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

项目摘要摘要 唐氏综合症(DS)是最常见的遗传性智力残疾形式，95%的人患有唐氏综合症。 到第七个十年，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患者预期寿命的增加，这一人群的死亡人数也有所增加。重要的是，当DS中的AD 个体的平均发病年龄比整倍体个体早20-30岁，有很大的 这一发病年龄(40至70岁)的异质性，强调迫切需要确定和 治疗DS中AD的可改变原因。我们在唐氏阿尔茨海默病巴塞罗那神经成像倡议(DABNI)中的工作 队列已确定临床和淀粉样蛋白/牛磺酸/神经变性(ATN)相关生物标记物在 DS的时间分布与散发性和常染色体显性AD相似，这意味着这些生物标志物 可用于在阿尔茨海默病发病前确定DS患者AD的可改变原因。现存文献 我们的初步数据表明，整倍体个体患阿尔茨海默病的潜在原因，即年龄相关睡眠 和体温(TB)昼夜节律紊乱相比，DS患者受到的干扰更严重 整倍体老年人：具体地说，结果表明更大阻塞性睡眠呼吸暂停(OSA)的严重程度和更低 结核病是DS中特别重要的可变型AD危险因素。这个项目将检验更大的假设 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 在最初认知稳定的DS成年人中出现下降。我们将招募60名40-60岁认知正常的DS成年人 年，并在超过两年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；在家中和实验室中进行多导睡眠图评估 数小时的远程测量结核病数据收集，以及包括淀粉样蛋白在内的ATN生物标记物的收集 Tau(PI-2620PET SUVR，血浆T-tau和P-tau181)和 神经退行性变(海马区体积、皮质厚度、血浆神经丝光)相关生物标志物。 所有三家公司每年都将进行后续认知评估和血浆生物标记物的收集 时间点，以及两个时间点(基线和2年)基于神经成像的生物标志物。这项研究的目标是 测试1)较大的基线OSA呼吸暂停低通气指数(AHI3A)是否与ATN生物标志物相关 严重性(目标1)，2)较低的基线结核病是否与较高的tau生物标志物严重性相关(目标2)，以及3) 阻塞性睡眠呼吸暂停综合征的严重程度和较低的结核病纵向上是否预示着AD生物标志物的估计变化率更大 (目标3)。将探索认知衰退的预测因素以及额外的睡眠和结核病参数。这部小说 该提案将促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--这三种疾病都是AD、OSA和体温的高危人群 调节失调-目的是在DS和整倍体个体中识别可改变的危险因素。

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.