Association of Sleep-Disordered Breathing With Alzheimer Disease Biomarkers in Community-Dwelling Older Adults: A Secondary Analysis of a Randomized Clinical Trial.
[en] 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.
Disciplines :
Neurosciences & behavior
Author, co-author :
André, Claire
Rehel, Stéphane
Kuhn, Elizabeth
Landeau, Brigitte
Moulinet, Inès
Touron, Edelweiss
Ourry, Valentin
Le Du, Gwendoline
Mézenge, Florence
Tomadesso, Clémence
de Flores, Robin
Bejanin, Alexandre
Sherif, Siya ; Université de Liège - ULiège > CRC In vivo Imaging-Sleep and chronobiology
Delcroix, Nicolas
Manrique, Alain
Abbas, Ahmed
Marchant, Natalie L.
Lutz, Antoine
Klimecki, Olga M.
Collette, Fabienne ; Université de Liège - ULiège > Département de Psychologie > Neuropsychologie
Association of Sleep-Disordered Breathing With Alzheimer Disease Biomarkers in Community-Dwelling Older Adults: A Secondary Analysis of a Randomized Clinical Trial.
Publication date :
2020
Journal title :
JAMA Neurology
ISSN :
2168-6149
eISSN :
2168-6157
Publisher :
American Medical Association, United States - Illinois
Volume :
77
Issue :
6
Pages :
1-10
Peer reviewed :
Peer Reviewed verified by ORBi
European Projects :
H2020 - 667696 - MEDIT-AGEING - Investigating the impact of meditation training on mental health and wellbeing in the ageing population
Malhotra A, White DP. Obstructive sleep apnoea. Lancet. 2002; 360 (9328): 237-245. doi: 10.1016/S0140-6736(02)09464-3 12133673
Ancoli-Israel S, Kripke DF, Mason W, Messin S. Comparisons of home sleep recordings and polysomnograms in older adults with sleep disorders. Sleep. 1981; 4 (3): 283-291. doi: 10.1093/sleep/4.3.283 7302459
Senaratna CV, Perret JL, Lodge CJ, Prevalence of obstructive sleep apnea in the general population: a systematic review. Sleep Med Rev. 2017; 34: 70-81. doi: 10.1016/j.smrv.2016.07.002 27568340
Emamian F, Khazaie H, Tahmasian M, The association between obstructive sleep apnea and Alzheimer's disease: a meta-analysis perspective. Front Aging Neurosci. 2016; 8: 78. doi: 10.3389/fnagi.2016.00078 27148046
Yaffe K, Laffan AM, Harrison SL, Sleep-disordered breathing, hypoxia, and risk of mild cognitive impairment and dementia in older women. JAMA. 2011; 306 (6): 613-619. doi: 10.1001/jama.2011.1115 21828324
Leng Y, McEvoy CT, Allen IE, Yaffe K. Association of sleep-disordered breathing with cognitive function and risk of cognitive impairment: a systematic review and meta-analysis. JAMA Neurol. 2017; 74 (10): 1237-1245. doi: 10.1001/jamaneurol.2017.2180 28846764
Huang X, Tang S, Lyu X, Yang C, Chen X. Structural and functional brain alterations in obstructive sleep apnea: a multimodal meta-analysis. Sleep Med. 2019; 54: 195-204. doi: 10.1016/j.sleep.2018.09.025 30580194
Shi Y, Chen L, Chen T, A meta-analysis of voxel-based brain morphometry studies in obstructive sleep apnea. Sci Rep. 2017; 7 (1): 10095. doi: 10.1038/s41598-017-09319-6 28855654
Tahmasian M, Rosenzweig I, Eickhoff SB, Structural and functional neural adaptations in obstructive sleep apnea: an activation likelihood estimation meta-analysis. Neurosci Biobehav Rev. 2016; 65: 142-156. doi: 10.1016/j.neubiorev.2016.03.026 27039344
Baril A-A, Gagnon K, Brayet P, Gray Matter hypertrophy and thickening with obstructive sleep apnea in middle-aged and older adults. Am J Respir Crit Care Med. 2017; 195 (11): 1509-1518. doi: 10.1164/rccm.201606-1271OC 28060546
Rosenzweig I, Kempton MJ, Crum WR, Hippocampal hypertrophy and sleep apnea: a role for the ischemic preconditioning? PLoS One. 2013; 8 (12): e83173. doi: 10.1371/journal.pone.0083173 24349453
Innes CRH, Kelly PT, Hlavac M, Melzer TR, Jones RD. Decreased regional cerebral perfusion in moderate-severe obstructive sleep apnoea during wakefulness. Sleep. 2015; 38 (5): 699-706. doi: 10.5665/sleep.4658 25669185
Baril A-A, Gagnon K, Arbour C, Regional cerebral blood flow during wakeful rest in older subjects with mild to severe obstructive sleep apnea. Sleep. 2015; 38 (9): 1439-1449. doi: 10.5665/sleep.4986 25761981
