Skip to main content
SpringerLink
Log in

Associations of sleep disorders with cerebrospinal fluid α-synuclein in prodromal and early Parkinson’s disease

  • Original Communication
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

Objectives

Our aim is to investigate the associations of sleep disorders with cerebrospinal fluid (CSF) α-synuclein (α-syn) in healthy controls (HCs), and patients with prodromal and early Parkinson’s disease (PD).

Methods

We included a total of 575 individuals, consisting of 360 PD individuals, 46 prodromal PD individuals, and 169 HCs. Multiple linear regression models and linear mixed-effects models were used to investigate the associations of sleep disorders with baseline and longitudinal CSF α-syn. Associations between the change rates of sleep disorders and CSF α-syn were further investigated via multiple linear regression models.

Results

In PD, probable Rapid-eye-movement sleep Behavior Disorder (pRBD) (β = − 0.1199; P = 0.0444) and RBD sub-items, such as aggressive dreams (β = − 0.1652; P = 0.0072) and hurting bed partner (β = − 0.2468; P = 0.0010), contributed to lower CSF α-syn. The association between aggressive dreams and lower CSF α-syn further survived Bonferroni correction (P < 0.0036). In prodromal PD, dream-enacting (a specific RBD behavior) was significantly associated with decreased CSF α-syn during the follow-up (β = − 0.0124; P = 0.0237). HCs with daytime sleepiness when inactive-sitting in public places (β = − 0.0033; P = 0.0135) showed decreased CSF α-syn. Furthermore, increased possibilities of daytime sleepiness when sitting and reading contributed to a greater decrease of CSF α-syn in HCs (β = − 196.8779; P = 0.0433).

Conclusions

Sleep disorders were associated with decreased CSF α-syn. Sleep management may be important for disease monitoring and preventing the progression of α-syn pathology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Availability of data and materials

The data generated and analyzed during the current study are available in the PPMI database.

Code availability

None.

References

  1. Mehta SH, Adler CH (2016) Advances in biomarker research in Parkinson’s disease. Curr Neurol Neurosci Rep 16(1):7. https://doi.org/10.1007/s11910-015-0607-4

    Article  CAS  PubMed  Google Scholar 

  2. Bohnen NI, Hu MTM (2019) Sleep disturbance as potential risk and progression factor for Parkinson’s disease. J Parkinsons Dis 9(3):603–614. https://doi.org/10.3233/JPD-191627

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ferini-Strambi L, Marelli S, Galbiati A, Rinaldi F, Giora E (2014) REM sleep behavior disorder (RBD) as a marker of neurodegenerative disorders. Arch Ital Biol 152(2–3):129–146. https://doi.org/10.12871/000298292014238

    Article  CAS  PubMed  Google Scholar 

  4. Dauvilliers Y, Schenck CH, Postuma RB et al (2018) REM sleep behaviour disorder. Nat Rev Dis Primers 4(1):19. https://doi.org/10.1038/s41572-018-0016-5

    Article  PubMed  Google Scholar 

  5. Frauscher B, Iranzo A, Gaig C et al (2012) Normative EMG values during REM sleep for the diagnosis of REM sleep behavior disorder. Sleep 35(6):835–847. https://doi.org/10.5665/sleep.1886

    Article  PubMed  PubMed Central  Google Scholar 

  6. Xiang Y-Q, Xu Q, Sun Q-Y et al (2019) Clinical features and correlates of excessive daytime sleepiness in Parkinson’s disease. Front Neurol 10:121. https://doi.org/10.3389/fneur.2019.00121

    Article  PubMed  PubMed Central  Google Scholar 

  7. Barone DA, Henchcliffe C (2018) Rapid eye movement sleep behavior disorder and the link to alpha-synucleinopathies. Clin Neurophysiol 129(8):1551–1564. https://doi.org/10.1016/j.clinph.2018.05.003

    Article  PubMed  PubMed Central  Google Scholar 

  8. Mollenhauer B, Caspell-Garcia CJ, Coffey CS et al (2019) Longitudinal analyses of cerebrospinal fluid alpha-Synuclein in prodromal and early Parkinson’s disease. Mov Disord. https://doi.org/10.1002/mds.27806

