[en] [en] OBJECTIVE: Parkinson's disease (PD) is one of the rare diseases in which sleep alteration is a true marker of disease outcome. Yet, how the association between sleep and PD emerges over the healthy lifetime is not established. We examined the association between the polygenic risk score (PRS) for PD and the variability in the electrophysiology of rapid eye movement (REM) sleep in 433 younger (18-31 years) healthy individuals and 85 late-midlife (50-69 years) healthy individuals.
METHODS: In this prospective cross-sectional study, in-lab electroencephalography recordings of sleep were recorded to extract REM sleep metrics. PRS was computed using SBayesR approach.
RESULTS: Generalized additive model for location, scale, and shape analysis showed significant association of REM duration (pcorrected = 0.03) and theta energy in REM (pcorrected = 0.004) with PRS for PD in interaction with the age group. In the younger subsample, REM duration and theta energy were positively associated with PD PRS. In contrast, in the late-midlife subsample, the same associations were negative (although only qualitatively for REM theta energy) and may differ between men and women.
INTERPRETATION: REM sleep is associated with the PRS for PD in early adulthood, 2 to 5 decades before typical symptoms onset. The association changes from positive in younger individuals, presumably free of alpha-synuclein, to negative in late-midlife individuals, possibly because of the progressive presence of alpha-synuclein aggregates or of the repeated increased oxidative metabolism imposed by REM sleep. Our findings may unravel core associations between PD and sleep and may contribute to novel intervention targets to prevent or delay PD. ANN NEUROL 2025.
ERDF - European Regional Development Fund WELBIO - Walloon Excellence in Life Sciences and Biotechnology FRA - Fondation pour la Recherche sur la Maladie d'Alzheimer
Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the global burden of disease study 2019. Lancet 2020;396:1204–1222.
Ben-Shlomo Y, Darweesh S, Llibre-Guerra J, et al. The epidemiology of Parkinson's disease. Lancet 2024;403:283–292.
Bloem BR, Okun MS, Klein C. Parkinson's disease. Lancet 2021;397:2284–2303.
Koeglsperger T, Rumpf SL, Schliesser P, et al. Neuropathology of incidental Lewy body & prodromal Parkinson's disease. Mol Neurodegener 2023;18:32.
Hung AY, Schwarzschild MA. Approaches to disease modification for Parkinson's disease: clinical trials and lessons learned. Neurotherapeutics 2020;17:1393–1405.
Al-Qassabi A, Fereshtehnejad SM, Postuma RB. Sleep disturbances in the prodromal stage of Parkinson disease. Curr Treat Options Neurol 2017;19:22.
Scammell TE, Arrigoni E, Lipton JO. Neural circuitry of wakefulness and sleep. Neuron 2017;93:747–765.
Sohail S, Yu L, Schneider JA, et al. Sleep fragmentation and Parkinson's disease pathology in older adults without Parkinson's disease. Mov Disord 2017;32:1729–1737.
Van Egroo M, Narbutas J, Chylinski D, et al. Sleep–wake regulation and the hallmarks of the pathogenesis of Alzheimer's disease. Sleep 2019;42:zsz017.
Mestre H, Mori Y, Nedergaard M. The Brain's glymphatic system: current controversies. Trends Neurosci 2020;43:458–466.
Koch S, Laabs BH, Kasten M, et al. Validity and prognostic value of a polygenic risk score for Parkinson's disease. Genes 2021;12:1859.
Dehestani M, Liu H, Gasser T. Polygenic risk scores contribute to personalized medicine of Parkinson's disease. J Personalized Med 2021;11:1030.
Cao Z, Hernandez DG, Li C, et al. Polygenic risk score for Parkinson's disease and olfaction among middle-aged to older women. Parkinsonism Relat Disord 2023;115:105815.
Diaz-Torres S, Lee SS, Ogonowski NS, et al. Macular structural integrity estimates are associated with Parkinson's disease genetic risk. Acta Neuropathol Commun 2024;2:130.
Maraki MI, Hatzimanolis A, Mourtzi N, et al. Association of the Polygenic Risk Score with the probability of prodromal Parkinson's disease in older adults. Front Mol Neurosci 2021;14:739571.
