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Original Investigation
March 23, 2020

Association of Sleep-Disordered Breathing With Alzheimer Disease Biomarkers in Community-Dwelling Older Adults: A Secondary Analysis of a Randomized Clinical Trial

Author Affiliations
  • 1Normandie Université, Université de Caen, Institut National de la Santé et de la Recherche Médicale, Unité 1237 "Physiopathology and Imaging of Neurological Disorders,” Institut Blood and Brain @ Caen-Normandie, GIP Cyceron, Caen, France
  • 2Normandie Université, Université de Caen, Paris Sciences & Lettres Université, École Pratique des Hautes Études, Institut National de la Santé et de la Recherche Médicale, Unité 1077 "Neuropsychologie et Imagerie de la Mémoire Humaine," Centre Hospitalier Universitaire de Caen, GIP Cyceron, Caen, France
  • 3Centre National de la Recherche Scientifique, Unité Mixte de Service 3048, GIP Cyceron, Caen, France
  • 4Normandie Université, Université de Caen, EA 4650 "Signalisation, Électrophysiologie et Imagerie des Lésions d'Ischémie-Reperfusion Myocardique", GIP Cyceron, Caen, France
  • 5Division of Psychiatry, University College London, London, United Kingdom
  • 6Lyon Neuroscience Research Center, Institut National de la Santé et de la Recherche Médicale Unité 1028, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5292, Lyon University, Lyon, France
  • 7Swiss Center for Affective Sciences, Department of Medicine, University of Geneva, Geneva, Switzerland
  • 8GIGA–Cyclotron Research Centre, In Vivo Imaging and Psychology and Cognitive Neuroscience Unit, Liège University, Liège, Belgium
  • 9Département de Recherche Clinique, Centre Hospitalier Universitaire de Caen-Normandie, Caen, France
  • 10Unité d’Exploration et de Traitement des Troubles du Sommeil, Centre Hospitalier Universitaire de Caen, Caen, France
  • 11Service de Neurologie, Centre Hospitalier Universitaire de Caen, Caen, France
JAMA Neurol. Published online March 23, 2020. doi:10.1001/jamaneurol.2020.0311
Key Points

Question  Which brain changes are associated with sleep-disordered breathing in aging?

Findings  In this cross-sectional study of 127 community-dwelling older individuals who were cognitively unimpaired, the presence of sleep-disordered breathing was associated with greater amyloid burden, gray matter volume, metabolism, and perfusion in the posterior cingulate cortex and precuneus. There was no association with cognitive performance, self-reported cognitive or sleep difficulties, or excessive daytime sleepiness.

Meaning  Sleep-disordered breathing–associated changes include amyloid deposition in brain regions typically involved in Alzheimer disease, which might explain why sleep-disordered breathing is associated with an increased risk for developing Alzheimer clinical syndrome at a younger age.

Abstract

Importance  Increasing evidence suggests that sleep-disordered breathing (SDB) increases the risk of developing Alzheimer clinical syndrome. However, the brain mechanisms underlying the link between SDB and Alzheimer disease are still unclear.

Objective  To determine which brain changes are associated with the presence of SDB in older individuals who are cognitively unimpaired, including changes in amyloid deposition, gray matter volume, perfusion, and glucose metabolism.

Design, Setting, and Participants  This cross-sectional study was conducted using data from the Age-Well randomized clinical trial of the Medit-Ageing European project, acquired between 2016 and 2018 at Cyceron Center in Caen, France. Community-dwelling older adults were assessed for eligibility and were enrolled in the Age-Well clinical trial if they did not meet medical or cognitive exclusion criteria and were willing to participate. Participants who completed a detailed neuropsychological assessment, polysomnography, a magnetic resonance imaging, and florbetapir and fluorodeoxyglucose positron emission tomography scans were included in the analyses.

Main Outcomes and Measures  Based on an apnea-hypopnea index cutoff of 15 events per hour, participants were classified as having SDB or not. Voxelwise between-group comparisons were performed for each neuroimaging modality, and secondary analyses aimed at identifying which SDB parameter (sleep fragmentation, hypoxia severity, or frequency of respiratory disturbances) best explained the observed brain changes and assessing whether SDB severity and/or SDB-associated brain changes are associated with cognitive and behavioral changes.

