Investigating the Temperature Dependence of Age-related Tau Pathology Relevant to Early Alzheimer's Disease

研究与早期阿尔茨海默病相关的年龄相关 Tau 病理学的温度依赖性

• 批准号: 10460555
• 负责人: Esther Marian Blessing
• 金额: $ 83.27万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10460555
• 关键词: Accounting; Age; Aging; Algorithm Design; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Area; Body Temperature; Body measure procedure; Brain; Clinical Research; Cognition; Cognitive; Cross-Sectional Studies; Data; Dependence; Elderly; Epitopes; Evaluation; Female; Foundations; Functional disorder; Future; Home; Hour; Human; Impaired cognition; Impairment; In Vitro; Intervention; Kinetics; Knowledge; Lead; Link; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Medical; Methods; Modeling; Molecular; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Neuropsychology; Non-Insulin-Dependent Diabetes Mellitus; Participant; Pathologic; Pathology; Pathway interactions; Peptides; Phase; Phosphoric Monoester Hydrolases; Phosphotransferases; Physiologic Thermoregulation; Plasma; Play; Polysomnography; Population; Positioning Attribute; Positron-Emission Tomography; Prevalence; Process; Property; Prospective Studies; Recording of previous events; Risk; Risk Factors; Rodent; Rodent Model; Role; Sampling; Scanning; Seasons; Senile Plaques; Sleep; Sleep Wake Cycle; Slow-Wave Sleep; Smoking; Symptoms; Synapses; System; Telemetry; Temperature; Testing; Thermometry; Time; Tracer; Translating; Translations; Visit; Work; abeta accumulation; actigraphy; age related; aging brain; aging population; apolipoprotein E-4; awake; base; blood-based biomarker; burden of illness; glymphatic clearance; hyperphosphorylated tau; insight; inter-individual variation; male; mild cognitive impairment; modifiable risk; neurofibrillary tangle formation; neuron loss; novel; pre-clinical; preclinical study; prevent; screening; sex; sleep quality; tau Proteins; tau aggregation; tau phosphorylation; tau-1; tomography; uptake; β-amyloid burden

PROJECT SUMMARY ABSTRACT Alzheimer's disease is a common neurodegenerative disease that is increasing in prevalence with the aging population, characterized by the accumulation of Amyloid-beta (Aβ) peptide associated plaques and hyperphosphorylated tau protein associated neurofibrillary tangles (NFTs). This proposal seeks to link a known feature of aging, namely impaired thermoregulation and lower body and brain temperature, with this age-related increase in NFT pathology. Older age is associated with a long (10–20 year) preclinical phase before symptom onset, in which Aβ and NFT pathology increases and can be measured with tau PET and plasma markers. Extensive and compelling preclinical (rodent and in vitro) findings show that tau phosphorylation is strongly potentiated by small decreases in temperature (decreases in molecular kinetic energy), owing to the differing dependence of regulatory kinases and phosphatases upon this property. Other molecular processes that cause NFT formation may be similarly temperature dependent. We will build upon the results of our preliminary study in older adults that was motivated by these preclinical findings, providing, to our knowledge, their first human translation. Our preliminary results showed that lower telemetrically measured body temperature (Tb) during the hours the subject was awake – but not during sleep – strongly predicted (R2 = 0.47, p < 0.005) the amount of tau NFT tangles measured with [18-F]-MK-6240 tau PET-MR in early Braak stage areas in cognitively normal (NL) older adults. The purpose of the current project is to verify this strong relationship between lower waking Tb and NFTs, using the same methods, in a larger sample of older adults (n = 100, 50 female, 60–80 years) who are NL or have mild cognitive impairment. Briefly, subjects will undergo medical screening (Visit 1), followed by 7 days of home actigraphy for sleep-wake cycle characterization and further screening, and neuropsychological evaluation in Visit 2. In Visit 3, to take place over 48 hours, subjects will undergo Tb measurement with ingestible telemetric thermometry over 48 hours, simultaneous with two nights of nocturnal polysomnography to integrate Tb with the sleep wake state and measure slow wave sleep, followed by plasma tau and p-tau sampling the following morning. Subjects will be free to return home during the day in between sleep studies. At Visit 4, 18- F]-MK-6240 tau and amyloid PiB PET-MR scanning will be completed. We aim to 1)Verify lower waking Tb prediction of NFT in this sample, 2)Incorporate and account for the effects of Aβ plaque load (known to increase NFTs) and older age into the model, and 3)Test the extent to which the known relationship between Tb and sleep plays a role in Tb–NFT associations. This cross-sectional study will lay the ground work for future prospective studies to determine whether Tb based interventions can prevent the progression of NFT pathology toward reducing Alzheimer’s Disease burden.

项目概要 摘要 阿尔茨海默病是一种常见的神经退行性疾病，随着年龄的增长，患病率不断增加 人群，其特征是淀粉样蛋白 - β (Aβ) 肽相关斑块的积累和 过度磷酸化的 tau 蛋白相关神经原纤维缠结 (NFT)。该提案旨在将已知的 衰老的特征，即体温调节受损以及身体和大脑温度降低，这与年龄有关 NFT 病理学增加。年龄较大与症状发生前较长（10-20 年）的临床前阶段相关 发病时，Aβ 和 NFT 病理学增加，可以使用 tau PET 和血浆标记物进行测量。 广泛且令人信服的临床前（啮齿动物和体外）研究结果表明，tau 磷酸化对 由于温度的小幅降低（分子动能的降低）而增强，这是由于不同的 调节激酶和磷酸酶对此特性的依赖性。其他导致的分子过程 NFT 的形成可能类似地依赖于温度。我们将根据初步研究的结果 在老年人中，受到这些临床前研究结果的激励，据​​我们所知，为他们提供了第一个人类 翻译。我们的初步结果表明，遥测测量的体温 (Tb) 在 受试者清醒的时间（但不是睡眠期间）强烈预测（R2 = 0.47，p < 0.005）tau 蛋白的量 使用 [18-F]-MK-6240 tau PET-MR 在认知正常 (NL) 的早期 Braak 阶段区域测量 NFT 缠结 老年人。当前项目的目的是验证较低的清醒 Tb 和 NFT，使用相同的方法，在更大的老年人样本中（n = 100，50 名女性，60-80 岁） NL 或有轻度认知障碍。简而言之，受试者将接受医疗筛查（访视 1），然后进行 7 用于睡眠-觉醒周期特征和进一步筛查的家庭体动记录仪天数，以及神经心理学 第 2 次访视中的评估。第 3 次访视将在 48 小时内进行，受试者将接受可摄入的 Tb 测量 48 小时内遥测体温，同时进行两晚夜间多导睡眠图整合 Tb 与睡眠觉醒状态并测量慢波睡眠，然后对血浆 tau 和 p-tau 进行采样 第二天早上。在睡眠研究之间的白天，受试者可以自由回家。在访问 4, 18- F]-MK-6240 tau 和淀粉样蛋白 PiB PET-MR 扫描将完成。我们的目标是 1) 验证较低的清醒 Tb 预测该样本中的 NFT，2）纳入并解释 Aβ 斑块负载的影响（已知会增加 将 NFTs）和年龄较大纳入模型，以及 3）测试 Tb 与睡眠之间已知关系的程度 在 Tb-NFT 协会中发挥作用。这项横断面研究将为未来的前瞻性研究奠定基础 研究以确定基于 Tb 的干预措施是否可以阻止 NFT 病理学进展 减轻阿尔茨海默病的负担。