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

 描述(申请人提供)：在阿尔茨海默病(AD)的治疗和生物标记物研究中，唐氏综合症(DS)患者在很大程度上被忽视了。成年DS患者30‘S一致受到AD病理的影响，60’S有70%-80%的机会出现临床痴呆。在95%的病例中，DS与21号染色体的三个副本有关，每个副本包含淀粉样β蛋白(Aβ)前体蛋白基因的副本(导致Aβ蛋白增加1.5%)。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，个人会有超过十年的这种病理。DS可以被视为一种对风险和保护性因素的放大敏感性，这些因素缓和了Aβ、神经退行性变和临床痴呆之间的关系。了解在DS中调节这种关系的因素以及这些因素的生物标记物在设计DS中的AD治疗试验和一般情况下是至关重要的。因此，这一点 老年DS中神经退行性变的纵向研究(NIAD)及其与认知的关系有可能：1)确定将Aβ沉积与神经退行性变，最终导致痴呆联系起来的关键因素；2)定义这些因素的生物标记物；以及，最重要的是，3)为从这项生物标记物研究有效地过渡到通过生物标记物结果增强的DS中对抗A的治疗试验奠定基础。在过去的5年里，本申请中包括的三个独立研究小组一直在研究Aβ沉积和其他成像生物标记物的过程及其对患有DS的成年人的认知/功能测量的影响[(A)匹兹堡/麦迪逊合并研究；(B)班纳阿尔茨海默氏症研究所研究；(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痴呆患者)接受了磁共振成像(MRI)和淀粉样正电子发射断层扫描(PET)以及神经心理/功能评估。这三个研究小组现在建议整合资源并协调所有方案，以响应NIA/NICHD的请求，在DS中开发一项大型AD生物标记物研究。通过将NIAD与三项正在进行的关于普通人群中AD生物标记物的最大纵向研究相结合，这项研究将得到进一步加强：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)和阿尔茨海默病预防倡议(API)。所有数据将采用类似于ADNI的模式以开放获取的格式提供。已建立的DS队列是一个显著的优势，它将缩短招募阶段，最大限度地提高可获得的纵向数据，并允许添加新的生物标记物，将其与纵向临床和成像措施进行比较。这项拟议的为期5年的纵向研究将检查180名患有DS的成年人的AD相关生物标记物(β、tau和氟脱氧葡萄糖-PET、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)以及认知/功能测量的进展。年龄)和40名生物标记物对照。受试者将每15个月重新评估一次，以评估认知/适应功能的变化，并每30个月重新评估一次，以检测生物标记物的变化。

 DESCRIPTION (provided by applicant): 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 sufficiet 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 A 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.