    Article  PubMed  PubMed Central  Google Scholar 

  9. Kang JH, Irwin DJ, Chen-Plotkin AS et al (2013) Association of cerebrospinal fluid β-amyloid 1–42, t-tau, p-tau 181, and α-synuclein levels with clinical features of drug-naive patients with early parkinson disease. JAMA Neurol 70(10):1277–1287. https://doi.org/10.1001/jamaneurol.2013.3861

    Article  PubMed  PubMed Central  Google Scholar 

  10. Goldman JG, Andrews H, Amara A et al (2018) Cerebrospinal fluid, plasma, and saliva in the BioFIND study: relationships among biomarkers and Parkinson’s disease features. Mov Disord 33(2):282–288. https://doi.org/10.1002/mds.27232

    Article  CAS  PubMed  Google Scholar 

  11. Cerri S, Mus L, Blandini F (2019) Parkinson’s disease in women and men: what’s the difference? J Parkinsons Dis 9(3):501–515. https://doi.org/10.3233/jpd-191683

    Article  PubMed  PubMed Central  Google Scholar 

  12. Wing YK, Lam SP, Li SX et al (2008) REM sleep behaviour disorder in Hong Kong Chinese: clinical outcome and gender comparison. J Neurol Neurosurg Psychiatry 79(12):1415–1416. https://doi.org/10.1136/jnnp.2008.155374

    Article  CAS  PubMed  Google Scholar 

  13. Zhou J, Zhang J, Li Y et al (2015) Gender differences in REM sleep behavior disorder: a clinical and polysomnographic study in China. Sleep Med 16(3):414–418. https://doi.org/10.1016/j.sleep.2014.10.020

    Article  PubMed  Google Scholar 

  14. Utsumi K, Fukatsu R, Yamada R, Takamaru Y, Hara Y, Yasumura S (2020) Characteristics of initial symptoms and symptoms at diagnosis in probable dementia with Lewy body disease: incidence of symptoms and gender differences. Psychogeriatrics 20(5):737–745. https://doi.org/10.1111/psyg.12586

    Article  PubMed  Google Scholar 

  15. The Parkinson Progression Marker Initiative (PPMI). Progr. Neurobiol. 2011;4:95

  16. Chahine LM, Urbe L, Caspell-Garcia C et al (2018) Cognition among individuals along a spectrum of increased risk for Parkinson’s disease. PLoS ONE 13(8):e0201964. https://doi.org/10.1371/journal.pone.0201964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Doty RL, Shaman P, Dann M (1984) Development of the University of Pennsylvania smell identification test: a standardized microencapsulated test of olfactory function. Physiol Behav 32(3):489–502. https://doi.org/10.1016/0031-9384(84)90269-5

    Article  CAS  PubMed  Google Scholar 

  18. Nomura T, Inoue Y, Kagimura T, Uemura Y, Nakashima K (2011) Utility of the REM sleep behavior disorder screening questionnaire (RBDSQ) in Parkinson’s disease patients. Sleep Med 12(7):711–713. https://doi.org/10.1016/j.sleep.2011.01.015

    Article  PubMed  Google Scholar 

  19. Simuni T, Caspell-Garcia C, Coffey C et al (2015) Correlates of excessive daytime sleepiness in de novo Parkinson’s disease: a case control study. Mov Disord 30(10):1371–1381. https://doi.org/10.1002/mds.26248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lu J, Sherman D, Devor M, Saper CB (2006) A putative flip-flop switch for control of REM sleep. Nature 441(7093):589–594. https://doi.org/10.1038/nature04767

    Article  CAS  PubMed  Google Scholar 

  21. Peever J, Luppi PH, Montplaisir J (2014) Breakdown in REM sleep circuitry underlies REM sleep behavior disorder. Trends Neurosci 37(5):279–288. https://doi.org/10.1016/j.tins.2014.02.009

