Natural History of Amyloid Deposition in Adults with Down Syndrome

描述（由申请人提供）：淀粉样蛋白- β (a - β)蛋白在大脑中的沉积被认为是阿尔茨海默病（AD）的主要原因。确定在阿尔茨海默病症状发作之前发生的淀粉样蛋白沉积特征和这种沉积的自然史是必不可少的。然而，在一般人群中，尽管可识别的风险因素增加了患AD的可能性，如年龄的增长和载脂蛋白e4等位基因（ApoE4）的存在，但我们没有办法确定哪些人注定会患AD。相反，唐氏综合症（DS）的成年人群提供了一个独特的机会来研究临床前淀粉样蛋白沉积。大约10%的成人退行性椎体滑移患者在40至49岁之间被诊断为AD。50-59岁的人群患病率为36%，60岁及以上人群患病率≥50%。这种早发性AD的DS被认为是由21号染色体上的a - β前体蛋白（APP）基因的多个突变引起的，这些突变都位于a - β肽区或附近。匹兹堡大学的一组研究人员对一种被称为PiB（匹兹堡化合物- b）的体内淀粉样蛋白成像正电子发射断层扫描（PET）示踪剂进行了开创性的人体研究。PiB选择性地保留在已知阿尔茨海默病患者死后淀粉样蛋白负荷重的大脑区域，而不保留在仅零星发现纤维状淀粉样蛋白沉积的区域，如小脑。2007年，该小组在8名患有退行性痴呆的成人样本中完成了使用PiB的试点研究。随后，在2009年，ARRA获得了资金，开始招募84名患有DS的健康受试者，最近获得了为期五年的持续拨款（与威斯康星大学麦迪逊分校合作）。已招募67名受试者，招募工作将于2014年8月完成。持续补助金用于维持招募工作，并开始对招募受试者进行30和60个月的重新评估，以检查该人群中淀粉样蛋白沉积和痴呆的自然过程。措施包括广泛的神经心理学评估以及适应性功能，AD症状和情绪/行为问题的评估。此外，ApoE状态可通过MRI和PET扫描获得。当前提案的主要目标是通过扩展母体研究方案来利用这一独特的个体队列，包括4个有前途和重要的生物标志物：[18F]氟-2-脱氧-d -葡萄糖（FDG-PET），脑血管反应性（CVR）的MRI测量，弥散张量成像（DTI）和血浆Aβ-40和42的评估。当目前登记的受试者返回进行随访评估时，将获得测量结果，并允许我们检查这些生物标志物与淀粉样蛋白沉积和功能之间的关联。当我们继续跟踪这组个体并检测到痴呆的早期迹象时，这一信息也将具有相当大的意义（为进一步研究这些调节因子与淀粉样蛋白沉积、认知能力下降和痴呆之间的关系提供机会）。

DESCRIPTION (provided by applicant): Deposition of amyloid-beta (A-beta) protein in the brain has been postulated to be a primary cause of Alzheimer's disease (AD). Identification of hallmarks of amyloid deposition that occur prior to onset of AD symptoms and the natural history of this deposition is essential. However, in the general population, despite identifiable risk factors that increase the likelihood of acquiring AD, such as increased age and the presence of an apolipoprotein-E4 allele (ApoE4), we have no way of identifying with certainty those individuals destined to develop AD. Conversely, the Down syndrome (DS) adult population provides a unique opportunity to study pre-clinical amyloid deposition. Approximately 10% of adults with DS are diagnosed with AD between 40 and 49 years of age. The rate increases to 36% for individuals 50-59 years of age and is ≥50% for those 60 years of age and older. This early onset of AD in DS is thought to be caused by multiple mutations in the A-beta precursor protein (APP) gene on chromosome 21, all lying in or near the A-beta peptide region. A group of researchers at the University of Pittsburgh has performed pioneering human studies of an in vivo amyloid imaging positron emission tomography (PET) tracer known as PiB (Pittsburgh compound-B). PiB is selectively retained in brain areas known to have heavy post-mortem amyloid loads in AD and is not retained in regions, such as cerebellum, where fibrillar amyloid deposits are found only sporadically. In 2007, this group completed a pilot study of the use of PiB in a sample of 8 adults with DS. Subsequently, in 2009, ARRA funding was obtained to begin to recruit a new cohort of 84 healthy subjects with DS and recently was awarded a five-year continuation grant (with the University of Wisconsin, Madison). Sixty-seven subjects have been enrolled, with recruitment to be completed by August 2014. The continuation grant has allowed for the maintenance of recruitment efforts and the initiation of 30 and 60 month reassessments of enrolled subjects to examine the natural course of amyloid deposition and dementia in this population. Measures include an extensive neuropsychological assessment battery as well as assessment of adaptive functioning, AD symptoms and emotional/behavioral concerns. In addition, ApoE status is obtained along with an MRI and PET scan. The primary objective of the current proposal is to leverage this unique cohort of individuals by expanding the Parent Study protocol to include 4 promising and important biomarkers: [18F]fluoro-2-deoxy-D-glucose (FDG-PET), an MRI measure of cerebrovascular reactivity (CVR), diffusion tensor imaging (DTI) and assessment of plasma Aβ-40 and 42. Measures will be obtained when currently enrolled subjects return for a follow-up assessment and will allow us to examine the association between these biomarkers and amyloid deposition and functioning. This information will also be of considerable significance as we continue to follow this cohort of individuals and early signs of dementia are detected (providing the opportunity to further examine the relationship between these moderators and amyloid deposition, cognitive decline and dementia).