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

唐氏综合症（DS）是遗传定义的智力残疾的主要原因， 影响所有种族和社会经济群体。除了智力残疾，大多数DS患者还表现出 过早衰老的特征和阿尔茨海默病（AD）样神经病理学的早期表现， 痴呆DS中的AD可能是由淀粉样前体蛋白基因的三倍化驱动的，但其他的AD可能是由淀粉样前体蛋白基因的三倍化驱动的。 散发性AD的神经退行性特征可能发生在DS中。了解这些神经退行性过程 对于评估DS中的AD与散发性AD的相似性或不同性以及这些因素如何影响 认知能力下降和痴呆的发生。在散发性AD中，进行性认知缺陷与 特定神经元群体的变性，最显著的是胆碱能神经元。胆碱能的丧失 完整性负面影响认知表现，特别是在注意力、学习和记忆形成方面。 然而，脑胆碱能系统尚未评估成人DS。目前的胆碱能标记物 不直接测量胆碱能完整性/功能，因此显示出适度的监测可转换性 疾病进展或治疗评价。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，称为[18F]FEOBV，作为一种直接/特异性方法，用于评估脑胆碱能完整性， 与年龄、认知/神经行为改变和 AD病理学，以确定拟定的胆碱能生物标志物是否可作为AD的新终点 最能反映疾病进展的DS临床试验。认知医学中心是试验的一个地点- 准备好的Cohort-Down综合征（TRC-DS）研究，以便能够系统地表征中间 通过使用神经影像学、认知和临床测量，为老年和老年DS患者做好准备， AD样预防试验（可能使用抗淀粉样蛋白药物）。由TRC-DS（作为母研究）促进， 这提供了良好的表征DS主题，我们建议启动一个新的途径，研究我们的新的 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 病理和认知能力下降将有助于验证胆碱能下降是否是痴呆的早期标志 DS的风险和标准AD成像和液体生物标志物的变化，从而帮助建立 DS中AD与散发性AD的相似程度。此外，我们的胆碱能生物标志物可以识别个体是否 DS患者可能会对未来的促胆碱能干预措施（包括新型胆碱能调节剂）产生反应 用于增强胆碱敏感性认知功能的药物我们希望利用这些数据 聚集在这里，为未来的TRC-DS治疗研究提供信息，其中新型胆碱能治疗可能提供 为DS的早期干预提供机会，并补充疾病修饰方法，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.