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 唐氏综合征（DS）是最常见的遗传性智力残疾形式，涉及95%以上的 阿尔茨海默病（AD）的累积风险。此外，AD现在是最常见的原因 随着DS个体预期寿命的增加，该人群的死亡率也在下降。重要的是，虽然DS中的AD 个体的平均发病年龄比整倍体个体小20-30岁， 发病年龄（40至70岁）的异质性，强调迫切需要确定和 在DS中治疗AD的可改变原因。巴塞罗那阿尔茨海默病神经影像学倡议（DABNI） 队列研究已经确定，临床和淀粉样蛋白/Tau/神经变性（ATN）相关的生物标志物的变化， DS与散发性和常染色体显性AD具有相似的时间特征，这意味着这些生物标志物 可用于在AD痴呆发作之前识别DS个体中AD的可改变的原因。现有文献 我们的初步数据表明，整倍体个体中AD的潜在原因，即与年龄相关的睡眠， 和体温（Tb）昼夜节律紊乱，在DS中受到更严重的干扰， 整倍体老年人：具体来说，研究结果表明，阻塞性睡眠呼吸暂停（OSA）的严重程度越高， 结核是DS中特别重要的可改变的AD危险因素。这个项目将测试假设， 基线OSA严重程度和较低的基线Tb将纵向预测ATN AD生物标志物的增加和认知功能的改善。 最初认知稳定的DS成人的下降。我们将招募60名40-60岁认知正常的DS成年人 岁，并在2年内的三个年度时间点纵向跟踪他们。基线评估将 包括筛查、认知评估、在家和实验室多导睡眠图评估， 小时的遥测Tb数据收集，以及ATN生物标志物的收集，包括淀粉样蛋白 （flutemetetaline PET SUVR，血浆Aβ）、tau（PI-2620 PET SUVR，血浆T-tau和P-tau 181）和 神经变性（海马体积、皮质厚度、血浆神经丝光）相关生物标志物。 在所有三个研究中心，每年都会进行随访认知评估和收集基于血浆的生物标志物。 时间点，以及两个时间点（基线和2年）的基于神经成像的生物标志物。本研究的目标 测试1）更大的基线OSA呼吸暂停低通气指数（AHI 3A）是否与ATN生物标志物相关 2）较低的基线Tb是否与较大的tau生物标志物严重性相关（Aim 2），和3） OSA严重程度和较低的Tb纵向是否预测AD生物标志物的估计变化率较大 (Aim 3）。将探讨认知下降和额外睡眠和Tb参数的预测因素。这本小说 这项提案将促进我们对年龄相关的睡眠和体温调节紊乱如何影响 DS患者的AD生物标志物进展-所有三种AD、OSA和体温的高风险人群 失调-目的是确定DS和整倍体个体中可改变的风险因素。