Neurodegeneration in Aging Down Syndrome (NiAD): A Longitudinal Study of Cognition and Biomarkers of Alzheimer's Disease

NiAD摘要/摘要： 患有唐氏综合征（DS）的个体在治疗和治疗中基本上被忽视了。 阿尔茨海默病（AD）的生物标志物研究。患有DS的成年人通过其 30多岁，60多岁时有70-80%的机会患上临床痴呆症。在95%的病例中，DS与三种 21号染色体的拷贝，每个拷贝含有淀粉样β（Aβ）前体蛋白基因的拷贝（导致A β基因突变）。 1.5-Aβ蛋白增加倍数）。然而，没有比DS更清楚的是，Aβ沉积不足以产生 痴呆症，因为在认知能力下降明显之前，个体具有这种病理超过十年。DS可 被视为对风险和保护因素的敏感性放大，这些因素可调节Aβ， 神经变性和临床痴呆。了解在DS中调节这种关系的因素， 这些因素的生物标志物在DS和一般AD治疗试验的设计中至关重要。 因此，这项关于老年性神经退行性变（NiAD）及其与认知关系的纵向研究具有重要意义。 可能：1）确定将Aβ沉积与神经变性并最终与痴呆联系起来的关键因素; 2） 为这些因素定义生物标志物;最重要的是，3）为从这一点有效过渡奠定基础 生物标志物研究到治疗试验，以对抗生物标志物结果增强的DS中的AD。过去5 多年来，本申请中包含的三个独立研究小组一直在研究Aβ的过程， 沉积和其他成像生物标志物及其对DS成人认知/功能测量的影响[（a） 匹兹堡/麦迪逊联合研究;（B）班纳阿尔茨海默病研究所研究;（c）剑桥研究]。 在他们正在进行的工作中，140名患有DS的成年人（包括23名DS/AD痴呆）接受了磁治疗。 共振成像（MRI）和淀粉样蛋白正电子发射断层扫描（PET）扫描和神经心理学/ 功能评估。这三个研究小组现在提议联合收割机资源， 方案，以响应NIA/NICHD在DS中开展大型AD生物标志物研究的要求。本研究将 通过将NiAD与三项最大的正在进行的AD生物标志物纵向研究进行比对， 一般人群：阿尔茨海默病神经影像学倡议（ADNI），显性遗传阿尔茨海默病 网络（DIAN）和阿尔茨海默病预防倡议（API）。所有数据都将以开放获取的方式提供， 格式使用类似于ADNI的模型。已建立的DS队列是一个显著的优势， 招募阶段，最大化可以获得的纵向数据，并允许添加新的生物标志物， 与纵向临床和成像测量进行比较。拟议的五年纵向研究将审查 AD相关生物标志物（Aβ-、tau-和氟脱氧葡萄糖-PET，结构和功能MRI， 脑脊液Aβ和tau，血浆Aβ和蛋白质组学，遗传学，神经病理学）和认知/功能 在180名患有DS的成年人（>25岁）和40名生物标志物对照中进行测量。受试者将在每隔 15个月评估认知/适应功能的变化，每30个月检测一次生物标志物的变化。

NiAD Summary/Abstract: Individuals with Down syndrome (DS) have been largely neglected in therapeutic and biomarker studies of Alzheimer's disease (AD). Adults with DS are uniformly affected by AD pathology by their 30's and have a 70-80% chance of clinical dementia by their 60's. In 95% of cases, DS is associated with three copies of chromosome 21, each containing of copy of the Amyloid-beta (Aβ) Precursor Protein gene (leading to a 1.5-fold increase in Aβ protein). Yet, nowhere is it clearer than in DS that Aβ deposition is not sufficient to produce dementia, as individuals harbor this pathology for over a decade before cognitive decline is apparent. DS can be seen as a setting of amplified sensitivity to risk and protective factors that moderate the relationship between Aβ, neurodegeneration and clinical dementia. Understanding the factors that moderate this relationship in DS and biomarkers for those factors is critically important in the design of therapeutic trials for AD in DS and in general. Thus, this longitudinal study of Neurodegeneration in Aging DS (NiAD) and its relationship to cognition has the potential to: 1) identify critical factors that link Aβ deposition to neurodegeneration and, ultimately, dementia; 2) define biomarkers for these factors; and, most importantly, 3) set a foundation for an efficient transition from this biomarker study to a therapeutic trial to combat AD in DS augmented by biomarker outcomes. For the past 5 years, the three independent research groups included in this application have been studying the course of Aβ deposition and other imaging biomarkers and their impact on cognitive/functional measures in adults with DS [(a) the combined Pittsburgh/Madison study; (b) the Banner Alzheimer's Institute study; and (c) the Cambridge study]. In their ongoing work, 140 adults with DS (including 23 with DS/AD-dementia) have undergone magnetic resonance imaging (MRI) and amyloid-positron emission tomography (PET) scans and neuropsychological/ functional assessments. These three research groups now propose to combine resources and harmonize all protocols in response to the request from NIA/NICHD to develop a large AD biomarker study in DS. This study will be further strengthened by aligning NiAD with the three largest ongoing longitudinal studies of AD biomarkers in the general population: the Alzheimer Disease Neuroimaging Initiative (ADNI), the Dominantly Inherited Alzheimer Network (DIAN) and the Alzheimer Prevention Initiative (API). All data will be made available in an open-access format using a model similar to ADNI. The established DS cohort is a significant advantage that will shorten the recruitment phase, maximize longitudinal data that can be acquired and allow for addition of new biomarkers to be compared to longitudinal clinical and imaging measures. The proposed 5-year longitudinal study will examine progression of AD related biomarkers (Aβ-, tau- and fluorodeoxyglucose-PET, structural and functional MRI, cerebrospinal fluid Aβ and tau, plasma Aβ and proteomics, genetics, neuropathology) and cognitive/functional measures in 180 adults with DS (>25 yrs. of age) and 40 biomarker-controls. Subjects will be re-evaluated every 15 months to assess changes in cognition/adaptive functioning and every 30 months to detect biomarker changes.