Wang YQ, Liu WY, Li L, et al. Neural circuitry underlying REM sleep: a review of the literature and current concepts. Prog Neurobiol 2021;204:102106.
Muto V, Koshmanova E, Ghaemmaghami P, et al. Alzheimer's disease genetic risk and sleep phenotypes in healthy young men: association with more slow waves and daytime sleepiness. Sleep 2021;44:zsaa137.
Chylinski D, Narbutas J, Balteau E, et al. Frontal grey matter microstructure is associated with sleep slow waves characteristics in late midlife. Sleep 2022;45:zsac178.
Koshmanova E, Muto V, Chylinski D, et al. Genetic risk for insomnia is associated with objective sleep measures in young and healthy good sleepers. Neurobiol Dis 2022;175:105924.
Riemann D, Spiegelhalder K, Nissen C, et al. REM sleep instability--a new pathway for insomnia? Pharmacopsychiatry 2012;45:167–176.
Nalls MA, Blauwendraat C, Vallerga CL, et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet Neurol 2019;18:1091–1102.
Ohayon MM, Carskadon MA, Guilleminault C, Vitiello MV. Meta-analysis of quantitative sleep parameters from childhood to old age in healthy individuals: developing normative sleep values across the human lifespan. Sleep 2004;27:1255–1273.
Moraes W, Piovezan R, Poyares D, et al. Effects of aging on sleep structure throughout adulthood: a population-based study. Sleep Med 2014;15:401–409.
Stasinopoulos MD, Rigby RA, Heller GZ, et al. Flexible regression and smoothing: using GAMLSS in R. United States: CRC Press, 2017.
Winer JR, Lok R, Weed L, et al. Impaired 24-h activity patterns are associated with an increased risk of Alzheimer's disease, Parkinson's disease, and cognitive decline. Alzheimers Res Ther 2024;16:35.
Kalinderi K, Papaliagkas V, Fidani L. The genetic landscape of sleep disorders in Parkinson's disease. Diagnostics (Basel) 2024;14:106.
Peever J, Fuller PM. The biology of REM sleep. Curr Biol 2017;27:R1237–R1248.
Breen DP, Vuono R, Nawarathna U, et al. Sleep and circadian rhythm regulation in early Parkinson disease. JAMA Neurol 2014;71:589–595.
Otaiku AI. Association of sleep abnormalities in older adults with risk of developing Parkinson's disease. Sleep 2022;45:zsac206.
Memon AA, Catiul C, Irwin Z, et al. Quantitative sleep electroencephalogram and cognitive performance in Parkinson's disease with and without rapid eye movement sleep behavior disorder. Front Neurol 2023;14:1223974.
Wetter TC, Brunner H, Hogl B, et al. Increased alpha activity in REM sleep in de novo patients with Parkinson's disease. Mov Disord 2001;16:928–933.
Maquet P. Sleep function(s) and cerebral metabolism. Behav Brain Res 1995;69:75–83.
Zucca FA, Segura-Aguilar J, Ferrari E, et al. Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson's disease. Prog Neurobiol 2017;155:96–119.
Osorio-Forero A, Foustoukos G, Cardis R, et al. Infraslow noradrenergic locus coeruleus activity fluctuations are gatekeepers of the NREM-REM sleep cycle. Nat Neurosci 2025;28:84-96.
Ehrminger M, Latimier A, Pyatigorskaya N, et al. The coeruleus/subcoeruleus complex in idiopathic rapid eye movement sleep behaviour disorder. Brain 2016;139:1180–1188.
Lima MM. Sleep disturbances in Parkinson's disease: the contribution of dopamine in REM sleep regulation. Sleep Med Rev 2013;17:367–375.
Takakusaki K, Saitoh K, Harada H, et al. Evidence for a role of basal ganglia in the regulation of rapid eye movement sleep by electrical and chemical stimulation for the pedunculopontine tegmental nucleus and the substantia nigra pars reticulata in decerebrate cats. Neuroscience 2004;124:207–220.
Braak H, Del Tredici K, Rub U, et al. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003;24:197–211.
