The cholinergic integrity in Down syndrome in association with aging, Alzheimer's disease pathology, and cognition

项目摘要唐氏综合症(DS)是遗传定义的智力残疾的主要原因， 影响到所有种族和社会经济群体。除了智力残疾，大多数DS患者都表现出 阿尔茨海默病(AD)样神经病理学和阿尔茨海默病(AD)的早衰和早期表现的特点 痴呆症。DS中的AD可能是由淀粉样前体蛋白基因的三倍体驱动的，但其他 散发性AD的神经退行性改变可能发生在DS中。了解这些神经退行性变化过程 对于评估DS中的AD与散发性AD的相似或不同以及这些因素如何影响 DS患者认知功能减退和痴呆的发病情况。在散发性AD中，进行性认知缺陷与 特定神经元群的退化，最显著的是胆碱能神经元。胆碱能的丧失 正直会对认知表现产生负面影响，特别是在注意力、学习和记忆形成方面。 然而，成人DS患者的脑胆碱能系统尚未得到评估。目前的胆碱能标记物 不直接测量胆碱能完整性/功能，从而表现出适度的监测可译性 疾病进展或治疗评估。我们建议使用一种新的正电子发射断层扫描(PET) 放射性示踪剂，被称为[18F]FEOBV，作为一种直接/特异的方法评估脑内胆碱能完整性。 患有DS的非痴呆成人与年龄、认知/神经行为改变和 AD病理学以确定所提出的胆碱能生物标记物是否可以作为AD的新终点 DS中最能反映疾病进展的临床试验。认知医学中心是这项试验的一个地点- 就绪队列唐氏综合征(TRC-DS)研究，以使系统的生物标记物表征中期 老年和老年DS患者通过使用神经成像、认知和临床测量，为 一项类似AD的预防试验(可能使用抗淀粉样药)。在TRC-DS(作为家长研究)的协助下， ，这为研究我们的小说开辟了一条新的途径 胆碱能生物标志物。DS患者胆碱能系统的检测及其与增龄和已知AD的关系 病理和认知功能减退有助于验证胆碱能减退是否是痴呆症的早期标志 DS的风险以及标准AD成像和液体生物标记物的变化，从而有助于确定 DS中的AD与散发性AD有多相似。此外，我们的胆碱能生物标记物可以识别个体 DS可能对未来的前胆碱能干预有反应，包括新的胆碱能调节剂 正在开发以增强胆碱能敏感的认知功能的药物。我们预计会使用这些数据 聚集在这里，为TRC-DS的未来治疗研究提供信息，在那里新的胆碱能治疗可能提供 为DS的早期干预提供机会，并与疾病修改方法相辅相成，如抗- 淀粉样蛋白治疗。

PROJECT SUMMARY Down Syndrome (DS) is the leading cause of a genetically-defined intellectual disability, affecting all racial and socioeconomic groups. In addition to intellectual disability, most individuals with DS show characteristics of premature aging and early presentation of Alzheimer’s disease (AD)-like neuropathology and dementia. AD in DS may be driven by triplication of the amyloid precursor protein gene, but other neurodegenerative features of sporadic AD may occur in DS. Understanding these neurodegenerative processes is critical to assessing how similar or different AD in DS is to sporadic AD and how these factors influence the onset of cognitive decline and dementia in DS. In sporadic AD, progressive cognitive deficits are associated with the degeneration of specific neuronal populations, most notably the cholinergic neurons. The loss of cholinergic integrity negatively affects the cognitive performance, particularly in attention, learning, and memory formation. However, the brain cholinergic system has not been evaluated in adult with DS. Current cholinergic markers do not directly measure the cholinergic integrity/function, thereby showing modest translatability for monitoring disease progression or treatment evaluation. We propose to use a novel positron emission tomography (PET) radiotracer, known as [18F]FEOBV, as a direct/specific method for assessing the brain cholinergic integrity in non-demented adults with DS in relationship to age, cognitive/neurobehavioral alterations, and biomarkers of AD pathologies to establish whether the proposed cholinergic biomarker can serve as a novel endpoint for AD clinical trials in DS that best reflect disease progression. The Center for Cognitive Medicine is a site for the Trial- Ready Cohort-Down Syndrome (TRC-DS) study, to enable a systematic biomarker characterization of middle aged and older individuals with DS by using neuroimaging, cognitive, and clinical measures, in preparation for an AD-like prevention trial (likely using anti-amyloid agents). Facilitated by the TRC-DS (as a parent study), which provides well-characterized DS subjects, we propose to initiate a new pathway for investigating our novel cholinergic biomarker. The examination of cholinergic system in DS and its relationship to aging and known AD pathologies and cognitive decline would help validate whether cholinergic decline is an early marker of dementia risk in DS and proceeds or follows changes in standard AD imaging and fluid biomarkers, thus helping establish how similar AD in DS is to that of sporadic AD. Also, our cholinergic biomarker may identify whether individuals with DS are likely to respond to future pro-cholinergic interventions, including the novel cholinergic modulators that are being developed to enhance cholinergic-sensitive cognitive functioning. We anticipate using the data gathered here to inform future treatment studies in TRC-DS where novel cholinergic treatments may offer opportunities for early intervention in DS and be complementary to disease-modifying approaches such as anti- amyloid treatments.