Orexin and Sleep Disturbances in Alpha-Synucleinopathies: a Systematic Review

Kausar Raheel¹, Qi Rui See¹, Veronica Munday¹, Basma Fakhroo¹, Olga Ivanenko¹, Marcello Luigi Salvatelli^{1

2}, Carlotta Mutti², Peter J Goadsby³, Alessio Delogu⁴, Sharon L Naismith⁵, Phil Holland⁴, Liborio Parrino^{2

6}, K Ray Chaudhuri⁷, Ivana Rosenzweig^{8

9}

Affiliations

¹ Sleep and Brain Plasticity Centre, Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, De Crespigny Park, London, SE5 8AF, UK.
² Sleep Disorders Center, Department of General and Specialized Medicine, University Hospital of Parma, 43125, Parma, Italy.
³ NIHR-Wellcome Trust King's Clinical Research Facility, King's College London, London, WC2R 2LS, UK.
⁴ Basic and Clinical Neuroscience, IoPPN, King's College London, London, WC2R 2LS, UK.
⁵ Healthy Brain Ageing Program, School of Psychology; Brain and Mind Centre, The University of Sydney, & Charles Perkins Centre, Camperdown, Sydney, Australia.
⁶ Department of Medicine and Surgery, Neurology Unit, University of Parma, 43125, Parma, Italy.
⁷ Movement Disorders Unit, King's College Hospital and Department of Clinical and Basic Neurosciences, Institute of Psychiatry, Psychology & Neuroscience and Parkinson Foundation Centre of Excellence, King's College London, London, UK.
⁸ Sleep and Brain Plasticity Centre, Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, De Crespigny Park, London, SE5 8AF, UK. ivana.1.rosenzweig@kcl.ac.uk.
⁹ Sleep Disorders Centre, Guy's and St Thomas' NHS Foundation Trust, London, UK. ivana.1.rosenzweig@kcl.ac.uk.

PMID: 39031323
PMCID: PMC11349833
DOI: 10.1007/s11910-024-01359-6

Orexin and Sleep Disturbances in Alpha-Synucleinopathies: a Systematic Review

Kausar Raheel et al. Curr Neurol Neurosci Rep. 2024 Sep.

. 2024 Sep;24(9):389-412.

doi: 10.1007/s11910-024-01359-6. Epub 2024 Jul 20.

Authors

Affiliations

¹ Sleep and Brain Plasticity Centre, Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, De Crespigny Park, London, SE5 8AF, UK.
² Sleep Disorders Center, Department of General and Specialized Medicine, University Hospital of Parma, 43125, Parma, Italy.
³ NIHR-Wellcome Trust King's Clinical Research Facility, King's College London, London, WC2R 2LS, UK.
⁴ Basic and Clinical Neuroscience, IoPPN, King's College London, London, WC2R 2LS, UK.
⁵ Healthy Brain Ageing Program, School of Psychology; Brain and Mind Centre, The University of Sydney, & Charles Perkins Centre, Camperdown, Sydney, Australia.
⁶ Department of Medicine and Surgery, Neurology Unit, University of Parma, 43125, Parma, Italy.
⁷ Movement Disorders Unit, King's College Hospital and Department of Clinical and Basic Neurosciences, Institute of Psychiatry, Psychology & Neuroscience and Parkinson Foundation Centre of Excellence, King's College London, London, UK.
⁸ Sleep and Brain Plasticity Centre, Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, De Crespigny Park, London, SE5 8AF, UK. ivana.1.rosenzweig@kcl.ac.uk.
⁹ Sleep Disorders Centre, Guy's and St Thomas' NHS Foundation Trust, London, UK. ivana.1.rosenzweig@kcl.ac.uk.