    Article  CAS  PubMed  Google Scholar 

  22. Zeighami Y, Ulla M, Iturria-Medina Y et al (2015) Network structure of brain atrophy in de novo Parkinson’s disease. Elife. https://doi.org/10.7554/eLife.08440

    Article  PubMed  PubMed Central  Google Scholar 

  23. Yau Y, Zeighami Y, Baker TE et al (2018) Network connectivity determines cortical thinning in early Parkinson’s disease progression. Nat Commun 9(1):12. https://doi.org/10.1038/s41467-017-02416-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Dolatshahi M, Pourmirbabaei S, Kamalian A, Ashraf-Ganjouei A, Yaseri M, Aarabi MH (2018) longitudinal alterations of alpha-synuclein, amyloid beta, total, and phosphorylated tau in cerebrospinal fluid and correlations between their changes in Parkinson’s disease. Front Neurol 9:560. https://doi.org/10.3389/fneur.2018.00560

    Article  PubMed  PubMed Central  Google Scholar 

  25. Postuma RB, Adler CH, Dugger BN et al (2015) REM sleep behavior disorder and neuropathology in Parkinson’s disease. Mov Disord 30(10):1413–1417. https://doi.org/10.1002/mds.26347

    Article  CAS  PubMed  Google Scholar 

  26. Compta Y, Valente T, Saura J et al (2015) Correlates of cerebrospinal fluid levels of oligomeric- and total-α-synuclein in premotor, motor and dementia stages of Parkinson’s disease. J Neurol 262(2):294–306. https://doi.org/10.1007/s00415-014-7560-z

    Article  CAS  PubMed  Google Scholar 

  27. Hu Y, Yu S-Y, Zuo L-J et al (2015) Parkinson disease with REM sleep behavior disorder: features, α-synuclein, and inflammation. Neurology 84(9):888–894. https://doi.org/10.1212/WNL.0000000000001308

    Article  CAS  PubMed  Google Scholar 

  28. Dahodwala N, Shah K, He Y et al (2018) Sex disparities in access to caregiving in Parkinson disease. Neurology 90(1):e48–e54. https://doi.org/10.1212/wnl.0000000000004764

    Article  PubMed  Google Scholar 

  29. Iranzo A, Tolosa E, Gelpi E et al (2013) Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder: an observational cohort study. Lancet Neurol 12(5):443–453. https://doi.org/10.1016/S1474-4422(13)70056-5

    Article  PubMed  Google Scholar 

  30. Postuma RB, Gagnon J-F, Bertrand J-A, Génier Marchand D, Montplaisir JY (2015) Parkinson risk in idiopathic REM sleep behavior disorder: preparing for neuroprotective trials. Neurology 84(11):1104–1113. https://doi.org/10.1212/WNL.0000000000001364

    Article  PubMed  PubMed Central  Google Scholar 

  31. Sundaram S, Hughes RL, Peterson E et al (2019) Establishing a framework for neuropathological correlates and glymphatic system functioning in Parkinson’s disease. Neurosci Biobehav Rev 103:305–315. https://doi.org/10.1016/j.neubiorev.2019.05.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fultz NE, Bonmassar G, Setsompop K et al (2019) Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Science (New York, NY) 366(6465):628–631. https://doi.org/10.1126/science.aax5440

    Article  CAS  Google Scholar 

  33. Iliff JJ, Wang M, Liao Y et al (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med 4(147):147. https://doi.org/10.1126/scitranslmed.3003748

    Article  CAS  Google Scholar 

  34. Jessen NA, Munk ASF, Lundgaard I, Nedergaard M (2015) The glymphatic system: a beginner’s guide. Neurochem Res 40(12):2583–2599. https://doi.org/10.1007/s11064-015-1581-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Xie L, Kang H, Xu Q et al (2013) Sleep drives metabolite clearance from the adult brain. Science (New York, NY) 342(6156):373–377. https://doi.org/10.1126/science.1241224

    Article  CAS  Google Scholar 

  36. Benveniste H, Lee H, Volkow ND (2017) The glymphatic pathway: waste removal from the CNS via cerebrospinal fluid transport. Neuroscientist 23(5):454–465. https://doi.org/10.1177/1073858417691030

