中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (8): 1757-1762.doi: 10.4103/1673-5374.360250

• 原著:退行性病与再生 • 上一篇    下一篇

阿尔茨海默病伴睡眠不足：临床特征、食欲能系统和血脑屏障相关性的横断面研究

  

  • 出版日期:2023-08-15 发布日期:2023-02-23
  • 基金资助:
    国家重点研发计划项目（2016YFC1306300，2016YFC1306 000）；中国欧盟地平线2020国家重点研发计划项目（2017YFE0118800-779238）；国家自然科学基金项目（81970992，81571229，81071015，30770745）；资本健康改善和研究基金项目（2022-2-2048）；北京市教委关键技术研发计划项目（kz201610025030）；北京市自然科学基金项目（7082032）；北京市自然科学基金重点项目（4161004）；资本临床特征应用研究（Z121107001012161）；北京市中医药科技发展项目（JJ2018-48）；北京市卫生系统高层次技术人才培养项目（2009-3-26）；北京市优秀人才培养项目（20071D0300400076）；国家重大科技专项（2011ZX09102-003-01）；北京市医疗卫生研究项目（JING-15-2）；首都医科大学基础临床研究合作基金项目（2015-JL-PT-X04，10JL49，14JL15）；首都医科大学自然科学基金项目（PYZ2018077）；首都医科大学北京天坛医院青年研究基金项目（2015-YQN-14，2015-YQN-15，2015-YQW-17）

Alzheimer’s disease with sleep insufficiency: a cross-sectional study on correlations among clinical characteristics, orexin, its receptors, and the blood-brain barrier

Peng Guo1, #, Wen-Jing Zhang2, #, Teng-Hong Lian1, Wei-Jiao Zhang2, Ming-Yue He2, Ya-Nan Zhang3, Yue Huang2, 4, 5, Du-Yu Ding2, Hui-Ying Guan2, Jing-Hui Li2, Dan-Ning Li2, Dong-Mei Luo2, Wei-Jia Zhang2, Hao Yue2, Xiao-Min Wang6, Wei Zhang1, 5, 7, 8, *#br#   

  1. 1Center for Cognitive Neurology, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; 2Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; 3Department of Blood Transfusion, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; 4Department of Pharmacology, School of Medical Sciences, Faculty of Medicine & Health, University of New South Wales, Sydney, Australia; 5China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; 6Department of Physiology, Capital Medical University, Beijing, China; 7Center of Parkinson’s Disease, Beijing Institute for Brain Disorders, Beijing, China; 8Beijing Key Laboratory on Parkinson’s Disease, Beijing, China
  • Online:2023-08-15 Published:2023-02-23
  • Contact: Wei Zhang, MD, ttyyzw@163.com.
  • Supported by:
    This work was supported by the National Key Research and Development Program of China, Nos. 2016YFC1306300 (to XMW), 2016YFC1306000; the National Key R&D Program of China-European Commission Horizon 2020, No. 2017YFE0118800-779238 (to YXW); the National Natural Science Foundation of China, Nos. 81970992 (to WZ), 81571229 (to WZ), 81071015 (to WZ), 30770745 (to WZ); Capital’s Funds for Health Improvement and Research (CFH), No. 2022-2-2048 (to WZ); the Key Technology R&D Program of Beijing Municipal Education Commission, No. kz201610025030 (to WZ); the Natural Science Foundation of Beijing, No. 7082032 (to WZ); the Key Project of the Natural Science Foundation of Beijing, No. 4161004 (to WZ); Capital Clinical Characteristic Application Research, No. Z121107001012161 (to WZ); Project of Scientific and Technological Development of Traditional Chinese Medicine in Beijing, No. JJ2018-48 (to WZ); High Level Technical Personnel Training Project of Beijing Health System of China, No. 2009-3-26 (to WZ); Excellent Personnel Training Project of Beijing, No. 20071D0300400076 (to WZ); Important National Science & Technology Specific Project, No. 2011ZX09102-003-01 (to WZ); Beijing Healthcare Research Project, No. JING-15-2 (to WZ); Basic-Clinical Research Cooperation Funding of Capital Medical University of China, Nos. 2015-JL-PT-X04 (to WZ), 10JL49 (to WZ), 14JL15 (to WZ); the Natural Science Foundation of Capital Medical University, Beijing, China, No. PYZ2018077 (to PG); Youth Research Fund of Beijing Tiantan Hospital of Capital Medical University of China, Nos. 2015-YQN-14 (to PG), 2015-YQN-15, 2015-YQN-17.

