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

衰老唐氏综合症 (NiAD) 中的神经退行性变：阿尔茨海默氏病认知和生物标志物的纵向研究

• 批准号: 9146760
• 负责人: Bradley T Christian
• 金额: $ 355.69万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9146760
• 关键词: Adult; Affect; Age; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid deposition; Appearance; Autopsy; Biochemical; Bioinformatics; Biological; Biological Markers; Blood; Brain; Cerebrospinal Fluid; Chromosomes, Human, Pair 21; Clinical; Clinical Trials; Cognition; Cognitive; Communities; Corpus striatum structure; Data; Dementia; Deposition; Development; Down Syndrome; Ensure; Event; Foundations; Functional Magnetic Resonance Imaging; Functional disorder; Future; Gene Proteins; General Population; Genes; Genetic; Goals; Health; Image; Impaired cognition; Individual; Inherited; Institutes; Laboratories; Late Onset Alzheimer Disease; Link; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Modeling; National Institute of Child Health and Human Development; Nerve Degeneration; Neurofibrillary Tangles; Outcome; Participant; Pathology; Pattern; Phase; Plasma; Plasma Proteins; Population; Positron-Emission Tomography; Protein Precursors; Proteins; Proteomics; Protocols documentation; Qualifying; Recruitment Activity; Research; Research Personnel; Resources; Risk; Sample Size; Sampling; Senile Plaques; Structure; Symptoms; Therapeutic Trials; Time; Universities; Wisconsin; Work; abeta deposition; age group; age related; cerebral atrophy; cohort; combat; cooperative study; design; fluorodeoxyglucose positron emission tomography; functional decline; functional disability; high risk; imaging biomarker; imaging genetics; mutation carrier; neglect; neuroimaging; neuropathology; neuropsychological; pre-clinical; prevent; response; symptomatology; tau Proteins; therapeutic biomarker; treatment trial

 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.

 描述（由申请人提供）：在阿尔茨海默病 (AD) 的治疗和生物标志物研究中，患有唐氏综合症 (DS) 的个体在很大程度上被忽视。患有 DS 的成年人在 30 多岁时普遍受到 AD 病理的影响，并且有 70-80% 的机会。在 95% 的病例中，DS 与 21 号染色体的三个拷贝有关，每个拷贝都含有 β 淀粉样蛋白 (Aβ) 的拷贝。前体蛋白基因（导致 Aβ 蛋白增加 1.5 倍）然而，没有什么比 DS 更清楚地表明 Aβ 沉积不足以产生痴呆，因为在认知能力明显下降之前，个体已经存在这种病理状态十多年。 DS 可以被视为对风险和保护性因素的敏感性增强，这些因素调节 Aβ、神经退行性变和临床痴呆之间的关系，了解 DS 中调节这种关系的因素以及这些因素的生物标志物对于治疗糖尿病至关重要。 AD 治疗试验的设计以及一般情况。 对衰老 DS 中的神经退行性变 (NiAD) 及其与认知的关系的纵向研究有可能：1) 确定 Aβ 沉积与神经退行性疾病以及最终痴呆相关的关键因素；2) 定义这些因素的生物标志物； 3) 为从该生物标志物研究过渡到生物标志物结果增强的对抗 DS 中的 A 的治疗试验奠定了基础。在过去 5 年中，本申请中包含的三个独立研究小组一直在有效地研究 Aβ 的过程。沉积物和其他影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；和 (c) 剑桥研究]。这三个研究小组对 140 名 DS 成人（包括 23 名 DS/AD 痴呆症）进行了磁共振成像 (MRI) 和淀粉样蛋白正电子发射断层扫描 (PET) 扫描以及神经心理学/功能评估。现在建议整合资源并协调所有协议，以响应 NIA/NICHD 在 DS 中开展大型 AD 生物标志物研究的要求。通过将 NiAD 与正在进行的三项最大的 AD 生物标志物纵向研究结合起来，这项研究将得到进一步加强。人群：阿尔茨海默病神经影像计划 (ADNI)、显性遗传阿尔茨海默病网络 (DIAN) 和阿尔茨海默病预防计划 (API) 所有数据都将使用类似于 ADNI 的模型以开放获取格式提供。建立的 DS 队列是一个显着的优势，它将缩短招募阶段，最大化可获取的纵向数据，并允许添加新的生物标志物与纵向临床和影像测量进行比较。拟议的 5 年纵向研究将检查 AD 的进展。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/功能每 15 个月对 180 名 DS 成人（> 25 岁）和 40 名生物标志物对照对象进行重新评估，以评估认知/适应性功能的变化，并每 30 个月重新评估一次，以检测生物标志物的变化。