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

项目总结摘要 阿尔茨海默病是一种常见的神经退行性疾病，其发病率随着年龄的增长而增加 人群，其特征是淀粉样β蛋白(Aβ)相关斑块和 过度磷酸化的tau蛋白相关神经原纤维缠结(NFTs)。这项提议寻求将一种已知的 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病理改变增多。年龄较大与症状前较长的临床前阶段(10-20岁)有关 发病时，Aβ和NFT病理增加，可用tau PET和血浆标记物测量。 广泛而令人信服的临床前(啮齿动物和体外)研究结果表明，tau的磷酸化作用很强。 温度的小幅下降(分子动能的降低)，由于不同的 调节激酶和磷酸酶对这一性质的依赖。其他分子过程导致 NFT的形成可能类似地依赖于温度。我们将在初步研究的基础上再接再厉 在老年人中，受这些临床前发现的激励，据我们所知，他们提供了第一个人类 翻译。我们的初步结果显示，较低的远程测量体温(Tb)在 受试者醒着的时间--但不是在睡眠中--强烈预测(R2=0.47p&lt；0.005)tau的数量 用[18-F]-MK-6240tau PET-MR测量认知正常(NL)Braak早期区的NFT缠结 上了年纪的人。当前项目的目的是验证清醒时间较短的结核病与 NFTS，使用相同的方法，对100名老年人(n=100，50名女性，60-80岁)进行更大样本的研究 NL或有轻度认知障碍。简而言之，受试者将接受体检(访问1)，然后是7 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 在访问2中进行评估。在访问3中，在超过48小时的时间内，受试者将通过进食进行结核病测量 超过48小时的遥测体温，同时进行两个晚上的夜间多导睡眠监测以积分 TB与睡眠唤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。受试者将可以在白天睡眠学习的间隙自由回家。在探访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)验证较低的清醒结核病 此样本中NFT的预测，2)合并并考虑β斑块负荷的影响(已知增加 NFTS)和年龄较大的人进入模型，以及3)测试已知的结核病与睡眠之间的关系 在结核病-NFT协会中发挥作用。这项横断面研究将为今后的研究奠定基础。 确定以结核病为基础的干预措施是否可以防止NFT病理进展为 减轻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.