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Review
Orthostatic hypotension and REM sleep behaviour disorder: impact on clinical outcomes in α-synucleinopathies
  1. Andrea Pilotto1,2,
  2. Alberto Romagnolo3,
  3. Jasmine A Tuazon4,5,
  4. Joaquin A Vizcarra4,
  5. Luca Marsili4,
  6. Maurizio Zibetti3,
  7. Michela Rosso6,
  8. Federico Rodriguez-Porcel4,7,
  9. Barbara Borroni1,
  10. Maria Cristina Rizzetti2,
  11. Carlo Rossi8,
  12. Darwin Vizcarra-Escobar9,
  13. Jennifer R Molano10,
  14. Leonardo Lopiano3,
  15. Roberto Ceravolo11,
  16. Mario Masellis12,
  17. Alberto J Espay4,
  18. Alessandro Padovani1,
  19. Aristide Merola4
  1. 1 Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
  2. 2 Parkinson’s Disease Rehabilitation Centre, FERB ONLUS – S. Isidoro Hospital, Trescore Balneario(BG), Italy
  3. 3 Department of Neuroscience “Rita Levi Montalcini”, University of Turin, Turin, Italy
  4. 4 Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, Ohio, USA
  5. 5 The Ohio State University College of Medicine, Columbus, Ohio, USA
  6. 6 Department of Neurology, The State University of New York (SUNY) Downstate Medical Center, Brooklyn, New York, USA
  7. 7 Department of Neurology, Medical University of South Carolina, Charleston, South Carolina, USA
  8. 8 Unit of Neurology, "F. Lotti" Hospital, Pontedera, Italy
  9. 9 Hypnos, Institutodel Sueño; Clinica San Felipe; Faculty of Medicine, Universidad PeruanaCayetano Heredia, Lima, Peru
  10. 10 Department of Neurology and Rehabilitation Medicine, The University of Cincinnati, Cincinnati, Ohio, USA
  11. 11 Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
  12. 12 Department of Medicine (Neurology) Hurvitz Brain Sciences Program, University of Toronto, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
  1. Correspondence to Dr Aristide Merola, Gardner Family Center for Parkinson's Disease and Movement Disorders, University of Cincinnati, Cincinnati, Ohio 45221, United States; aristidemerola{at}hotmail.com

Abstract

Objective Review the effect of orthostatic hypotension (OH) and rapid-eye-movement sleep behavioural disorder (RBD) on survival, cognitive impairment and postural stability, and discuss pathogenic mechanisms involved in the association of these two common non-motor features with relevant clinical outcomes in α-synucleinopathies.

Methods We searched PubMed (January 2007–February 2019) for human studies of OH and RBD evaluating cognitive impairment, postural instability, and survival in Parkinson’s disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA) and pure autonomic failure (PAF). Included studies were analysed for design, key results and limitations as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

Results OH and RBD showed a positive association with cognitive impairment in PD and DLB, conflicting association in PAF, and no association in MSA. OH was correlated with incident falls and postural instability in PD and DLB but not in MSA. The association between RBD and postural instability was inconclusive; positive in five studies, negative in seven. OH, but not RBD, correlated with reduced survival in PD, DLB and MSA. The combination of OH and RBD was associated with cognitive impairment and more rapid progression of postural instability.

Conclusions OH and RBD yielded individual and combined negative effects on disability in α-synucleinopathies, reflecting a ‘malignant’ phenotype of PD with early cognitive impairment and postural instability. Underlying mechanisms may include involvement of selected brainstem cholinergic and noradrenergic nuclei.

  • Parkinson’s disease
  • autonomic
  • sleep disorders
  • cognition
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Footnotes

  • AP and AR contributed equally.

