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、非侵入性的体内PET示踪剂，用于对活体人体中的淀粉样蛋白沉积进行成像。这种示踪剂最初被称为[C-11]6-OH-BTA-1，现在通常被称为匹兹堡化合物-B（PiB）。这种化合物在记录注定发展为阿尔茨海默病（AD）的活体受试者中的症状前淀粉样蛋白沉积方面显示出很大的希望。此外，PiB提供了一种方法来确定这些受试者中淀粉样蛋白沉积的自然史。虽然越来越多地使用PiB作为评估认知正常个体（有和没有AD症状）中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获得AD的可能性（例如，年龄增加、载脂蛋白-E4（ApoE 4）等位基因的存在），目前没有办法确定地鉴定那些注定要发展AD的个体。这使得在一般人群中研究临床前淀粉样蛋白沉积变得困难。相反，患有唐氏综合征（DS）的个体由于存在额外的21号染色体拷贝而处于发展AD的高风险中，该染色体拷贝编码A前体蛋白（APP）基因。事实上，尸检研究已经证明，60 - 90%的DS成人存在AD病理学（随着年龄的增长，病理学程度更高）。此外，在50至59岁的DS个体中，与AD诊断一致的症状发生率超过40%。因此，对DS成人的研究提供了一个难得的机会，可以跟踪一组AD神经病理学和神经病理学高风险个体。本研究的目的是记录84例无症状成年DS患者的淀粉样蛋白沉积，并随访这些患者，以了解淀粉样蛋白沉积的过程及其对功能的影响。这项研究将集中在30岁以上的DS个体，这是一个有淀粉样斑块存在和AD发展风险的群体。将淀粉样蛋白沉积（通过PiB-PET测量）与典型AD病例、典型对照以及一小群已诊断为AD的DS个体进行比较。此外，我们将评估ApoE 4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。发现具有可检测的淀粉样蛋白斑块的受试者将以24个月的间隔进行随访，以记录淀粉样蛋白沉积的自然史，并确定他们是否处于可预测的临床AD的轨迹上。类似地，还将以24个月的间隔对未显示淀粉样蛋白沉积证据的受试者进行随访，从而有可能检测淀粉样蛋白沉积的发作。拟定的随访研究可能会提供关于DS受试者淀粉样蛋白沉积自然史的重要信息。这些数据对于加深我们对唐氏综合征AD病理生理学的理解是必要的，并且可能对普通人群产生额外的影响。 公共卫生相关性：患有唐氏综合征（DS）的成年人患阿尔茨海默病（AD）的风险极高，大多数40岁以上的人都有淀粉样蛋白沉积（被认为与症状的出现有关）。本研究的目的是记录84例无症状成年DS患者的淀粉样蛋白沉积，并随访这些患者，以了解淀粉样蛋白沉积的过程及其对功能的影响。这些数据不仅是必要的，以加深我们对AD的病理生理学DS的理解，但也可能提供的信息，将被证明是有用的，在预防和治疗AD的一般人群。

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.