    Article  PubMed  PubMed Central  Google Scholar 

  37. Bobela W, Aebischer P, Schneider BL (2015) Αlpha-synuclein as a mediator in the interplay between aging and Parkinson’s disease. Biomolecules 5(4):2675–2700. https://doi.org/10.3390/biom5042675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kudo T, Loh DH, Truong D, Wu Y, Colwell CS (2011) Circadian dysfunction in a mouse model of Parkinson’s disease. Exp Neurol 232(1):66–75. https://doi.org/10.1016/j.expneurol.2011.08.003

    Article  PubMed  Google Scholar 

  39. Abbott RD, Ross GW, White LR et al (2005) Excessive daytime sleepiness and subsequent development of Parkinson disease. Neurology 65(9):1442–1446. https://doi.org/10.1212/01.wnl.0000183056.89590.0d

    Article  CAS  PubMed  Google Scholar 

  40. Abbott RD, Ross GW, Duda JE et al (2019) Excessive daytime sleepiness and topographic expansion of Lewy pathology. Neurology 93(15):e1425–e1432. https://doi.org/10.1212/WNL.0000000000008241

    Article  PubMed  PubMed Central  Google Scholar 

  41. Videnovic A, Klerman EB, Wang W, Marconi A, Kuhta T, Zee PC (2017) Timed light therapy for sleep and daytime sleepiness associated with Parkinson disease: a randomized clinical trial. JAMA Neurol 74(4):411–418. https://doi.org/10.1001/jamaneurol.2016.5192

    Article  PubMed  PubMed Central  Google Scholar 

  42. Zhou J, Zhang J, Lam SP et al (2017) Excessive daytime sleepiness predicts neurodegeneration in idiopathic REM sleep behavior disorder. Sleep. https://doi.org/10.1093/sleep/zsx041

    Article  PubMed  PubMed Central  Google Scholar 

  43. Valera E, Spencer B, Fields JA et al (2017) Combination of alpha-synuclein immunotherapy with anti-inflammatory treatment in a transgenic mouse model of multiple system atrophy. Acta Neuropathol Commun. https://doi.org/10.1186/s40478-016-0409-1

    Article  PubMed  PubMed Central  Google Scholar 

  44. Trotti LM, Saini P, Crosson B, Meltzer CC, Rye DB, Nye JA (2021) Regional brain metabolism differentiates narcolepsy type 1 and idiopathic hypersomnia. Sleep. https://doi.org/10.1093/sleep/zsab050

    Article  PubMed  PubMed Central  Google Scholar 

  45. Gencer M, Akbayır E, Şen M et al (2019) Serum orexin-A levels are associated with disease progression and motor impairment in multiple sclerosis. Neurol Sci 40(5):1067–1070. https://doi.org/10.1007/s10072-019-3708-z

    Article  PubMed  Google Scholar 

  46. Kallweit U, Bassetti CLA, Oberholzer M et al (2018) Coexisting narcolepsy (with and without cataplexy) and multiple sclerosis: six new cases and a literature review. J Neurol 265(9):2071–2078. https://doi.org/10.1007/s00415-018-8949-x

    Article  CAS  PubMed  Google Scholar 

  47. Türkoğlu R, Benbir G, Özyurt S et al (2020) Sleep disturbance and cognitive decline in multiple sclerosis patients with isolated optic neuritis as the first demyelinating event. Int Ophthalmol 40(1):151–158. https://doi.org/10.1007/s10792-019-01157-x

    Article  PubMed  Google Scholar 

  48. Han X, Wu P, Alberts I et al (2020) Characterizing the heterogeneous metabolic progression in idiopathic REM sleep behavior disorder. NeuroImage Clin 27:102294. https://doi.org/10.1016/j.nicl.2020.102294

    Article  PubMed  PubMed Central  Google Scholar 

  49. Chen H, Schernhammer E, Schwarzschild MA, Ascherio A (2006) A prospective study of night shift work, sleep duration, and risk of Parkinson’s disease. Am J Epidemiol 163(8):726–730

