Sleep disruption in elderly has been associated with an increased risk of cognitive impairment and its transition into Alzheimer’s disease (AD). High arousal indices (AIs) during sleep may serve as an early-stage biomarker of cognitive impairment non-dementia (CIND).
Objective:
Using full-night polysomnography (PSG), we investigated whether CIND is related to different AIs between NREM and REM sleep stages.
Methods:
Fourteen older adults voluntarily participated in this population-based study that included Mini-Mental State Examination, Neuropsi battery, Katz Index of Independence in Activities of Daily Living, and single-night PSG. Subjects were divided into two groups (n = 7 each) according to their results in Neuropsi memory and attention subtests: cognitively unimpaired (CU), with normal results; and CIND, with –2.5 standard deviations in memory and/or attention subtests. AIs per hour of sleep during N1, N2, N3, and REM stages were obtained and correlated with Neuropsi total score (NTS).
Results:
AI (REM) was significantly higher in CU group than in CIND group. For the total sample, a positive correlation between AI (REM) and NTS was found (r = 0.68, p = 0.006), which remained significant when controlling for the effect of age and education. In CIND group, the AI (N2) was significantly higher than the AI (REM) .
Conclusion:
In CIND older adults, this attenuation of normal arousal mechanisms in REM sleep are dissociated from the relative excess of arousals observed in stage N2. We propose as probable etiology an early hypoactivity at the locus coeruleus noradrenergic system, associated to its early pathological damage, present in the AD continuum.
CaiS, LiT, ZhangL, ShiL, LiaoJ, LiW, ChengG, TanW, RongS (2020) Characteristics of sleep structure assessed by objective measurements in patients with amnestic mild cognitive impairment: A meta-analysis. Front Neurol11, 577126.
van der HoekMD, NieuvwnhuizenA, KeijerJ, AshfordJW (2019) The MemTrax test compared to the Montreal Cognitive Assessment estimation of mild cognitive impairment. J Alzheimers Dis67, 1045–1054.
DavisM, O’ConnellT, JohnsonS, ClineS, MerikleE, MartenyiF, SimpsonK (2018) Estimating Alzheimer’s disease progression rates from normal cognition through mild cognitive impairment and stages of dementia. Curr Alzheimer Res15, 777–788.
7.
Roldán-TapiaMD, CánovasR, LeónI, García-GarcíaJ (2017) Cognitive vulnerability in aging may be modulated by education and reserve in healthy people. Front Aging Neurosci24, 340.
8.
SternY (2013) Cognitive reserve: Implications for assessment and intervention. Folia Phoniatr Logop65, 49–54.
9.
RossJA, GliebusG, Van BockstaeleEJ (2018) Stress induced neural reorganization: A conceptual framework linking depression and Alzheimer’s disease. Prog Neuro-Psychopharmacol Biol Psychiatry85, 136–151.
10.
JohanssonM, StomrudE, LindbergO, WestmanE, JohanssonPM, van WestenD, MattssonN, HanssonO (2020) Apathy and anxiety are early markers of Alzheimer’s disease. Neurobiol Aging85, 74–82.
11.
HaneFT, RobinsonM, LeeBY, BaiO, LeonenkoZ, AlbertMS (2017) Recent progress in Alzheimer’s disease research, part 3: Diagnosis and treatment. J Alzheimers Dis57, 645–665.
12.
ElmanJA, OhH, MadisonCM, BakerSL, VogelJW, MarksSM, CrowleyS, NeilJPO, JagustWJ (2014) Neural compensation in older people with brain amyloid-β deposition. Nat Neurosci17, 1316–1318.
13.
LuceyBP, McCulloughA, LandsnessEC, ToedebuschCD, McLelandJS, ZazaAM, FaganAM, McCueL, XiongC, MorrisJC, BenzingerTLS, HoltzmanDM (2019) Reduced non–rapid eye movement sleep is associated with tau pathology in early Alzheimer’s disease. Sci Transl Med11, eaau65501–13.
14.
DecourtB, NoordaK, NoordaK, ShiJ, SabbaghMN (2022) Review of advanced drug trials focusing on the reduction of brain beta-amyloid to prevent and treat dementia. J Exp Pharmacol14, 331–352.
