Natural History of Amyloid Deposition in Adults with Down Syndrome

描述(申请人提供)：淀粉样β蛋白(A-beta)在大脑中的沉积被认为是阿尔茨海默病(AD)的主要原因。识别淀粉样蛋白沉积的特征，这些特征发生在阿尔茨海默病症状和这种沉积的自然历史之前是至关重要的。然而，在普通人群中，尽管可识别的危险因素会增加患AD的可能性，如年龄增加和载脂蛋白-E4等位基因(ApoE4)的存在，但我们无法确定哪些人注定会患上AD。相反，唐氏综合征(DS)成人人群提供了一个研究临床前淀粉样蛋白沉积的独特机会。大约10%的患有DS的成年人在40岁到49岁之间被诊断为AD。对于50-59岁的人，这一比例增加到36%，对于60岁及以上的人，这一比例为≥50%。这种早发的阿尔茨海默病被认为是由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多肽区域或附近。匹兹堡大学的一组研究人员对一种名为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AD患者死后淀粉样蛋白负荷较大的大脑区域，而不保留在小脑等仅零星发现纤维淀粉样沉积的区域。2007年，该小组完成了一项对8名患有DS的成人样本使用PIB的初步研究。随后，在2009年，获得了ARRA的资金，开始招募84名患有DS的健康受试者的新队列，最近获得了为期五年的继续补助金(与威斯康星大学麦迪逊分校)。已招收67门科目，招生工作将于2014年8月前完成。延续补助金允许维持招募工作，并开始对登记的受试者进行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症的自然病程。措施包括广泛的神经心理评估单元以及对适应功能、AD症状和情绪/行为担忧的评估。此外，在进行核磁共振和正电子发射计算机断层扫描的同时，还可以获得载脂蛋白E状态。当前建议的主要目标是通过扩展父母研究方案来利用这一独特的个体队列，将4个有希望和重要的生物标志物包括在内：[18F]氟-2-脱氧-D-葡萄糖、脑血管反应性的核磁共振测量、弥散张量成像和血浆Aβ-40和42的评估。当目前登记的受试者返回进行后续评估时，将获得这些措施，并将使我们能够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。随着我们继续跟踪这群人并检测到痴呆症的早期迹象(提供了进一步检查这些调节剂与淀粉样蛋白沉积、认知能力下降和痴呆症之间的关系的机会)，这些信息也将具有相当重要的意义。

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).