  • Contributors AP: study concept and design, analysis and interpretation of data, drafting/revising the manuscript for content. AR: study concept and design, acquisition of data, drafting/revising the manuscript for content. JAT: acquisition of data, revising the manuscript for content. JAV: acquisition of data, revising the manuscript for content. LM: acquisition of data, revising the manuscript for content. MZ: acquisition of data, revising the manuscript for content. MR: acquisition of data, revising the manuscript for content. FR-P: acquisition of data, revising the manuscript for content. BB: acquisition of data, revising the manuscript for content. MCR: acquisition of data, revising the manuscript for content. CR: acquisition of data, revising the manuscript for content. DV-E: acquisition of data, revising the manuscript for content. JRM: acquisition of data, revising the manuscript for content. LL: interpretation of data, revising the manuscript for content. RC: interpretation of data, revising the manuscript for content. MM: interpretation of data, revising the manuscript for content. AJE: study concept and design, revising the manuscript for content. AP: study concept and design, revising the manuscript for content. AM: study concept and design, analysis and interpretation of data, drafting/revising the manuscript for content.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests AP received speaker honoraria from BioMarin Pharmaceutical, Chiesi Pharmaceuticals, Nutricia Pharmaceuticals, UCB Pharma and Zambon Pharmaceuticals. He received travel grants from AbbVie Pharmaceuticals, BioMarin Pharmaceutical, Nutricia Pharmaceuticals, Zambon Pharmaceuticals and the Italian movement disorder society. AR received speaker honoraria from AbbVie and Chiesi Pharmaceuticals and travel grants from Medtronic, Lusofarmaco and UCB Pharma. JAT has no financial conflicts to disclose. JAV has no financial conflicts to disclose. LM has no financial conflicts to disclose. MZ received speaker honoraria from AbbVie, Medtronic, Zambon and UCB Pharma and received travel grants from AbbVie. MR has no financial conflicts to disclose. FR-P has no financial conflicts to disclose. BB has no financial conflicts to disclose. MCR has no financial conflicts to disclose. CR received speaker honoraria from Zambon and UCB Pharma and received travel grants from Zambon, UCB Pharma, Medtronic and Chiesi Pharmaceuticals. DV-E has no financial conflicts to disclose. JRM has received research support from Axovant. She is also an editorial board member for NEJM Journal Watch Neurology. Leonardo Lopiano received honoraria for lecturing and travel grants from Medtronic, UCB Pharma, and AbbVie. RC received speaker honoraria from General Electric, AbbVie, UCB Pharma, Zambon. He received consulting fees from General Electric and Zambon and grant support from Ministry of Health (MINSAL). MM receives salary support from the Department of Medicine at Sunnybrook Health Sciences Centre and the University of Toronto, as well as the Sunnybrook Research Institute. He has received grants/research Support from: Parkinson Canada, Canadian Institutes of Health Research, Teva, Early Researcher Award - Ministry of Economic Development and Innovation, C5R, Weston Brain Institute, Ontario Brain Institute, Sunnybrook AFP Innovation Fund, Novartis, Washington University, Roche, Alzheimer’s Drug Discovery Foundation (ADDF), Brain Canada, Heart and Stroke Foundation Centre for Stroke Recovery. He has received consulting Fees from UCB, Ionis, Novartis, and Arkuda Therapeutics, as well as royalties from Henry Stewart Talks Ltd. Alberto Espay has received grant support from the NIH, Great Lakes Neurotechnologies and the Michael J Fox Foundation; personal compensation as a consultant/scientific advisory board member for Abbvie, Adamas, Acadia, Acorda, Neuroderm, TEVA, Impax, Sunovion, Lundbeck, Osmotica Pharmaceutical and USWorldMeds; publishing royalties from Lippincott Williams and honoraria from Abbvie, UCB, USWorldMeds, Lundbeck, Acadia, Sunovion, the American Academy of Neurology and the Movement Disorders Society. AP received grant support from Ministry of Health (MINSAL) and Ministry of Education, Research and University (MIUR), from CARIPLO Foundation; personal compensation as a consultant/scientific advisory board member for Avanir, Lundbeck, Eli-Lilly, Neuraxpharma, Biogen, GE Health. AM is supported by NIH (KL2 TR001426) and has received speaker honoraria from CSL Behring, Cynapsus Therapeutics, Lundbeck, AbbVie, and Abbott. He has received grant support from Lundbeck and Abbott.

  • Patient consent for publication Not required.

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

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