Kim JS, Seo JH, Kang M-R, Effect of continuous positive airway pressure on regional cerebral blood flow in patients with severe obstructive sleep apnea syndrome. Sleep Med. 2017; 32: 122-128. doi: 10.1016/j.sleep.2016.03.010 28366323
Nie S, Peng D-C, Gong H-H, Li H-J, Chen L-T, Ye C-L. Resting cerebral blood flow alteration in severe obstructive sleep apnoea: an arterial spin labelling perfusion fMRI study. Sleep Breath. 2017; 21 (2): 487-495. doi: 10.1007/s11325-017-1474-9 28210922
Bu X-L, Liu Y-H, Wang Q-H, Serum amyloid-beta levels are increased in patients with obstructive sleep apnea syndrome. Sci Rep. 2015; 5 (1): 13917. doi: 10.1038/srep13917 26351108
Bubu OM, Pirraglia E, Andrade AG,; Alzheimer's Disease Neuroimaging Initiative. Obstructive sleep apnea and longitudinal Alzheimer's disease biomarker changes. Sleep. 2019; 42 (6): zsz048. doi: 10.1093/sleep/zsz048 30794315
Liguori C, Mercuri NB, Izzi F, Obstructive sleep apnea is associated with early but possibly modifiable Alzheimer's disease biomarkers changes. Sleep. 2017; 40 (5). doi: 10.1093/sleep/zsx011 28329084
Sharma RA, Varga AW, Bubu OM, Obstructive sleep apnea severity affects amyloid burden in cognitively normal elderly: a longitudinal study. Am J Respir Crit Care Med. 2018; 197 (7): 933-943. doi: 10.1164/rccm.201704-0704OC 29125327
Elias A, Cummins T, Tyrrell R, Risk of Alzheimer's disease in obstructive sleep apnea syndrome: amyloid-β and tau imaging. J Alzheimers Dis. 2018; 66 (2): 733-741. doi: 10.3233/JAD-180640 30320587
Yun C-H, Lee H-Y, Lee SK, Amyloid burden in obstructive sleep apnea. J Alzheimers Dis. 2017; 59 (1): 21-29. doi: 10.3233/JAD-161047 28550245
Spira AP, Yager C, Brandt J, Objectively measured sleep and β-amyloid burden in older adults: a pilot study. SAGE Open Med. 2014; 2. doi: 10.1177/2050312114546520 25621174
Poisnel G, Arenaza-Urquijo E, Collette F,; Medit-Ageing Research Group. The Age-Well randomized controlled trial of the Medit-Ageing European Project: effect of meditation or foreign language training on brain and mental health in older adults. Alzheimers Dement (N Y). 2018; 4: 714-723. doi: 10.1016/j.trci.2018.10.011 30581977
McNair DM, Kahn RJ, Crook T, Ferris S, Bartus R. Assessment in Geriatric Psychopharmacology. Mark Powley Associates; 1983.
Buysse DJ, Reynolds CF III, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989; 28 (2): 193-213. doi: 10.1016/0165-1781(89)90047-4 2748771
Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep. 1991; 14 (6): 540-545. doi: 10.1093/sleep/14.6.540 1798888
Müller-Gärtner HW, Links JM, Prince JL, Measurement of radiotracer concentration in brain gray matter using positron emission tomography: MRI-based correction for partial volume effects. J Cereb Blood Flow Metab. 1992; 12 (4): 571-583. doi: 10.1038/jcbfm.1992.81 1618936
Sateia MJ. International classification of sleep disorders-third edition: highlights and modifications. Chest. 2014; 146 (5): 1387-1394. doi: 10.1378/chest.14-0970 25367475
Ju Y-ES, Finn MB, Sutphen CL, Obstructive sleep apnea decreases central nervous system-derived proteins in the cerebrospinal fluid. Ann Neurol. 2016; 80 (1): 154-159. doi: 10.1002/ana.24672 27129429
Osorio RS, Ayappa I, Mantua J, Interaction between sleep-disordered breathing and apolipoprotein E genotype on cerebrospinal fluid biomarkers for Alzheimer's disease in cognitively normal elderly individuals. Neurobiol Aging. 2014; 35 (6): 1318-1324. doi: 10.1016/j.neurobiolaging.2013.12.030 24439479
Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage. 2002; 15 (1): 273-289. doi: 10.1006/nimg.2001.0978 11771995
Sun X, He G, Qing H, Hypoxia facilitates Alzheimer's disease pathogenesis by up-regulating BACE1 gene expression. Proc Natl Acad Sci U S A. 2006; 103 (49): 18727-18732. doi: 10.1073/pnas.0606298103 17121991