Sakata M, Sei H, Toida K, et al. Mesolimbic dopaminergic system is involved in diurnal blood pressure regulation. Brain Res 2002;928:194–201.
Buzsaki G. Hippocampal sharp wave-ripple: a cognitive biomarker for episodic memory and planning. Hippocampus 2015;25:1073–1188.
Liu AA, Henin S, Abbaspoor S, et al. A consensus statement on detection of hippocampal sharp wave ripples and differentiation from other fast oscillations. Nat Commun 2022;13:6000.
Sei H, Ikemoto K, Arai R, Morita Y. Injection of 6-hydroxydopamine into the ventral tegmental area suppresses the increase in arterial pressure during REM sleep in the rat. Sleep Res Online: SRO 1999;2:1–6.
Li J, Vitiello MV, Gooneratne NS. Sleep in Normal Aging. Sleep Med Clin 2018;13:1–11.
Eggert T, Dorn H, Danker-Hopfe H. Nocturnal brain activity differs with age and sex: comparisons of sleep EEG power spectra between young and elderly men, and between 60-80-year-old men and women. Nat Sci Sleep 2021;13:1611–1630.
Cerri S, Mus L, Blandini F. Parkinson's disease in women and men: What's the difference? J Parkinsons Dis 2019;9:501–515.
Rorabaugh JM, Chalermpalanupap T, Botz-Zapp CA, et al. Chemogenetic locus coeruleus activation restores reversal learning in a rat model of Alzheimer's disease. Brain: J Neurol 2017;140:3023–3038.
Phillips C, Fahimi A, Das D, et al. Noradrenergic system in down syndrome and Alzheimer's disease a target for therapy. Curr Alzheimer Res 2016;13:68–83.
Pierantozzi M, Placidi F, Liguori C, et al. Rotigotine may improve sleep architecture in Parkinson's disease: a double-blind, randomized, placebo-controlled polysomnographic study. Sleep Med 2016;21:140–144.
Vandewalle G, Archer SN, Wuillaume C, et al. Functional magnetic resonance imaging-assessed brain responses during an executive task depend on interaction of sleep homeostasis, circadian phase, and PER3 genotype. J Neurosci 2009;29:7948–7956.
Ly JQM, Gaggioni G, Chellappa SL, et al. Circadian regulation of human cortical excitability. Nat Commun 2016;7:11828.
Muto V, Jaspar M, Meyer C, et al. Local modulation of human brain responses by circadian rhythmicity and sleep debt. Science 2016;353:687–690.
Mascetti L, Foret A, Schrouff J, et al. Concurrent synaptic and systems memory consolidation during sleep. J Neurosci 2013;33:10182–10190.
Gaggioni G, Ly JQM, Muto V, et al. Age-related decrease in cortical excitability circadian variations during sleep loss and its links with cognition. Neurobiol Aging 2019;78:52–63.
Berthomier C, Muto V, Schmidt C, et al. Exploring scoring methods for research studies: accuracy and variability of visual and automated sleep scoring. J Sleep Res 2020;29:e12994.
Chylinski D, Rudzik F, Coppieters TWD, et al. Validation of an automatic arousal detection algorithm for whole-night sleep EEG recordings. Clocks Sleep 2020;2:258–272.
Dijk DJ, Landolt HP. Sleep Physiology, Circadian Rhythms, Waking Performance and the Development of Sleep–Wake Therapeutics. Handb Exp Pharmacol. Vol 253. Germany: Springer International Publishing, 2019:441-481.
Purcell S, Neale B, Todd-Brown K, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007;81:559–575.
Murphy AE, Schilder BM, Skene NG. MungeSumstats: a Bioconductor package for the standardization and quality control of many GWAS summary statistics. Bioinformatics 2021;37:4593–4596.
Rigby RA, Stasinopoulos MD, Heller GZ, De Bastiani F. Distributions for modeling location, scale, and shape: using GAMLSS in R. United States: Chapman and Hall/CRC, 2019.
Faul F, Erdfelder E, Buchner A, Lang AG. Statistical power analyses using G*power 3.1: tests for correlation and regression analyses. Behav Res Methods 2009;41:1149–1160.
