警惕!睡眠紊乱或是“老年痴呆”早早期症状
2018/02/01
记忆衰退、认知力下降、情绪失常……这些都是阿尔兹海默症(AD)患者表现出的典型症状。而在此之前,往往会发生生物钟紊乱的迹象。最新一项研究揭示,这种现象一般发生在AD的早早期,且会加剧病情发展。


图片来源:网络

阿尔兹海默症是一种慢性神经衰退性疾病,起病隐袭,多发于中老年群体。越来越多的学者认识到,在痴呆症状出现15-20年前,大脑已经开始出现损伤。

现在,来自于华盛顿大学医学院的睡眠专家Yo-El Ju博士带领团队发现:虽然记忆能力良好,但是大脑中有阿尔兹海默症发生迹象的患者多伴随有生物钟紊乱的症状。而且,这一紊乱会加剧大脑中老年斑块的累积。

这一发现有助于帮助医生评估患者发生老年痴呆的风险,相关研究成果以“Circadian Rest-Activity Pattern Changes in Aging and Preclinical Alzheimer Disease”为题于1月29日发表在《JAMA Neurology》期刊。


图片来源:JAMA Neurology(doi:10.1001/jamaneurol.2017.4719)

生物钟紊乱出现在记忆衰退之前

研究团队调研了189名年龄在66以上的老年人,记录了他们的睡眠规律。其中一些参与者会接受PET扫描以分析大脑中淀粉样蛋白累积的情况。而另一部分参与者则通过脑脊液获取蛋白信息。

结果显示,139名参与者未检测出与老年痴呆密切相关的淀粉样蛋白,他们大多数人都拥有正常的睡眠周期,小部分睡眠紊乱多与高龄、睡眠呼吸暂停等原因有关。

但是,对于其他50名受试对象而言,他们的脑补扫描、脑脊液检查都表现出异常。与此同时,通过追踪参与者白天、晚上的活动规律,研究人员发现这些参与者的生物钟都存在严重的紊乱,睡眠周期中断明显

研究团队发现,已被确诊的阿尔兹海默症患者其睡眠周期更为分散,具体表现为白天不活动或者睡眠时间增加,而晚上睡眠时间却减少。

“这并不意味,研究对象睡眠不足。”文章一作、神经学助理教授Erik S. Musiek表示,“相反,生物钟紊乱是指他们的睡眠时间是分散的。”


文章通讯作者Yo-El Ju教授(图片来源:华盛顿大学医学院)

生物钟紊乱会加剧痴呆

之前已有研究表明,无论是人还是其他模式动物,白天、黑夜大脑中的淀粉样蛋白水平会出现波动。具体而言,睡眠期间淀粉样蛋白水平会降低。当睡眠中断或者深度睡眠不足时,淀粉样蛋白水平会增加。

研究团队在小鼠模型上进行了另一项研究,于1月30日发表在《Journal of Experimental Medicine》期刊。他们发现,生物钟紊乱会加速小鼠大脑中淀粉样蛋白斑块(与AD有关)的形成,远超于正常小鼠累积的蛋白量。

这是第一份揭示昼夜节律紊乱加速痴呆病斑沉淀的证据。

谁引发谁尚需研究

那么,到底是阿尔兹海默症导致昼夜节律混乱?还是昼夜节律紊乱容易引发阿尔兹海默症?

研究人员认为,现在回答这个问题(chicken-and-egg question)还为时尚早。“至少,已有研究提示,昼夜节律紊乱可以作为临床期疾病的生物标志物。”Ju强调道,他希望,未来这批受试对象依然能够被随访,从而了解更多关于“昼夜问题与老年痴呆症”的问题。

参考资料:

Body clock disruptions occur years before memory loss in Alzheimer's

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  • Circadian Rest-Activity Pattern Changes in Aging and Preclinical Alzheimer Disease

    Importance Circadian rhythm disturbances occur in symptomatic Alzheimer disease (AD) and have been hypothesized to contribute to disease pathogenesis. However, it is unknown whether circadian changes occur during the presymptomatic phase of the disease. Objective To examine the associations between circadian function, aging, and preclinical AD pathology in cognitively normal adults. Design, Setting, and Participants This cross-sectional study was conducted using community volunteers from the Knight Alzheimer’s Disease Research Center at Washington University in St Louis. Cognitively normal participants (n = 205) underwent 7 to 14 days of actigraphy in their home environment between 2010 and 2012, in addition to clinical assessment, amyloid imaging with Pittsburgh Compound B (PiB), and cerebrospinal fluid biomarker collection. Data collected from 3 years before to 6 months after actigraphy were included. Sixteen participants were excluded owing to incomplete data collection. Main Outcomes and Measures Circadian rhythm analysis was performed on actigraphy data using 3 methods: cosinor, nonparametric, and empirical mode decomposition. Preclinical AD was assessed by longitudinal clinical assessment, amyloid imaging with PiB, and cerebrospinal fluid biomarker collection. Results Data from 189 participants were included in the analyses. The mean (SD) age was 66.6 (8.3) years, and 121 participants (64%) were women. Older age (β = .247; P = .003) and male sex (β = .170; P = .04), in the absence of amyloid pathology, were associated with a significant increase in intradaily variability, a nonparametric measure of rest-activity rhythm fragmentation, as well as decreased amplitude by several measures. After correction for age and sex, the presence of preclinical amyloid plaque pathology, assessed by positive PiB imaging (mean [SD], 0.804 [0.187] for PiB negative vs 0.875 [0.178] for PiB positive; P = .05) or increasing cerebrospinal fluid phosphorylated-tau to amyloid β 42 ratio (β = .231; P = .008), was associated with increased intradaily variability, indicating rest-activity rhythm fragmentation. Conclusions and Relevance Preclinical AD is associated with rest-activity rhythm fragmentation, independent of age or sex. Aging was also associated with circadian dysfunction independently of preclinical AD pathology, particularly in men. The presence of circadian rhythm abnormalities in the preclinical phase of AD suggests that circadian dysfunction could contribute to early disease pathogenesis or serve as a biomarker of preclinical disease.

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