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Research paper
Longitudinal assessment of excessive daytime sleepiness in early Parkinson’s disease
  1. Amy W Amara1,
  2. Lama M Chahine2,
  3. Chelsea Caspell-Garcia3,
  4. Jeffrey D Long3,
  5. Christopher Coffey3,
  6. Birgit Högl4,
  7. Aleksandar Videnovic5,
  8. Alex Iranzo6,
  9. Geert Mayer7,
  10. Nancy Foldvary-Schaefer8,
  11. Ron Postuma9,
  12. Wolfgang Oertel10,11,
  13. Shirley Lasch12,
  14. Ken Marek12,
  15. Tanya Simuni13
  16. the Parkinson’s Progression Markers Initiative
  1. 1 Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
  2. 2 Department of Neurology, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
  3. 3 Department of Biostatistics, The University of Iowa, Iowa City, Iowa, USA
  4. 4 Department of Neurology, Innsbruck Medical University, Innsbruck, Austria
  5. 5 Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA
  6. 6 Neurology Service, Hospital Clinic de Barcelona, IDIBAPS, CIBERNED, Barcelona, Spain
  7. 7 Department of Neurology, Hephata-Klinik, Hephata Hessisches Diakoniezentrum, e.V., Schwalmstadt-Treysa, Germany
  8. 8 Cleveland Clinic Neurological Institute, Cleveland, Ohio, USA
  9. 9 Division of Neurology, McGill University, Montreal, Québec, Canada
  10. 10 Department of Neurology, Philipps University, Marburg, Germany
  11. 11 Charitable Hertie Foundation, Frankfurt, Germany
  12. 12 Institute for Neurodegenerative Disorders, New Haven, Connecticut, USA
  13. 13 Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  1. Correspondence to Amy W Amara, Department of Neurology, The University of Alabama at Birmingham, SC 350A 1720 2nd Ave S., Birmingham, AL 35294-0017, USA; amyamara{at}uab.edu

Abstract

Background Excessive daytime sleepiness (EDS) is common and disabling in Parkinson’s disease (PD). Predictors of EDS are unclear, and data on biological correlates of EDS in PD are limited. We investigated clinical, imaging and biological variables associated with longitudinal changes in sleepiness in early PD.

Methods The Parkinson’s Progression Markers Initiative is a prospective cohort study evaluating progression markers in participants with PD who are unmedicated at baseline (n=423) and healthy controls (HC; n=196). EDS was measured with the Epworth Sleepiness Scale (ESS). Clinical, biological and imaging variables were assessed for associations with EDS for up to 3 years. A machine learning approach (random survival forests) was used to investigate baseline predictors of incident EDS.

Results ESS increased in PD from baseline to year 3 (mean±SD 5.8±3.5 to 7.55±4.6, p<0.0001), with no change in HC. Longitudinally, EDS in PD was associated with non-tremor dominant phenotype, autonomic dysfunction, depression, anxiety and probable behaviour disorder, but not cognitive dysfunction or motor severity. Dopaminergic therapy was associated with EDS at years 2 and 3, as dose increased. EDS was also associated with presynaptic dopaminergic dysfunction, whereas biofluid markers at year 1 showed no significant associations with EDS. A predictive index for EDS was generated, which included seven baseline characteristics, including non-motor symptoms and cerebrospinal fluid phosphorylated-tau/total-tau ratio.

Conclusions In early PD, EDS increases significantly over time and is associated with several clinical variables. The influence of dopaminergic therapy on EDS is dose dependent. Further longitudinal analyses will better characterise associations with imaging and biomarkers.

  • Parkinson’s disease
  • Excessive daytime sleepiness
  • Sleep
  • Biomarkers
  • Non-motor symptoms

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Footnotes

  • Contributors AWA: research project: conception and execution; statistical analysis: review and critique; manuscript preparation:writing the first draft, review and critique. LMC: research project:conception; statistical analysis: review and critique; manuscript preparation:drafting/revising manuscript and review and critique. CC-G and JDL: statistical analysis: design, execution and review and critique; manuscript preparation:review and critique. CC: statistical analysis: review and critique; manuscript preparation: review and critique. BH and AV: research project: conception;statistical analysis: review and critique; manuscript preparation: review and critique. AI: research project: organisation; statistical analysis: review and critique; manuscript preparation: review and critique. GM: research project:conception and execution; manuscript preparation: review and critique. NF-S:manuscript preparation: review and critique. RP: statistical analysis: review and critique; manuscript preparation: review and critique. WO: research project: conception and organisation; statistical analysis: review and critique; manuscript preparation: review and critique. SL: research project:conception, organisation and execution; statistical analysis: review and critique; manuscript preparation: review and critique. KM: research project:conception, organisation and execution; statistical analysis: design and review and critique; manuscript preparation: review and critique. TS: research project: conception, organisation and execution; statistical analysis: designand review and critique: manuscript preparation: drafting and review and critique.

  • Funding AWA receives grant funding from the NIH NINDS (K23 NS080912), the National Institute on Aging (P30 AG022838) and the UAB Center for Clinical and Translational Science (UL1 TR00141). LMC (i) receives support from the NIH (P50 NS053488), (ii) receives support as site principal investigator of the Parkinson’s Progression Marker’s Initiative and (iii) receives royalties from Wolters Kluwer (for book authorship). JDL receives funding from CHDI, Michael J. Fox Foundation and NIH. RP received grants from the Fonds de la Recherche en Sante Quebec, the Canadian Institute of Health Research, the Parkinson Society, the Weston-Garfield Foundation and the Webster Foundation, as well as funding for consultancy from Biotie, Roche and Biogen. WO is a Hertie Senior Research Professor supported by the Charitable Hertie Foundation, Frankfurt/Main, Germany. TS received research funding from the Michael J. Fox Foundation for Parkinson’s Research, the National Institutes of Health and the National Parkinson Foundation.

  • Competing interests AWA is an investigator for studies sponsored by the Michael J. Fox Foundation for Parkinson’s Research and Abbvie. JDL has a consulting agreement with NeuroPhage and is a paid consultant for Roche Pharma and Azevan Pharmaceuticals. BH received honoraria as a consultant, for advisory board and/or for speaking for UCB, Otsuka, Lundbeck, Lilly, Axovant and Mundipharma, and Travel Support from Habel Medizintechnik and Vivisol, Austria. GM is an investigator for studies sponsored by UCB Pharma Brussels, Novartis, Michael J. Fox Foundation for Parkinson’s Research, Paul Ehrlich Institute Langen/Germany, Jazz Pharma/USA and Bioprojet; serves on speaker’s bureau for UCB Pharma Brussels; and is on the advisory board of UCB Pharma. RP receives speaker fees from Boehringer, Novartis Canada and Teva Neurosciences. SL is employed by Molecular NeuroImaging, LLC. KM has ownership in inviCRO, LLC and a consultant for Pfizer, GE Healthcare, Lilly, BMS, Piramal, Biogen, Prothena, Roche, Neuropore, US WorldMeds, Neurophage, UCB, Oxford Biomedica and Lysosomal Therapetic, Inc. TS has received consulting honoraria from National Parkinson Foundation, Teva Pharmaceuticals, Pfizer, Harbor, UCB, IMPAX, Acadia, Lundbeck, Eli Lilly and Company, Allergan, Merz Inc and US WorldMeds.

  • Patient consent Obtained.

  • Ethics approval Institutional Review Board.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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