Li L, Zhang X, Yang D, Luo G, Chen S, Le W. Hypoxia increases Abeta generation by altering beta-and gamma-cleavage of APP. Neurobiol Aging. 2009; 30 (7): 1091-1098. doi: 10.1016/j.neurobiolaging.2007.10.011 18063223
Blackwell T, Yaffe K, Laffan A,; Osteoporotic Fractures in Men Study Group. Associations between sleep-disordered breathing, nocturnal hypoxemia, and subsequent cognitive decline in older community-dwelling men: the Osteoporotic Fractures in Men Sleep Study. J Am Geriatr Soc. 2015; 63 (3): 453-461. doi: 10.1111/jgs.13321 25803785
Rosenzweig I, Williams SCR, Morrell MJ. The impact of sleep and hypoxia on the brain: potential mechanisms for the effects of obstructive sleep apnea. Curr Opin Pulm Med. 2014; 20 (6): 565-571. doi: 10.1097/MCP.0000000000000099 25188719
Cross NE, Memarian N, Duffy SL, Structural brain correlates of obstructive sleep apnoea in older adults at risk for dementia. Eur Respir J. 2018; 52 (1): 1800740. doi: 10.1183/13993003.00740-2018 29973356
Aviles-Reyes RX, Angelo MF, Villarreal A, Rios H, Lazarowski A, Ramos AJ. Intermittent hypoxia during sleep induces reactive gliosis and limited neuronal death in rats: implications for sleep apnea. J Neurochem. 2010; 112 (4): 854-869. doi: 10.1111/j.1471-4159.2009.06535.x 20002528
Li K, Zhang J, Qin Y, Wei Y-X. Association between serum homocysteine level and obstructive sleep apnea: a meta-analysis. Biomed Res Int. 2017; 2017: 7234528. doi: 10.1155/2017/7234528 28831396
Daulatzai MA. Death by a thousand cuts in Alzheimer's disease: hypoxia-the prodrome. Neurotox Res. 2013; 24 (2): 216-243. doi: 10.1007/s12640-013-9379-2 23400634
Bero AW, Yan P, Roh JH, Neuronal activity regulates the regional vulnerability to amyloid-β deposition. Nat Neurosci. 2011; 14 (6): 750-756. doi: 10.1038/nn.2801 21532579
Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA, Shulman GL. A default mode of brain function. Proc Natl Acad Sci U S A. 2001; 98 (2): 676-682. doi: 10.1073/pnas.98.2.676 11209064
Buckner RL, Sepulcre J, Talukdar T, Cortical hubs revealed by intrinsic functional connectivity: mapping, assessment of stability, and relation to Alzheimer's disease. J Neurosci. 2009; 29 (6): 1860-1873. doi: 10.1523/JNEUROSCI.5062-08.2009 19211893
Cirrito JR, Yamada KA, Finn MB, Synaptic activity regulates interstitial fluid amyloid-β levels in vivo. Neuron. 2005; 48 (6): 913-922. doi: 10.1016/j.neuron.2005.10.028 16364896
Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT. Inflammation as a central mechanism in Alzheimer's disease. Alzheimers Dement (N Y). 2018; 4: 575-590. doi: 10.1016/j.trci.2018.06.014 30406177
Fortea J, Vilaplana E, Alcolea D,; Alzheimer's Disease Neuroimaging Initiative. Cerebrospinal fluid β-amyloid and phospho-tau biomarker interactions affecting brain structure in preclinical Alzheimer disease. Ann Neurol. 2014; 76 (2): 223-230. doi: 10.1002/ana.24186 24852682
Stern Y, Arenaza-Urquijo EM, Bartrés-Faz D,; Reserve, Resilience and Protective Factors PIA Empirical Definitions and Conceptual Frameworks Workgroup. Whitepaper: defining and investigating cognitive reserve, brain reserve, and brain maintenance. Alzheimers Dement. 2018; pii: S1552-5260(18)33491-5. doi: 10.1016/j.jalz.2018.07.219 30222945
Olaithe M, Bucks RS, Hillman DR, Eastwood PR. Cognitive deficits in obstructive sleep apnea: Insights from a meta-review and comparison with deficits observed in COPD, insomnia, and sleep deprivation. Sleep Med Rev. 2018; 38: 39-49. doi: 10.1016/j.smrv.2017.03.005 28760549
Boland LL, Shahar E, Iber C, Knopman DS, Kuo TF, Nieto FJ; Sleep Heart Health Study (SHHS) Investigators. Measures of cognitive function in persons with varying degrees of sleep-disordered breathing: the Sleep Heart Health Study. J Sleep Res. 2002; 11 (3): 265-272. https://www.ncbi.nlm.nih.gov/pubmed/12220323. doi: 10.1046/j.1365-2869.2002.00308.x 12220323
Sforza E, Roche F, Thomas-Anterion C, Cognitive function and sleep related breathing disorders in a healthy elderly population: the SYNAPSE study. Sleep. 2010; 33 (4): 515-521. doi: 10.1093/sleep/33.4.515 20394321