展。 ADRC联盟拥有进行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。

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.