Sleep and Temperature Disturbance as risk factors for Alzheimer's Disease in Down Syndrome: a Longitudinal Study

睡眠和体温紊乱是唐氏综合症中阿尔茨海默病的危险因素：一项纵向研究

• 批准号: 10591135
• 负责人: Esther Marian Blessing
• 金额: $ 187.12万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591135
• 关键词: Acceleration; Adult; Affect; Age; Age of Onset; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Apnea; Biological Markers; Blood; Body Temperature; Brain; Brain region; Cause of Death; Cerebrospinal Fluid; Circadian Dysregulation; Circadian Rhythms; Clinical; Cognition; Cognitive; Collection; Data; Data Collection; Dementia; Disease Marker; Disease Progression; Down Syndrome; Early Onset Alzheimer Disease; Elderly; Evaluation; Functional disorder; Genetic; Genetic Diseases; Goals; Heterogeneity; High Prevalence; Hippocampus; Home; Hour; Impaired cognition; Individual; Intellectual functioning disability; Intervention; Lead; Life; Life Expectancy; Light; Literature; Longitudinal Studies; Longitudinal, observational study; Magnetic Resonance Imaging; Measurement; Measures; Medical; Modeling; Nerve Degeneration; Obstructive Sleep Apnea; Onset of illness; Outcome; Pathology; Persons; Physiologic Thermoregulation; Plasma; Polysomnography; Population; Positron-Emission Tomography; Research; Risk Factors; Severities; Sleep; Sleep disturbances; Slow-Wave Sleep; Structure; Study models; Telemetry; Temperature; Testing; Thick; Work; Wrist; actigraphy; age related; aged; apolipoprotein E-4; autosomal dominant Alzheimer' s disease; circadian; cognitive change; cognitive performance; cognitive testing; cohort; follow-up; high risk; indexing; lifetime risk; modifiable risk; neurofilament; neuroimaging; novel; pre-clinical; progression marker; rate of change; recruit; screening; sex; symptomatology; tau Proteins; tau-1; uptake

Project Summary Abstract Down syndrome (DS), the most frequent form of intellectual disability of genetic origin, involves a >95% cumulative risk of Alzheimer’s Disease (AD) by the seventh decade. Further, AD is now the most common cause of death in this population as life expectancy in DS individuals has increased. Importantly, while AD in DS individuals has a mean age of onset 20–30 years younger compared to euploid individuals, there is substantial heterogeneity in this age of onset (between 40 and 70 years old), emphasizing the urgent need to identify and treat modifiable causes of AD in DS. Our work in the Down Alzheimer Barcelona Neuroimaging Initiative (DABNI) Cohort has established that clinical and Amyloid/Tau/Neurodegeneration (ATN) related biomarker changes in DS have a similar temporal profile to that in sporadic and autosomal dominant AD, meaning these biomarkers may be used to identify modifiable causes of AD in DS individuals prior to AD dementia onset. Existing literature and our preliminary data suggest that potential causes of AD in euploid individuals, namely age-related sleep and body temperature (Tb) circadian rhythm disturbance, are more severely perturbed in DS compared to euploid older adults: specifically, results suggest that greater obstructive sleep apnea (OSA) severity and lower Tb are particularly important modifiable AD risk factors in DS. This project will test the hypotheses that greater baseline OSA severity and lower baseline Tb will longitudinally predict ATN AD biomarker increase and cognitive decline in initially cognitively stable DS adults. We will recruit 60 DS adults with normal cognition aged 40–60 years old and follow them longitudinally at three annual timepoints over 2 years. Baseline assessments will include screening; cognitive evaluation; at home and in lab polysomnographic assessments overlapping with 36 hours of telemetrically measured Tb data collection, and collection of ATN biomarkers including amyloid (flutemetamol PET SUVR, plasma Aβ), tau (PI-2620 PET SUVR, plasma T-tau and P-tau181) and neurodegeneration (hippocampal volume, cortical thickness, plasma neurofilament light) related biomarkers. Follow-up cognitive evaluations and collection of plasma-based biomarkers will occur annually at all three timepoints, and neuroimaging-based biomarkers at two timepoints (baseline and 2 years). The goals of this study are to test 1) Whether greater baseline OSA apnea hypopnea index (AHI3A) is associated with ATN biomarker severity (Aim 1), 2) Whether lower baseline Tb is associated with greater tau biomarker severity (Aim 2), and 3) Whether OSA severity and lower Tb longitudinally predict greater estimated rate of change in AD biomarkers (Aim 3). Predictors of cognitive decline and additional sleep and Tb parameters will be explored. This novel proposal will advance our understanding of how age-related sleep and thermoregulatory disturbances impact AD biomarker progression in people with DS—a population at high risk for all three AD, OSA, and temperature dysregulation—with the aim of identifying modifiable risk factors in both DS and euploid individuals.

项目摘要摘要 唐氏综合症（DS）是遗传起源最常见的智力残疾形式，涉及> 95％ 第七个十年来，阿尔茨海默氏病（AD）的累积风险。此外，广告现在是最常见的原因 DS个人的预期寿命随着这种人群的死亡增加。重要的是，在DS中的广告时 与多倍体个体相比 在这个发病时代（40至70岁之间）的异质性，强调迫切需要识别和 处理DS中的AD的可修改原因。我们在阿尔茨海默氏症巴塞罗那神经影像倡议（DABNI）中的工作 队列确定临床和淀粉样蛋白/tau/神经变性（ATN）相关的生物标志物变化 DS具有与零星和常染色体显性AD相似的临时概况，这意味着这些生物标志物 可以在AD痴呆发作之前识别DS个体中AD的可修改原因。现有文献 并且我们的初步数据表明，杜布类个体的AD的潜在原因，即与年龄相关的睡眠 与体温（结核病）昼夜节律灾难相比，DS在DS中更加严重 Eploid老年人：具体来说，结果表明，更大的阻塞性睡眠呼吸暂停（OSA）严重程度较低 TB是DS中特别重要的可修改AD风险因素。该项目将检验更大的假设 基线OSA严重程度和较低的基线结核将纵向预测ATN AD生物标志物的增加和认知 最初认知稳定的DS成年人的下降。我们将招募60 ds的成年人，具有40-60岁的正常认知 年龄，并在2年内在三个年度时间点上纵向跟随它们。基线评估将 包括筛选；认知评估；在家里和实验室多渗透学评估中与36重叠 远程测量的TB数据收集时间和ATN生物标志物的收集时间包括淀粉样蛋白 （氟甲摩甲PET SUVR，等离子体Aβ），tau（PI-2620 PET SUVR，等离子体T-TAU和P-TAU181）和P-TAU181）和 神经变性（海马体积，皮质厚度，血浆神经丝光）相关的生物标志物。 在这三种 时间点和基于神经影像学的生物标志物在两个时间点（基线和2年）。这项研究的目标 测试1）较大的基线OSA呼吸暂停呼吸呼吸呼吸指数（AHI3A）是否与ATN生物标志物有关 严重程度（AIM 1），2）较低的基线结核是否与更大的Tau生物标志物严重程度（AIM 2）和3有关 OSA的严重程度和较低的TB是否纵向预测AD生物标志物的估计变化率更高 （目标3）。将探讨认知能力下降和额外睡眠和结核病参数的预测因素。这本小说 提案将提高我们对年龄相关的睡眠和温度调节灾害的影响 DS患者的AD生物标志物进展 - 这三个AD，OSA和温度的高风险 失调 - 目的是识别DS和多倍体个体中可修改的危险因素。