    Article  PubMed  Google Scholar 

  50. Campbell MC, Jackson JJ, Koller JM, Snyder AZ, Kotzbauer PT, Perlmutter JS (2020) Proteinopathy and longitudinal changes in functional connectivity networks in Parkinson disease. Neurology 94(7):e718–e728. https://doi.org/10.1212/wnl.0000000000008677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank all of individuals who have given their time and themselves to be participants in this study. This study was supported by grants from the Shanghai Municipal Science and Technology Major Project (No. 2018SHZDZX01), National Clinical Research Center for Aging and Medicine (Huashan), ZJLab, Tianqiao and Chrissy Chen Institute, and the State Key Laboratory of Neurobiology and Frontiers Center for Brain Science of Ministry of Education, Fudan University. Data used in the preparation of the article were obtained from the Parkinson’s Progression Markers Initiative (PPMI) database (www.ppmi-info.org/data). PPMI is funded by The Michael J. Fox Foundation for Parkinson’s Research and funding partners, such as AbbVie, Avid Radiopharmaceuticals, Biogen, Bristol-Myers Squibb, Covance, Eli Lily&Co., F. Hoffman-La Roche, Ltd., GE Healthcare, Genentech, GlaxoSmithKline, Lundbeck, Merck, MesoScale Discovery, Piramal, Pfizer, and UCB (all of the PPMI funding partners found at www.ppmi-info.org/fundingpartners).

Funding

This study was supported by grants from the Shanghai Municipal Science and Technology Major Project (No.2018SHZDZX01), National Clinical Research Center for Aging and Medicine (Huashan), ZJLab, Tianqiao and Chrissy Chen Institute, and the State Key Laboratory of Neurobiology and Frontiers Center for Brain Science of Ministry of Education, Fudan University. Data used in the preparation of the article were obtained from the Parkinson’s Progression Markers Initiative (PPMI) database (www.ppmi-info.org/data). PPMI is funded by The Michael J. Fox Foundation for Parkinson’s Research and funding partners, such as AbbVie, Avid Radiopharmaceuticals, Biogen, Bristol-Myers Squibb, Covance, Eli Lily&Co., F. Hoffman-La Roche, Ltd., GE Healthcare, Genentech, GlaxoSmithKline, Lundbeck, Merck, MesoScale Discovery, Piramal, Pfizer, and UCB (all of the PPMI funding partners found at www.ppmi-info.org/fundingpartners).

Author information

Author notes

  1. Xiao-Tong Wang, Huan Yu, and Feng-Tao Liu have contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No.5 Donghai Middle Road, Qingdao, China

    Xiao-Tong Wang, Ya-Hui Ma & Lan Tan

  2. Department of Neurology and Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, 12th Wulumuqi Zhong Road, Shanghai, 200040, China

    Huan Yu, Feng-Tao Liu, Jian Wang, Qiang Dong & Jin-Tai Yu

  3. Department of Neurology, Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Diseases (MIND), Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129-2060, USA

    Can Zhang

  4. Department of Neurology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China

    Han Wang

Authors
  1. Xiao-Tong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Huan Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Feng-Tao Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Can Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ya-Hui Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jian Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Qiang Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lan Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Han Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jin-Tai Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JTY, LT, and HW were responsible for the conception and design of the study. XTW, FTL, HY, YHM, and JTY: acquisition and analysis of data. XTW, FTL, HY, CZ, JTY, LT, and HW: drafting of the manuscript. YHM, JW, and QD coedited the article.

Corresponding authors

Correspondence to Lan Tan, Han Wang or Jin-Tai Yu.

Ethics declarations

Conflicts of interest

None.

Ethics approval

Ethical approval was obtained from the individual PPMI study sites.

Consent to participants

Informed consent was obtained from the individual PPMI study sites.

Consent for publication

Not applicable.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 103 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, XT., Yu, H., Liu, FT. et al. Associations of sleep disorders with cerebrospinal fluid α-synuclein in prodromal and early Parkinson’s disease. J Neurol 269, 2469–2478 (2022). https://doi.org/10.1007/s00415-021-10812-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-021-10812-2

Keywords

Search

Navigation