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

项目摘要 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，患病率逐渐增加 人群，特征为淀粉样β（Aβ）肽相关斑块的蓄积， 过度磷酸化的tau蛋白相关的神经元缠结（NFT）。该提案旨在将已知的 衰老的特征，即体温调节受损，身体和大脑温度降低，与此年龄相关 NFT病理学增加。年龄较大与出现症状前较长（10-20年）的临床前阶段相关 发病，其中Aβ和NFT病理学增加，并且可以用tau PET和血浆标志物测量。 广泛和令人信服的临床前（啮齿动物和体外）研究结果表明，tau蛋白磷酸化强烈 通过温度的小幅降低（分子动能的降低）来增强，这是由于 调节激酶和磷酸酶依赖于这种性质。其他分子过程导致 NFT形成可以类似地依赖于温度。我们会在初步研究的基础上， 在老年人中，这些临床前发现的动机，提供了，据我们所知，他们的第一个人类， 翻译.我们的初步研究结果表明，较低的遥测体温（Tb）在 受试者醒着的时间-但不是在睡眠期间-强烈预测（R2 = 0.47，p < 0.005）tau蛋白的量 在认知正常（NL）患者的早期Braak阶段区域中使用[18-F]-MK-6240 tau PET-MR测量的NFT缠结 老年人本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，受试者将接受医学筛选（访视1），随后是7次 用于睡眠-觉醒周期表征和进一步筛查的家庭活动记录天数，以及神经心理学 访视2中的评价。在访视3中，将在48小时内进行，受试者将接受Tb测量， 遥测体温超过48小时，同时进行两个晚上的夜间多导睡眠图， Tb与睡眠觉醒状态和测量慢波睡眠，随后对血浆tau和p-tau进行采样， 第二天早上。受试者可在睡眠研究之间的白天自由回家。访视4、18- 将完成[F]-MK-6240 tau和淀粉样蛋白PiB PET-MR扫描。我们的目标是1）验证较低的唤醒Tb 2）纳入并说明Aβ斑块负荷（已知增加）的影响 NFT）和老年人进入模型，以及3）测试Tb和睡眠之间的已知关系的程度 在结核-NFT关联中起作用。这项横断面研究将为未来的前瞻性研究奠定基础。 研究，以确定是否Tb为基础的干预措施可以防止NFT病理进展， 减少阿尔茨海默病的负担。

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.