YangP, SunF (2021) Aducanumab: The first targeted Alzheimer’s therapy. Drug Discov Ther15, 166–168.
17.
ManderBA, MarksSM, VogelJW, RaoV, LuB, SaletinJM, Ancoli-IsraelS, JagustWJ, WalkerMP (2015) β-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation. Nat Neurosci18, 1051–1057.
18.
ManderBA, ZhuAH, LindquistJR, VilleneuveS, RaoV, LuB, SaletinXM, Ancoli-IsraelS, JagustWJ, WalkerMP (2017) White matter structure in older adults moderates the benefit of sleep spindles on motor memory consolidation. J Neurosci37, 11675–11687.
19.
WinerJR, ManderBA, HelfrichRF, MaassA, HarrisonTM, BakerSL, KnightRT, JagustWJ, WalkerWP (2019) Sleep as a potential biomarker of tau and β-amyloid burden in the human brain. J Neurosci39, 6315–6324.
20.
MaestriM, CarnicelliL, TognoniG, Di CoscioE, GiorgiFS, VolpiL, EconomouNT, KtonasP, FerriR, BonuccelliU, BonanniE (2015) Non-rapid eye movement sleep instability in mild cognitive impairment: A pilot study. Sleep Med16, 1139–1145.
21.
CarnicelliL, MaestriM, Di CoscioE, TognoniG, FabbriniM, SchirruA, GiorgiFS, SicilianoG, BonuccelliU, BonanniE (2019) A longitudinal study of polysomnographic variables in patients with mild cognitive impairment converting to Alzheimer’s disease. J Sleep Res28, e12821.
22.
D’AtriA, ScarpelliS, GorgoniM, MarraC, RossiniPM, DeGennaroL (2021) EEG alterations during wake and sleep in mild cognitive impairment and Alzheimer’s disease. iScience24, 102386.
23.
RossiniPM, Di IorioR, VecchioR, AnfossiM, BabiloniC, BozzaliM, BruniAC, CappaSF, EscuderoJ, FragaFJ, GiannakopoulosmIP, GuntekinB, LogroscinoG, MarraC, MiragliaF, PanzaF, TecchioF, Pascual-LeoneA, DuboisB (2020) Early diagnosis of Alzheimer’s disease: The role of biomarkers including advanced EEG signal analysis. Report from the IFCN-sponsored panel of experts. . Clin Neurophysiol131, 1287–1310.
24.
BlackmanJ, StankeviciuteL, Arenaza-UrquijoEM, Suárez-CalvetM, Sánchez-BenavidesG, Vilor-TejedorN, IranzoA, MolinuevoJL, GispertJD, CoulthardE, Grau-RiveraO, European Prevention of Alzheimer’s Disease (EPAD) Consortium (2022) Cross-sectional and longitudinal association of sleep and Alzheimer biomarkers in cognitively unimpaired adults. Brain Commun4, fcac257.
25.
Hita-YañezE, AtienzaM, CanteroJL (2013) Polysomnographic and subjective sleep markers of mild cognitive impairment. Sleep36, 1327–1334.
26.
ManderBA (2013) Disturbed sleep in preclinical cognitive impairment: Cause and effect?Sleep36, 1275–1276.
27.
ManderBA (2020) Local sleep and Alzheimer’s disease pathophysiology. Front Neurosci14, 525970.
28.
WesterbergCE, ManderBA, FlorczakSM, WeintraubS, MesulamMM, ZeePC, PallerKA (2012) Concurrent impairments in sleep and memory in amnestic mild cognitive impairment. J Int Neuropsychol Soc18, 490–500.
29.
LimASP, YuL, KowgierM, SchneiderJA, BuchmanAS, BennettDA (2013) Modification of the relationship of the apolipoprotein E ɛ4 allele to the risk of Alzheimer disease and neurofibrillary tangle density by sleep. JAMA Neurol70, 1544–1551.
30.
WangC, HoltzmanDM (2020) Bidirectional relationship between sleep and Alzheimer’s disease: Role of amyloid, tau, and other factors. Neuropsychopharmacology45, 104–120.
31.
LimASP, KowgierM, YuL, BuchmanAS, BennettDA (2013) Sleep fragmentation and the risk of incident Alzheimer’s disease and cognitive decline in older persons. Sleep36, 1027–1032.
