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

唐氏综合症的胆碱能完整性与衰老、阿尔茨海默病病理学和认知的关系

• 批准号: 10353561
• 负责人: PAUL A. NEWHOUSE
• 金额: $ 47.58万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10353561
• 关键词: Acetylcholine; Acetylcholinesterase; Adult; Affect; Affinity; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease therapeutic; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Atrophic; Attention; Binding; Biological Markers; Biological Process; Blood; Brain; Cerebrospinal Fluid; Characteristics; Clinical; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Collaborations; Cues; Data; Degenerative Disorder; Dementia; Disease; Disease Progression; Down Syndrome; Early Diagnosis; Early Intervention; Electroencephalogram; Evaluation; Exhibits; Functional Magnetic Resonance Imaging; Future; Gene Proteins; Image; Impaired cognition; Individual; Intellectual functioning disability; Intervention; Learning; Liquid substance; Measures; Medicine; Memory; Methods; Monitor; Nerve Degeneration; Neurons; Parents; Participant; Pathology; Pathway interactions; Performance; Population; Positron-Emission Tomography; Premature aging syndrome; Preparation; Prevention trial; Process; Public Health; Research Institute; Signal Transduction; Site; Specificity; System; Testing; acetylcholine transporter; age related; basal forebrain; base; cholinergic; cholinergic neuron; cognitive function; cognitive performance; cognitive testing; cohort; dementia risk; imaging biomarker; in vivo; instrument; interest; mental state; middle age; molecular imaging; molecular marker; negative affect; neurobehavioral; neuroimaging; neuron loss; neuropathology; neurotransmission; non-demented; novel; presynaptic; radiotracer; socioeconomics; specific biomarkers; targeted treatment; tau Proteins; uptake

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.

项目摘要唐氏综合症（DS）是普遍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，大多数患有DS的人 过早衰老的特征和阿尔茨海默氏病（AD）的神经病理学和早期表现 失智。 DS中的AD可能是由淀粉样蛋白前体蛋白基因的一式三次驱动的，但是其他 DS中可能发生零星AD的神经退行性特征。了解这些神经退行性过程 对于评估DS中的AD与零星AD的相似或不同是至关重要的，以及这些因素如何影响 DS认知下降和痴呆症的发作。在零星的广告中，进行性认知定义与 特定神经元种群的变性，最著名的是胆碱能神经元。胆碱能的丧失 诚信对认知表现产生负面影响，尤其是在注意力，学习和记忆形成方面。 但是，尚未在成年DS中评估脑胆碱能系统。当前的胆碱能标记 不直接测量胆碱能完整性/功能，从而显示出适度的可翻译性以进行监测 疾病进展或治疗评估。我们建议使用新型的正电子发射断层扫描（PET） radiotracer，称为[18F] FEOBV，是评估脑胆碱能完整性的直接/特定方法 与年龄相关的非痴呆成年人，认知/神经行为改变以及生物标志物 AD病理学确定提出的胆碱能生物标志物是否可以作为AD的新终点 最能反映疾病进展的DS的临床试验。认知医学中心是试验的场所 - 现成的队列降低综合征（TRC-DS）研究，以实现中间的系统生物标志物表征 通过使用神经成像，认知和临床措施，年龄和老年人患有DS 一项类似AD的预防试验（可能使用抗淀粉样剂）。由TRC-DS促进（作为父母研究）， 提供良好的DS主题，我们建议启动一条新的途径来研究我们的小说 胆碱能生物标志物。 DS中胆碱能系统的检查及其与衰老和已知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的风险和进行或遵循标准AD成像和流体生物标志物的变化，从而有助于建立 DS中的AD与零星广告的相似性。另外，我们的胆碱能生物标志物可以确定个人是否 使用DS可能会响应未来的促胆碱能干预措施，包括新型的胆碱能调节剂 正在开发以增强胆碱能敏感的认知功能。我们预计使用数据 聚集在这里为未来的胆碱能治疗可能提供的TRC-DS的治疗研究提供信息 早期干预DS的机会，并与疾病改良的方法相辅相成，例如 淀粉样蛋白治疗。