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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. 1Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
  2. 2Department of Neurology, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
  3. 3Department of Biostatistics, The University of Iowa, Iowa City, Iowa, USA
  4. 4Department of Neurology, Innsbruck Medical University, Innsbruck, Austria
  5. 5Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA
  6. 6Neurology Service, Hospital Clinic de Barcelona, IDIBAPS, CIBERNED, Barcelona, Spain
  7. 7Department of Neurology, Hephata-Klinik,Hephata Hessisches Diakoniezentrum, e.V., Schwalmstadt-Treysa, Germany
  8. 8Cleveland Clinic Neurological Institute, Cleveland, Ohio, USA
  9. 9Division of Neurology, McGill University, Montreal, Québec, Canada
  10. 10Department of Neurology, Philipps University, Marburg, Germany
  11. 11Charitable Hertie Foundation, Frankfurt, Germany
  12. 12Institute for Neurodegenerative Disorders, New Haven, Connecticut, USA
  13. 13Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  1. Correspondence to Amy W Amara; 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

  • Appeuthorsnded A List for The Parkinson’s Progression Markers Initiative* PPMI Sleep Working Group: Kumar Budur, MD45, Barbara Saba57, Cindy Comella, MD58, David Tattersall, PhD50, Ana Fernandez38, Madeline Kelly50, Bradley Boeve, MD59, Arie Struyk48.

    Steering Committee and Study Cores: Kenneth Marek, MD1 (Principal Investigator); Danna Jennings, MD1 (Site Investigator, Olfactory Core, PI); Shirley Lasch, MBA1; Caroline Tanner, MD, PhD9 (Site Investigator); Tanya Simuni, MD3 (Site Investigator); Christopher Coffey, PhD4 (Statistics Core, PI); Karl Kieburtz, MD, MPH5 (Clinical Core, PI); Renee Wilson, MA5; Werner Poewe, MD7 (Site Investigator); Tatiana Foroud, PhD16 (Genetics Coordination Core, BioRepository PI); Daniel Weintraub, MD (Cognitive and Behavioural)13; John Trojanowski, MD, PhD13; Les Shaw, PhD13; Todd Sherer, PhD6; Sohini Chowdhury6; Mark Frasier, PhD6; Catherine Kopil, PhD6; Vanessa Arnedo6.

    Clinical Coordination Core: Cynthia Casaceli, MBA5.

    Imaging Core: John Seibyl, MD(Principal Investigator); Nichole Deagle1; Duygu Tosun-Turgut9; Norbert Schuff, PhD9.

    Statistics Core: Christopher Coffey, PhD4; Chelsea Caspell4; Liz Uribe4; Eric Foster4; Katherine Gloer, PhD4; Jon Yankey, MS4.

    Bioinformatics Core: Arthur Toga, PhD10 (Principal Investigator); Karen Crawford, MLIS10.

    BioRepository: Danielle Elise Smith16; Paola Casalin12; Giulia Malferrari12.

    Bioanalytics Core: Brit Mollenhauer, MD8 (Principal Investigator/Site Investigator); Douglas Galasko, MD15 (Co-Principal/Site Investigator).

    Genetics Core: Andrew Singleton, PhD14 (Principal Investigator).

    Genetics Coordination Core: Cheryl Halter16; Laura Heathers16.

    Site Investigators: David Russell, MD, PhD1; Stewart Factor, DO17; Penelope Hogarth, MD18; David Standaert, MD, PhD19; Robert Hauser, MD, MBA20; Joseph Jankovic, MD21; Matthew Stern, MD13; Lama Chahine, MD13; Shu-Ching Hu, MD, PhD22; Marie Saint-Hilaire, MD23; Samuel Frank, MD23; Claudia Trenkwalder, MD8; Wolfgang Oertel, MD34; Irene Richard, MD24; Klaus Seppi, MD7; Eva Reiter, MD7; Holly Shill, MD25; Hubert Fernandez, MD26; Anwar Ahmed, MD26; Daniela Berg, MD27; Isabel Wurster, MD27; Zoltan Mari, MD28; David Brooks, MD29; Nicola Pavese, MD29; Paolo Barone, MD, PhD30; Stuart Isaacson, MD31; Alberto Espay, MD, MSc32; Dominic Rowe, MD, PhD33; Melanie Brandabur, MD2; James Tetrud, MD2; Grace Liang, MD10; Karen Marder35; Jean-Christophe Corvol36; Jose Felix Martí Masso37; Eduardo Tolosa38; Jan O Aasly39; Nir Giladi40; Leonidas Stefanis41.

    Coordinators: Laura Leary1; Cheryl Riordan1; Linda Rees, MPH1; Barbara Sommerfeld, RN, MSN17; Cathy Wood-Siverio, MS17; Alicia Portillo18; Art Lenahan18; Karen Williams3; Stephanie Guthrie, MSN19; Ashlee Rawlins19; Sherry Harlan20; Christine Hunter, RN21; Baochan Tran13; Abigail Darin13; Carly Linder13; Gretchen Todd22; Cathi-Ann Thomas, RN, MS23; Raymond James, RN23; Cheryl Deeley, MSN24; Courtney Bishop BS24; Fabienne Sprenger, MD7; Diana Willeke8; Sanja Obradov25; Jennifer Mule26; Nancy Monahan26; Katharina Gauss27; Kathleen Comyns9; Deborah Fontaine, BSN, MS, RN, GNP, MS15; Christina Gigliotti15; Arita McCoy28; Becky Dunlop28; Bina Shah, BSc29; Susan Ainscough30; Angela James32; Rebecca Silverstein31; Kristy Espay32; Madelaine Ranola33; Helen M Santana35; Nelly Ngono36; Elisabet Rezola37; Delores Vilas Rolan38; Bjorg Waro39; Anat Mirlman40; Maria Stamelou41.