32.
LimASP, YuL, SchneiderJA, BennettDA, BuchmanAS (2016) Sleep fragmentation, cerebral arteriolosclerosis, and brain infarct pathology in community-dwelling older people. Stroke47, 516–518.
33.
MuehlrothBE, RaschB, Werkle-BergnerM (2020) Episodic memory consolidation during sleep in healthy aging. Sleep Med Rev52, 101304.
34.
EhrenbergAJ, NguyAK, TheofilasP, DunlopS, SuemotoCK, Di LorenzoA, LeiteRP, RodriguezRD, MejiaMB, RüU, FarfelJM (2017) Quantifying the accretion of hyperphosphorylated tau in the locus coeruleus and dorsal raphe nucleus: The pathological building blocks of early Alzheimer’s disease. Neuropathol Appl Neurobiol43, 393–408.
35.
EserRA, EhrenbergAJ, PetersenC, DunlopS, MejiaMB, SuemotoCK, WalshCM, RajanaH, OhJ, TheofilasP, SeeleyWW (2018) Selective vulnerability of brainstem nuclei in distinct tauopathies: A postmortem study. J Neuropathol Exp Neurol77, 149–161.
36.
AshfordJW (2019) Treatment of Alzheimer’s disease: Trazodone, sleep, serotonin, norepinephrine, and future directions. J Alzheimers Dis67, 923–930.
37.
LaAL, WalshCM, NeylanTC, VosselKA, YaffeK, KrystalAD, MillerBL, KarageorgiouE (2019) Longterm trazodone use and cognition: A potential therapeutic role for slow-wave sleep enhancers. J Alzheimers Dis67, 911–921.
38.
HuM, Zhang, LiC, TanY, LiY, XuD (2017) Sleep disturbance in mild cognitive impairment: A systematic review of objective measures. Neurol Sci38, 1363–1371.
39.
D’RozarioJ, ChapmanL, PhillipsCL, PalmerJR, HoyosCM, MowszowskiL, DuffySL, MarshallSL, BencaR, ManderB, GrunsteinRR, NaismithSL (2020) Objective measurement of sleep in mild cognitive impairment: A systematic review and meta-analysis. Sleep Med Rev52, 101308.
40.
GorgoniM, LauriG, TrugliaI, CordoneS, SarassoS, ScarpelliS, MangiarugaA, D’AtriA, TempestaD, FerraraM, MarraC, RossiniPM, De GennaroL (2016) Parietal fast sleep spindle density decrease in Alzheimer’s disease and amnesic mild cognitive impairment. Neural Plast2016, 8376108.
41.
RedaF, GorgoniM, LauriG, TrugliaI, CordoneS, ScarpelliS, MangiarugaA, D’AtriA, FerraraM, LacidognaG, MarraC, RossiniPM, De GennaroL (2017) In search of sleep biomarkers of Alzheimer’s disease: K-Complexes do not discriminate between patients with mild cognitive impairment and healthy controls. Brain Sci7, 51.
42.
JonesBE (2020) Arousal and sleep circuits. Neuropsychopharmacology45, 6–20.
Van EgrooM, KoshmanovaE, VandewalleG, JacobsH (2022) Importance of the locus coeruleus-norepinephrine system in sleep-wake regulation: Implications for aging and Alzheimer’s disease. Sleep Med Rev62, 101592.
51.
SohailS, YuL, SchneiderJA, BennettDA, BuchmanAS, LimASP (2016) Sleep fragmentation and Parkinson’s disease pathology in older adults without Parkinson’s disease. Mov Disord32, 1729–1737.
52.
BoselliM, ParrinoL, SmerieriA, TerzanoMG (1998) Effect of age on EEG arousals in normal sleep. Sleep21, 363–367.
53.
MinerB, KrygerMH (2018) Sleep in the aging population. Sleep Med Clin12, 31–38.
54.
JanitzkyK (2020) Impaired phasic discharge of locus coeruleus neurons based on persistent high tonic discharge—A new hypothesis with potential implications for neurodegenerative diseases. Front Neurol11, 371.
55.
JamesT, KulaB, ChoiS, KhanSS, BekarLK, SmithNA (2021) Locus coeruleus in memory formation and Alzheimer’s disease. Eur J Neurosci54, 6948–6959.
