Medical Biodynamics Program, Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
Medical Biodynamics Program, Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Lancet Healthy Longev. 2020 Dec;1(3):e96-e105. doi: 10.1016/s2666-7568(20)30015-5. Epub 2020 Nov 12.
Circadian disturbances are commonly seen in people with Alzheimer's disease and have been reported in individuals without symptoms of dementia but with Alzheimer's pathology. We aimed to assess the temporal relationship between circadian disturbances and Alzheimer's progression.
We did a prospective cohort study of 1401 healthy older adults (aged >59 years) enrolled in the Rush Memory and Aging Project (Rush University Medical Center, Chicago, IL, USA) who had been followed up for up to 15 years. Participants underwent annual assessments of cognition (with a battery of 21 cognitive performance tests) and motor activities (with actigraphy). Four measures were extracted from actigraphy to quantify daily and circadian rhythmicity, which were amplitude of 24-h activity rhythm, acrophase (representing peak activity time), interdaily stability of 24-h activity rhythm, and intradaily variability for hourly fragmentation of activity rhythm. We used Cox proportional hazards models and logistic regressions to assess whether circadian disturbances predict an increased risk of incident Alzheimer's dementia and conversion of mild cognitive impairment to Alzheimer's dementia. We used linear mixed-effects models to investigate how circadian rhythms changed longitudinally and how the change integrated to Alzheimer's progression.
Participants had a median age of 81·8 (IQR 76·3-85·7) years. Risk of developing Alzheimer's dementia was increased with lower amplitude (1 SD decrease, hazard ratio [HR] 1·39, 95% CI 1·19-1·62) and higher intradaily variability (1 SD increase, 1·22, 1·04-1·43). In participants with mild cognitive impairment, increased risk of Alzheimer's dementia was predicted by lower amplitude (1 SD decrease, HR 1·46, 95% CI 1·24-1·72), higher intradaily variability (1 SD increase, 1·36, 1·15-1·60), and lower interdaily stability (1 SD decrease, 1·21, 1·02-1·44). A faster transition to Alzheimer's dementia in participants with mild cognitive impairment was predicted by lower amplitude (1 SD decrease, odds ratio [OR] 2·08, 95% CI 1·53-2·93), increased intradaily variability (1 SD increase, 1·97, 1·43-2·79), and decreased interdaily stability (1 SD decrease, 1·35, 1·01-1·84). Circadian amplitude, acrophase, and interdaily stability progressively decreased over time, and intradaily variability progressively increased over time. Alzheimer's progression accelerated these aging effects by doubling or more than doubling the annual changes in these measures after the diagnosis of mild cognitive impairment, and further doubled them after the diagnosis of Alzheimer's dementia. The longitudinal change of global cognition positively correlated with the longitudinal changes in amplitude and interdaily stability and negatively correlated with the longitudinal change in intradaily variability.
Our results indicate a link between circadian dysregulation and Alzheimer's progression, implying either a bidirectional relation or shared common underlying pathophysiological mechanisms.
National Institutes of Health, and the BrightFocus Foundation.
在阿尔茨海默病患者中，昼夜节律紊乱很常见，在没有痴呆症状但有阿尔茨海默病病理的个体中也有报道。我们旨在评估昼夜节律紊乱与阿尔茨海默病进展之间的时间关系。
我们对 1401 名年龄大于 59 岁的健康老年人（来自 Rush 记忆和衰老项目（Rush 大学医学中心，芝加哥，IL，美国））进行了前瞻性队列研究，这些老年人的随访时间长达 15 年。参与者每年接受认知评估（使用 21 项认知表现测试的电池）和运动活动（使用活动记录仪）。从活动记录仪中提取了四个指标来量化日常和昼夜节律性，分别是 24 小时活动节律的振幅、高峰时间（代表活动时间的高峰）、24 小时活动节律的日内稳定性以及活动节律每小时碎片化的日内可变性。我们使用 Cox 比例风险模型和逻辑回归来评估昼夜节律紊乱是否预示着阿尔茨海默病痴呆的发病风险增加，以及轻度认知障碍向阿尔茨海默病痴呆的转化。我们使用线性混合效应模型来研究昼夜节律如何随时间纵向变化，以及这种变化如何整合到阿尔茨海默病的进展中。
参与者的中位年龄为 81.8 岁（IQR 76.3-85.7）。振幅降低（1 个标准差下降，风险比 [HR] 1.39，95%CI 1.19-1.62）和日内可变性增加（1 个标准差增加，1.22，1.04-1.43）与发生阿尔茨海默病痴呆的风险增加相关。在患有轻度认知障碍的参与者中，阿尔茨海默病痴呆的发病风险增加与振幅降低（1 个标准差下降，HR 1.46，95%CI 1.24-1.72）、日内可变性增加（1 个标准差增加，1.36，1.15-1.60）和日内稳定性降低（1 个标准差下降，1.21，1.02-1.44）相关。在患有轻度认知障碍的参与者中，向阿尔茨海默病痴呆的更快过渡与振幅降低（1 个标准差下降，比值比 [OR] 2.08，95%CI 1.53-2.93）、日内可变性增加（1 个标准差增加，1.97，1.43-2.79）和日内稳定性降低（1 个标准差下降，1.35，1.01-1.84）相关。随着时间的推移，昼夜节律振幅、高峰时间和日内稳定性逐渐降低，日内可变性逐渐增加。阿尔茨海默病的进展通过将这些指标的年度变化在轻度认知障碍诊断后的两倍或更多倍加速，并且在阿尔茨海默病痴呆诊断后进一步将这些指标的年度变化加倍。总体认知的纵向变化与振幅和日内稳定性的纵向变化呈正相关，与日内可变性的纵向变化呈负相关。
我们的结果表明昼夜节律紊乱与阿尔茨海默病进展之间存在联系，这表明两者之间存在双向关系或共同的潜在病理生理机制。
美国国立卫生研究院和光明基金会。
Zotero 插件
