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.

项目概要摘要 唐氏综合症 (DS) 是最常见的遗传性智力障碍，涉及 >95% 到了七十岁，阿尔茨海默病 (AD) 的累积风险进一步增加。此外，AD 现在是最常见的原因。 重要的是，DS 个体的预期寿命有所增加，而 DS 中的 AD 则增加了。 与整倍体个体相比，个体的平均发病年龄年轻 20-30 岁， 该发病年龄（40 至 70 岁）的异质性，强调迫切需要识别和 治疗 DS 中可改变的 AD 病因。我们在巴塞罗那阿尔茨海默氏症神经影像计划 (DABNI) 中的工作 队列已确定临床和淀粉样蛋白/Tau/神经退行性变 (ATN) 相关的生物标志物变化 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 现有文献可用于在 DS 个体出现 AD 痴呆之前确定可改变的 AD 病因。 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，与 DS 相比，受到更严重的干扰 整倍体老年人：具体而言，结果表明阻塞性睡眠呼吸暂停 (OSA) 的严重程度更高，且 Tb 是 DS 中特别重要的可改变 AD 风险因素，该项目将测试更大的假设。 基线 OSA 严重程度和较低基线 Tb 将纵向预测 ATN AD 生物标志物增加和认知能力 最初认知稳定的 DS 成年人的下降 我们将招募 60 名 40-60 岁认知正常的 DS 成年人。 岁，并在两年内的三个年度时间点纵向跟踪它们。 包括筛查；在家中和实验室进行的多导睡眠图评估与 36 重叠 数小时的遥测测量 Tb 数据收集以及 ATN 生物标志物（包括淀粉样蛋白）的收集 （氟替他莫 PET SUVR、血浆 Aβ）、tau（PI-2620 PET SUVR、血浆 T-tau 和 P-tau181）和 神经退行性变（海马体积、皮质厚度、血浆神经丝光）相关的生物标志物。 所有三个中心每年都会进行后续认知评估和血浆生物标志物收集 时间点和两个时间点（基线和 2 年）的基于神经影像的生物标志物。 要测试 1) 较高的基线 OSA 呼吸暂停低通气指数 (AHI3A) 是否与 ATN 生物标志物相关 严重程度（目标 1）、2） 较低的基线 Tb 是否与较高的 tau 生物标志物严重程度相关（目标 2）和 3） OSA 严重程度和较低 Tb 是否纵向预测 AD 生物标志物的估计变化率更大 （目标 3）。这本小说将探讨认知能力下降的预测因素以及额外的睡眠和结核病参数。 该提案将增进我们对与年龄相关的睡眠和体温调节障碍如何影响的理解 DS 患者的 AD 生物标志物进展——AD、OSA 和体温这三种疾病的高危人群 失调——目的是识别 DS 和整倍体个体中可改变的危险因素。