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摘要：

由于既往研究发现阿尔茨海默病患者的睡眠时间减少、睡眠片段化和睡眠质量下降与食欲素系统功能失调有关，且血脑屏障破坏被认为是阿尔茨海默病的早期生物标记，但是尚无有关阿尔茨海默病伴发睡眠不足患者中脑脊液食欲素系统以及金属基质蛋白变化的报道。此次横断面研究于2019年在首都医科大学北京天坛医院招募了50例阿尔茨海默病患者，依据睡眠时间≤6h和>6h将患者分为阿尔茨海默病伴发睡眠不足组（n=19，年龄61.58±8.54岁，男10例）和阿尔茨海默病不伴发睡眠不足组（n=31，年龄63.19±10.09岁，男18例），继而收集人口统计学变量，评估认知功能、神经精神症状和日常生活活动的临床表现，测量脑脊液中食欲能系统和血脑屏障相关因子的水平。结果显示，阿尔茨海默病患者睡眠潜伏期延长和觉醒增加，且其睡眠不足显著损害患者的整体认知以及记忆、语言及执行等多个认知领域。阿尔茨海默病伴发睡眠不足患者脑脊液中食欲素系统因子表达上调，且血脑屏障受到破坏，两者相互促进，并加速阿尔茨海默病的发展。这一发现首次阐明了阿尔茨海默病伴发睡眠不足的临床特点和潜在机制，并说明在这组病例中抑制食欲素系统上调和防止血脑屏障破坏可能是治疗阿尔茨海默病的潜在靶点。

https://orcid.org/0000-0002-9056-5675 (Wei Zhang)

关键词: 阿尔茨海默病, 睡眠不足, 临床特征, 认知功能, 神经精神症状, 食欲能系统, 血脑屏障, 基质金属蛋白酶, 基质金属蛋白酶3, 脑脊液

Abstract: Previous studies have shown that reduced sleep duration, sleep fragmentation, and decreased sleep quality in patients with Alzheimer’s disease are related to dysfunction in orexin signaling. At the same time, blood-brain barrier disruption is considered an early biomarker of Alzheimer’s disease. However, currently no report has examined how changes in orexin signaling relate to changes in the blood-brain barrier of patients who have Alzheimer’s disease with sleep insufficiency. This cross-sectional study included 50 patients with Alzheimer’s disease who received treatment in 2019 at Beijing Tiantan Hospital. Patients were divided into two groups: those with insufficient sleep (sleep duration ≤ 6 hours, n = 19, age 61.58 ± 8.54 years, 10 men) and those with normal sleep durations (sleep duration > 6 hours, n = 31, age 63.19 ± 10.09 years, 18 men). Demographic variables were collected to evaluate cognitive function, neuropsychiatric symptoms, and activities of daily living. The levels of orexin, its receptor proteins, and several blood-brain barrier factors were measured in cerebrospinal fluid. Sleep insufficiency was associated with impaired overall cognitive function that spanned multiple cognitive domains. Furthermore, levels of orexin and its receptors were upregulated in the cerebrospinal fluid, and the blood–brain barrier was destroyed. Both these events precipitated each other and accelerated the progression of Alzheimer’s disease. These findings describe the clinical characteristics and potential mechanism underlying Alzheimer’s disease accompanied by sleep deprivation. Inhibiting the upregulation of elements within the orexin system or preventing the breakdown of the blood-brain barrier could thus be targets for treating Alzheimer’s disease.

Key words: Alzheimer’s disease, blood-brain barrier, cerebrospinal fluid, clinical characteristics, cognitive function, matrix metalloproteinases, matrix metalloproteinase-3, neuropsychiatric symptoms, orexin signaling, sleep insufficiency