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

NIAD摘要/摘要： 唐氏综合征(DS)患者在治疗和治疗方面基本上被忽视 阿尔茨海默病(AD)的生物标志物研究。患有DS的成年人一致受到AD病理的影响， 30岁的S和60岁的S患临床痴呆症的几率为70%-80%。在95%的病例中，DS与三个 21号染色体的拷贝，每个拷贝包含淀粉样β蛋白(Aβ)前体蛋白基因的拷贝(导致 Aβ蛋白增加1.5倍)。然而，在DS中最清楚的是，β沉积不足以产生 痴呆症，因为在认知能力下降明显之前，个体会有超过十年的这种病理。DS可以是 被视为对风险和保护性因素的敏感性被放大，这些因素缓和了Aβ之间的关系， 神经退行性变与临床痴呆。了解在DS和DS中调节这种关系的因素 这些因素的生物标记物在设计DS和一般AD的治疗试验中至关重要。 因此，这项关于老年DS神经退行性变(NIAD)及其与认知关系的纵向研究具有 潜在的：1)确定将Aβ沉积与神经退行性变，并最终导致痴呆症联系起来的关键因素； 定义这些因素的生物标志物；最重要的是，为从这一点进行有效过渡奠定基础 生物标记物研究在DS中对抗AD的治疗试验通过生物标记物的结果增强。在过去5年中 多年来，本申请中包括的三个独立研究小组一直在研究Aβ的课程 沉积和其他成像生物标记物及其对成人DS患者认知/功能测量的影响[(A)] 匹兹堡/麦迪逊联合研究；(B)班纳阿尔茨海默氏症研究所研究；以及(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痴呆症患者)接受了磁疗 磁共振成像(MRI)和淀粉样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建议整合资源，协调所有 响应NIA/NICHD的请求，在DS中开发一项大型AD生物标记物研究。这项研究将 通过将NIAD与正在进行的关于AD生物标记物的三项最大纵向研究相结合，进一步加强 普通人群：阿尔茨海默病神经成像倡议(ADNI)，主要遗传性阿尔茨海默病 网络(DIAN)和预防阿尔茨海默氏症倡议(API)。所有数据都将以开放访问的方式提供 使用类似于ADNI的模型进行格式化。已建立的DS队列是一个显著的优势，它将缩短 招募阶段，最大化可获得的纵向数据，并允许添加新的生物标记物 可与纵向临床和影像措施相比较。拟议的为期5年的纵向研究将审查 阿尔茨海默病相关生物标志物(β、tau和氟脱氧葡萄糖-正电子发射计算机断层扫描、结构和功能磁共振、 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 对180例成人DS患者(25岁)进行测量。年龄)和40名生物标记物对照。科目将每隔一年进行重新评估 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记物的变化。

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.