Results  Of 157 participants initially assessed, 137 were enrolled in the Age-Well clinical trial, and 127 were analyzed in this study. The mean (SD) age of the 127 participants was 69.1 (3.9) years, and 80 (63.0%) were women. Participants with SDB showed greater amyloid burden (t114 = 4.51; familywise error–corrected P = .04; Cohen d, 0.83), gray matter volume (t119 = 4.12; familywise error–corrected P = .04; Cohen d, 0.75), perfusion (t116 = 4.62; familywise error–corrected P = .001; Cohen d, 0.86), and metabolism (t79 = 4.63; familywise error–corrected P = .001; Cohen d, 1.04), overlapping mainly over the posterior cingulate cortex and precuneus. No association was found with cognition, self-reported cognitive and sleep difficulties, or excessive daytime sleepiness symptoms.

Conclusions and Relevance  The SDB-associated brain changes in older adults who are cognitively unimpaired include greater amyloid deposition and neuronal activity in Alzheimer disease–sensitive brain regions, notably the posterior cingulate cortex and precuneus. These results support the need to screen and treat for SDB, especially in asymptomatic older populations, to reduce Alzheimer disease risk.

Trial Registration  ClinicalTrials.gov Identifier: NCT02977819

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    1 Comment for this article
    EXPAND ALL
    RE: Association of sleep-disordered breathing with Alzheimer disease biomarkers in community-dwelling older adults
    Tomoyuki Kawada, MD | Nippon Medical School
    André et al. conducted a cross-sectional study to evaluate the association of sleep-disordered breathing (SDB) with amyloid deposition and neuronal activity in 127 older cognitively unimpaired individuals (1). Based on an apnea-hypopnea index cutoff of 15 events per hour, participants were classified as having SDB or not. Participants with SDB showed greater amyloid burden, gray matter volume, perfusion, and glucose metabolism, notably in the posterior cingulate cortex and precuneus. In contrast, there were no significant associations of SDB with cognition, self-reported cognitive and sleep difficulties, or excessive daytime sleepiness symptoms. They recommended the screening and treatment for SDB, especially in asymptomatic older populations, to reduce Alzheimer disease (AD) risk. I have some concerns about their study with special reference to the effect of SDB treatment on cognitive impairment and AD.

    Bubu et al. conducted a systematic review on the association between obstructive sleep apnea (OSA), cognition and AD (2). OSA is significantly associated with mild impairment in attention, memory and executive function in middle-aged adults. In older-adults, OSA is significantly associated with the development of mild cognitive impairment (MCI) or Alzheimer disease having symptoms of disturbed sleep/cognitive-impairment by prospective studies. They also recognize that continuous positive airway pressure (CPAP) treatment may be effective in improving cognition in OSA patients with AD.

    Regarding the effect of treatment, Tsai et al. conducted a retrospective cohort study to assess the risk of AD in patients with OSA with or without treatment (3). Adjusted hazard ratio (95% confidence interval [CI]) of OSA for AD was 2.12 (1.27-3.56). In addition, adjusted rate ratio (95% CI) of OSA treatment by CPAP for AD was 0.23 (0.06-0.98). Furthermore, the average period of AD incidence from OSA occurrence was 5.44 years with one standard deviation of 2.96 years. Risk factors for AD incidence have been reported (4), and OSA/SDB should also be included for the risk assessment of AD incidence.

    Finally, Perez-Cabezas et al. conducted a systematic review to evaluate the treatment of OSA with CPAP in patients with AD (5). Treatment decreases excessive daytime sleepiness and improves sleep quality. In addition, CPAP treatment has a preventive effect on the progression of cognitive impairment and AD incidence. This report handled a limited number of papers, and the association should be verified by prospective/interventional studies.


    References
    1. André C, et al. Association of sleep-disordered breathing with Alzheimer disease biomarkers in community-dwelling older adults: A secondary analysis of a randomized clinical trial. JAMA Neurol. 2020 Mar 23. doi: 10.1001/jamaneurol.2020.0311

    2. Bubu OM, et al. Obstructive sleep apnea, cognition and Alzheimer's disease: A systematic review integrating three decades of multidisciplinary research. Sleep Med Rev. 2020;50:101250. doi: 10.1016/j.smrv.2019.101250

    3. Tsai MS, et al. Risk of Alzheimer's disease in obstructive sleep apnea patients with or without treatment: Real-world evidence. Laryngoscope. 2020 Feb 11. doi: 10.1002/lary.28558

    4. Sperling RA, et al. Association of factors with elevated amyloid burden in clinically normal older individuals. JAMA Neurol. 2020 Apr 6. doi: 10.1001/jamaneurol.2020.0387

    5. Perez-Cabezas V, et al. Continuous positive airway pressure treatment in patients with Alzheimer's disease: A systematic review. J Clin Med. 2020;9(1):E181. doi: 10.3390/jcm9010181
    CONFLICT OF INTEREST: None Reported
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