    ISAB (Industry Scientific Advisory Board): Thomas Comery, PhD42; Spyros Papapetropoulos, MD, PhD42; Bernard Ravina, MD, MSCE43; Igor D Grachev, MD, PhD44; Jordan S Dubow, MD45; Michael Ahlijanian, PhD46; Holly Soares, PhD46; Suzanne Ostrowizki, MD, PhD47; Paulo Fontoura, MD, PhD47; Alison Chalker, PhD48; David L Hewitt, MD48; Marcel van der Brug, PhD49; Alastair D Reith, PhD50; Peggy Taylor, ScD51; Jan Egebjerg, PhD52; Mark Minton, MD53; Andrew Siderowf, MD, MSCE53; Pierandrea Muglia, PhD54; Robert Umek, PhD55; Ana Catafau, MD, PhD56, Jesse Cedarbaum, MD43, Vera Kiyasova, PhD57.

    1 Institute for Neurodegenerative Disorders, New Haven, Connecticut, USA

    2 The Parkinson’s Institute, Sunnyvale, California, USA

    3 Northwestern University, Chicago, Illinois, USA

    4 University of Iowa, Iowa City, Iowa, USA

    5 Clinical Trials Coordination Center, University of Rochester, Rochester, New York, USA

    6 The Michael J. Fox Foundation for Parkinson’s Research, New York, New York, USA

    7 Innsbruck Medical University, Innsbruck, Austria

    8 Paracelsus-Elena Klinik, Kassel, Germany

    9 University of California, San Francisco, California, USA

    10 Laboratory of Neuroimaging (LONI), University of Southern California, Los Angeles, California, USA

    11 Coriell Institute for Medical Research, Camden, New Jersey, USA

    12 BioRep, Milan, Italy

    13 University of Pennsylvania, Philadelphia, Pennsylvania, USA

    14 National Institute on Aging, NIH, Bethesda, Maryland, USA

    15 University of California, San Diego, California, USA

    16 Indiana University, Indianapolis, Indiana, USA

    17 Emory University of Medicine, Atlanta, Georgia, USA

    18 Oregon Health and Science University, Portland, Oregon, USA

    19 University of Alabama at Birmingham, Birmingham, Alabama, USA

    20 University of South Florida, Tampa, Florida, USA

    21 Baylor College of Medicine, Houston, Texas, USA

    22 University of Washington, Seattle, Washington, USA

    23 Boston University, Boston, Massachusetts, USA

    24 University of Rochester, Rochester, New York, USA

    25 Banner Research Institute, Sun City, Arizona, USA

    26 Cleveland Clinic, Cleveland, Ohio, USA

    27 University of Tübingen, Tübingen, Germany

    28 Johns Hopkins University, Baltimore, Maryland, USA

    29 Imperial College of London, London, UK

    30 University of Salerno, Salerno, Italy

    31 Parkinson’s Disease and Movement Disorders Center, Boca Raton, Florida, USA

    32 University of Cincinnati, Cincinnati, Ohio, USA

    33 Macquarie University, Sydney, Australia

    34 Philipps University, Marburg, Germany

    35 Columbia Medical, New York, New York, USA

    36 Pitié-Salpêtrière Hospital, Paris, France

    37 University of Donostia-Service of Neurology Hospital, San Sebastian, Spain

    38 University of Barcelona-Hospital Clinic of Barcelona, Barcelona, Spain

    39 Norwegian University of Science and Technology, Trondheim, Norway

    40 Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    41 Foundation for Biomedical research of the Academy of Athens, Athens, Greece

    42 Pfizer, Inc., Groton, Connecticut, USA

    43 Biogen Idec, Cambridge, Massachusetts, USA

    44 GE Healthcare, Princeton, New Jersey, USA

    45 AbbVie, Abbot Park, Illinois, USA

    46 Bristol-Myers Squibb Company, New York, New York, USA

    47 F.Hoffmann La-Roche, Basel, Switzerland

    48 Merck & Co., North Wales, Pennsylvania, USA

    49 Genentech, Inc., South San Francisco, California, USA

    50 GlaxoSmithKline, Stevenage, UK

    51 Covance, Dedham, Massachusetts, USA

    52 Lundbeck A/S Copenhagen, Denmark

    53 Avid Radiopharmaceuticals, Philadelphia, Pennsylvania, USA

    54 UCB Pharma S.A., Brussels, Belgium

    55 Meso Scale Discovery, Rockville, Maryland, USA

    56 Piramal Life Sciences, Berlin, Germany

    57 Servier, Neuilly-sur-Seine, France

    58 Rush University, Chicago, Illinois, USA

    59 Mayo Clinic, Rochester, Minnesota, USA

  • 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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