56.
HollandN, RobbinsTW, RoweJB (2021) The role of noradrenaline in cognition and cognitive disorders. Brain144, 2243–2256.
57.
IberC (2007) The AASM Manual for the scoring of sleep and associated events. American Academy of Sleep Medicine. Westchester, IL, USA.
58.
BaglioniC, NanovskaS, RegenW, SpiegelhalderK, FeigeB, NissenC, Reynolds IIICF, RiemannD (2016) Sleep and mental disorders: A meta-analysis of polysomnographic research. Psychol Bull142, 969–990.
59.
Rosales-LagardeA, Rodríguez-TorresEE, Itzá-OrtizB, MiramontesP, Vázquez-TagleG, Enciso-AlvaJC, García-MuñozV, Cubero-RegoL, Pineda-SánchezJE, Martínez-AlcaláCI, Lopez-NoguerolaJS (2018) The color of noise and weak stationarity at the NREM to REM transition in mild cognitive impaired subjects. Front Psychol9, 1205.
60.
Rosales-Lagarde, Rodríguez-TorresEE, Contreras-AlcaláF, MiramontesP, Itzá-OrtizB, Quezada-TellezLA, Martínez-AlcaláCI, Enciso-AlvaJC (2019) The inverse relationship between cognitive performance and non-stationarity during stage 1 and rapid eye movement sleep in older adults: Arousals and leg movements. Sleep42(Suppl 1), A42–A43.
61.
FolsteinMF, FolsteinSE, McHughPR (1975) Mini-Mental State: A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res12, 189–198.
62.
KatzS, DownsTD, CashHR, GrotzR (1970) Progress in development of the index of ADL. Gerontology10, 20–30.
63.
UgaldeO (2010) Clinical Guide for the Treatment of Psychogeriatric Disorders. Instituto Nacional de Psiquiatría Ramón de la Fuente, México.
64.
Corsi-CabreraM, Figueredo-RodríguezP, Del Río-PortillaY, Sánchez-RomeroJ, GalánL, Bosch-BayardJ (2012) Enhanced frontoparietal synchronized activation during the wake-sleep transition in patients with primary insomnia. Sleep35, 501–511.
65.
Ostrosky-SolísF, Gómez-PérezME, MatuteE, RosselliM, ArdilaA, PinedaD (2007) Neuropsi attention and memory: A neuropsychological test battery in spanish with norms by age and educational level. Appl Neuropsychol14, 156–170.
66.
MejiaS, GutierrezLM, VillaAR, Ostrosky-SolisF (2010) Cognition, functional status, education, and the diagnosis of dementia and mild cognitive impairment in Spanish-speaking elderly. Appl Neuropsychol11, 194–201.
67.
Abrisqueta-GomezJ, Ostrosky-SolisF, BertolucciP, BuenoF (2008) Applicability of the abbreviated neuropsychologic battery (Neuropsi) in Alzheimer’s disease patients. Alzheimer Dis Assoc Disord22, 72–78.
68.
ZlatarZZ, MunizMC, EspinozaSG, GratianneR, GollanTH, GalaskoD, SalmonDP (2018) Subjective cognitive decline, objective cognition, and depression in older Hispanics screened for memory impairment. J Alzheimers Dis63, 949–956.
69.
LevineAJ, PalomoM, HinkinCH, Valdes-SueirasM, LopezE, MathisenG, DonovanS, SingerEJ (2011) A comparison of screening batteries in the detection of neurocognitive impairment in HIV-infected Spanish speakers. Neurobehav HIV Med3, 79–86.
70.
MatioliMN, CaramelliP (2012) NEUROPSI battery subtest profile in subcortical vascular dementia and Alzheimer’s disease. Dement Neuropsychol6, 170–174.
71.
Gómez-PérezME, Ostrosky-SolísF (2006) Attention and memory evaluation across the life span: Heterogeneous effects of age and education. J Clin Exp Neuropsychol28, 477–494.
72.
SawilowskyS (2009) New effect size rules of thumb. J Mod Appl Stat Methods8, 467–474.
73.
Hae-YoungK (2014) Statistical notes for clinical researchers: Nonparametric statistical methods: 2. Nonparametric methods for comparing three or more groups and repeated measures. Restor Dent Endod39, 329–332.
