Natural History of Amyloid Deposition in adults with Down Syndrome

描述（由申请人提供）：匹兹堡大学的研究人员开发了一种开创性的、无创的、体内PET示踪剂，用于成像活体淀粉样蛋白沉积。这种示踪剂最初被称为[C-11]6-OH-BTA-1，现在被称为匹兹堡化合物- b （PiB）。该化合物在记录注定发展为阿尔茨海默病（AD）的活的受试者的症状前淀粉样蛋白沉积方面显示出很大的希望。此外，PiB提供了一种确定这些受试者中淀粉样蛋白沉积的自然史的方法。虽然越来越多地使用PiB作为评估认知正常个体（有或没有AD症状）淀粉样蛋白沉积的工具，但事实仍然是，尽管可识别的风险因素增加了患AD的可能性（例如，年龄增加，载脂蛋白e4 （ApoE4）等位基因的存在），但目前还没有办法确定哪些个体一定会患AD。这使得临床前淀粉样蛋白沉积的研究在一般人群中变得困难。相反，患有唐氏综合症（DS）的人患AD的风险很高，因为21号染色体存在额外的拷贝，该拷贝编码A前体蛋白（APP）基因。事实上，尸检研究表明，60 - 90%的成人退行性椎体滑移患者存在AD病理（随着年龄的增长，病理程度更高）。此外，在50 - 59岁的退行性痴呆患者中，超过40%的患者出现与AD诊断相符的症状。因此，对成人退行性痴呆患者的研究提供了一个难得的机会，可以跟踪一组发生AD神经病理和症状的高风险个体。当前提案的目标是记录84例无症状成人退行性椎体滑移的淀粉样蛋白沉积，并跟踪这些个体以了解淀粉样蛋白沉积的过程及其随时间对功能的影响。该研究将重点关注30岁以上的退行性痴呆患者，这一人群有淀粉样斑块存在和AD发展的风险。淀粉样蛋白沉积（通过PiB-PET测量）将与典型AD病例、典型对照以及一小部分诊断为AD的DS患者进行比较。此外，我们将评估ApoE4等位基因的存在，以检查其与淀粉样斑块加速沉积的可能关联。还将进行广泛的神经心理学测试，以记录当前的功能水平。发现可检测到淀粉样斑块的受试者将每隔24个月随访一次，以记录淀粉样蛋白沉积的自然历史，并确定他们是否处于可预测的临床AD发展轨迹上。同样，没有显示淀粉样蛋白沉积证据的受试者也将每隔24个月进行随访，以便有可能检测淀粉样蛋白沉积的开始。提出的后续研究可能会提供有关DS受试者淀粉样蛋白沉积的自然史的重要信息。这些数据对于加深我们对唐氏综合症AD的病理生理学的理解是必要的，并且可能对普通人群有额外的影响。

DESCRIPTION (provided by applicant): Researchers at the University of Pittsburgh have developed a pioneering, non-invasive, in vivo PET tracer for use in imaging amyloid deposition in living humans. The tracer, originally called [C-11]6-OH-BTA-1, has become commonly known as Pittsburgh Compound-B (PiB). This compound has shown much promise in documenting pre-symptomatic amyloid deposition in living subjects destined to develop Alzheimer's disease (AD). In addition, PiB provides a means to determine the natural history of amyloid deposition in these subjects. While there has been increasing use of PiB as a tool for assessing amyloid deposition in cognitively normal individuals (both with and without symptoms of AD), the fact remains that despite identifiable risk factors that increase the likelihood of acquiring AD (e.g., increased age, presence of the apolipoprotein-E4 (ApoE4) allele), there is currently no way to identify with certainty those individuals that are destined to develop AD. This makes the study of pre-clinical amyloid deposition difficult in the general population. Conversely, individuals with Down syndrome (DS) are at high risk for developing AD due to the presence of an extra copy of chromosome 21, which codes for the A precursor protein (APP) gene. In fact, post-mortem studies have documented the presence of AD pathology in 60 to 90% of adults with DS (with greater pathology with increasing age). Additionally, symptoms consistent with a diagnosis of AD occur in over 40% for DS individuals between 50 and 59 years of age. Thus, the study of adults with DS provides a rare opportunity to follow a group of individuals at high risk for developing AD neuropathology and symptomotology. The goal of the current proposal is to document amyloid deposition in 84 asymptomatic adults with DS and to follow these individuals to understand the course of amyloid deposition and its effect on functioning over time. The study will focus on DS individuals over the age of 30, a group who is at risk for the presence of amyloid plaque and for the development of AD. Amyloid deposition (as measured by PiB-PET) will be compared to typical AD cases, typical controls, as well as to a small group of individuals with DS who have been diagnosed with AD. Additionally, we will assess for the presence of the ApoE4 allele to examine its possible association with accelerated deposition of amyloid plaque. Extensive neuropsychological testing will also be conducted to document current functioning levels. Subjects found to have detectable amyloid plaque will be followed at 24 month intervals to document the natural history of amyloid deposition and to determine if they are on a predictable trajectory toward clinical AD. Similarly, subjects who show no evidence of amyloid deposition will be also be followed at 24 month intervals, allowing the possibility of detecting th very onset of amyloid deposition. The follow-up studies proposed will likely provide important information regarding the natural history of amyloid deposition in DS subjects. This data is necessary to deepen our understanding of the pathophysiology of AD in Down syndrome and may have additional implications for the general population. PUBLIC HEALTH RELEVANCE: Adults with Down syndrome (DS) are at an extremely high risk for developing Alzheimer's disease (AD), with most individuals over age 40 evidencing amyloid deposits (which are thought to be associated with the appearance of symptoms). The goal of the current proposal is to document amyloid deposition in 84 asymptomatic adults with DS and to follow these individuals to understand the course of amyloid deposition and its effect on functioning over time. This data is not only necessary to deepen our understanding of the pathophysiology of AD in DS but may also offer information that will prove useful in the prevention and treatment of AD in the general population.