PMID: 39031323
PMCID: PMC11349833
DOI: 10.1007/s11910-024-01359-6

Abstract

Purpose of review: Sleep disturbances are amongst most frequent non-motor symptoms of Parkinson's Disease (PD), and they are similarly frequently reported in other alpha-syncleinopathies, such as Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA). More recently, the orexin system has been implicated in control of arousal based on salient environmental set points, and its dysregulation in sleep issues in alpha-synucleinopathies suggested by the findings from the translational animal models. However, its role in the patients with alpha-synucleinopathies remains unclear. We thus set to systematically review, and to critically assess, contemporary evidence on the association of the orexinergic system and sleep disturbances in alpha-synucleinopathies. In this systematic review, studies investigating orexin and sleep in alpha-synucleinopathies (Rapid Eye Movement (REM) Behaviour Disorder (RBD), Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA)) were identified using electronic database searches of PubMed, Web of Science and PsychINFO using MeSH terms, keywords, and title words such as "Alpha-synucleinopathies" AND "Orexin" AND "Sleep Disturbances".

Recent findings: 17 studies were included in this systemic review, of which 2 studies on RBD, 10 on PD, 4 on DLB, and 1 on MSA patients. Taken together, RBD and PD studies suggest a potential adaptive increase in orexin levels in early stages of the neurodegenerative process, with reduced levels more often reported for later, more advanced stages of illness. To date, no differences in orexin levels were demonstrated between MSA patients and healthy controls. There is a dearth of studies on the role of orexin levels in alpha-synucleinopathies. Moreover, significant methodologic limitations in the current body of work, including use of non-standardised research protocols and lack of prospective, multi-centre studies, disallow for any finite conclusion in regards to underlying pathomechanisms. Nonetheless, a picture of a complex, multifaceted relationship between the dysregulation of the orexinergic pathway and sleep disturbances in alpha-synucleinopathies is emerging. Hence, future studies disentangling orexinergic pathomechanisms of alpha-syncleinopathies are urgently needed to obtain a more comprehensive account of the role of orexinergic pathway in alpha-synucleinopathies. Pharmacological manipulations of orexins may have multiple therapeutic applications in treatment strategies, disease diagnosis, and might be effective for treating both motor and non-motor symptoms.

Keywords: Alpha-synucleinopathies; Orexin; Parkinson's Disease (PD); Dementia with Lewy Bodies (DLB); Sleep Disturbances.

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Conflict of interest statement

The authors declare the following competing financial interest(s): grants from Celgene and Kallyope, Massachusetts Medical Society, Oxford University Press, UptoDate and Wolters Kluwer (P.J.G); consulting fees from Aeon Biopharma, Abbvie, Amgen, CoolTech LLC, Epalex, Eli Lilly, Sanofi, Gerson Lehrman Group, Guidepoint, Linpharma, Lundbeck, Novartis, Pfizer, Vector Metric, SAI Med Partners, Satsuma, Shiratronics and Teva Pharmaceuticals (P.J.G). Grants from the Medical Research Council (MRC) (MR/P006264/1 and MR/N013700/1, PhD studentship for E.C.S and grant from Eli Lilly and Company (Eli Lilly Research Award Program (LRAP)) (P.H.). The advisory board for AbbVie, UCB, GKC, Bial Cynapsus, Lobsor, Stada, Zambon, Profile Pharma, Synovion, Roche, Therevance, Scion, Britannia, Acadia, 4D Pharma, receives grants from Bial, Britannia Pharmaceuticals, AbbVie, UCB, GKC, EU Horizon 2020, Parkinson's UK, NIHR, Parkinson’s Foundation, Wellcome Trust, Kirby Laing Foundation, MRC, MDS (MDS NMS Project), royalties or licenses from Oxford (book), Cambridge publishers (book), MAPI institute (KPPS, PDSS 2) and expert testimony from GMC, NICE, NIHR (K.R.C). Authors K.R., S.Q.R, V.M., B.F., O.I., M.L.S., C.M., A.D., S.L.N., L.P., I.R. have no competing interests.

Figures

**Fig. 1**
PRISMA 2020 Flow Diagram of study selection process

See this image and copyright information in PMC

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Orexin and Sleep Disturbances in Alpha-Synucleinopathies: a Systematic Review

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Orexin and Sleep Disturbances in Alpha-Synucleinopathies: a Systematic Review

Authors

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Abstract

Conflict of interest statement

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