74.
R Core Team (2013) R: A Language and Environment for Statistical Computing. Foundation for Statistical Computing. Available from: https://www.R-project.org/. Accessed May 1, 2020.
75.
FerriR, RundoF, ZucconiM, ManconiM, BruniO, Ferini-StrambiL, FuldaS (2015) An evidence-based analysis of the association between periodic leg movements during sleep and arousals in restless legs syndrome. Sleep38, 919–924.
76.
BahrK, GeislerV, HuppertzT, GroppaS, MatthiasC, GouverisH, MuthuramanM (2021) Intensity of respiratory cortical arousals is a distinct pathophysiologic feature and is associated with disease severity in obstructive sleep apnea patients. Brain Sci11, 282.
77.
TheofilasP, EhrenbergAJ, NguyA, ThackreyJM, DunlopS, MejiaMB, AlhoAT, ParaizoRT (2018) Probing the correlation of neuronal loss, neurofibrillary tangles, and cell death markers across the Alzheimer’s disease’s Braak stages: A quantitative study in humans. Neurobiol Aging61, 1–12.
78.
BeardmoreR, HouR, DarekarA, HolmesC, BocheD (2021) The locus coeruleus in aging and Alzheimer’s disease: A postmortem and brain imaging. J Alzheimers Dis83, 5–22.
79.
ŠimicG, Babic LekoM, WrayS, HarringtonCR, DelalleI, Jovanov-MiloševicN, BažadonaD, BuéeL, de SilvaR, Di GiovanniG, WischikCM, HofPR (2017) Monoaminergic neuropathology in Alzheimer’s disease. Prog Neurobiol151, 101–138.
80.
RossJA, Van BockstaeleEJ (2021) The Locus coeruleus-norepinephrine system in stress and arousal: Unraveling historical, current, and future perspectives. Front Psychiatry11, 601519.
81.
BraakH, DietmarR, ThalDR, GhebremedhinE, Del TrediciK (2011) Stages of the pathologic process in Alzheimer disease: Age categories from 1 to 100 years. J Neuropathol Exp Neurol70, 960–969.
82.
CassidyCM, TherriaultJ, PascoalTA, CheungV, SavardM, TuominenL, ChamounM, McCallA, CelebiS, LussierF, MassarwehG, SoucyJP, WeinshenkerD, TardifC, IsmailZ, GauthierS, Rosa-NetoP (2022) Association of locus coeruleus integrity with Braak stage and neuropsychiatric symptom severity in Alzheimer’s disease. Neuropsychopharmacology47, 1128–1136.
83.
MatherM (2021) Noradrenaline in the aging brain: Promoting cognitive reserve or accelerating Alzheimer’s disease?Semin Cell Dev Biol116, 108–124.
Corsi-CabreraM, Rosales-LagardeA, Del Río-PortillaY, Sifuentes-OrtegaR, Alcántara-QuinteroB (2015) Effects of selective REM sleep deprivation on prefrontal gamma activity and executive functions. Int J Psychophysiol96, 115–124.
86.
BoyceR, WilliamsS, AdamantidisA (2017) REM sleep and memory. Curr Opin Neurobiol44, 167–177.
87.
TamakiM, BangJW, WatanabeT, SasakiY (2016) Night watch in one brain hemisphere during sleep associated with the first-night effect in humans. Curr Biol26, 1190–1194.
88.
Hof zum BergeA, KellmannM and
JakowskiS (2021) The first-night effect in elite sports: An initial glance on polysomnography in home-based settings. Front Psychol12, 641451.
89.
OmoluabiT, TorravilleSE, MaziarA, GhoshA, PowerKD, ReinhardtC, HarleyCW, YuanQ (2021) Novelty-like activation of locus coeruleus protects against deleterious human pretangle tau effects while stress-inducing activation worsens its effects. Alzheimers Dement7, e12231.
90.
KentBA, FeldmanHH, NygaardHB (2021) Sleep and its regulation: An emerging pathogenic and treatment frontier in Alzheimer’s disease. Prog Neurobiol197, 101902.
91.
CohenJ (1988) Statistical Power Analysis for the Behavioral Sciences (2nd ed.). Lawrence Erlbaum Associates, Hillsdale, NJ.
