Cholinergic dysfunction in isolated rapid eye movement sleep behaviour disorder links to impending phenoconversion.

Publisher: Wiley Country of Publication: England NLM ID: 9506311 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1468-1331 (Electronic) Linking ISSN: 13515101 NLM ISO Abbreviation: Eur J Neurol Subsets: MEDLINE

Publication: <2014- > : Oxford : Wiley
Original Publication: Oxford ; New York : Rapid Communications, [1994-

REM Sleep Behavior Disorder*/diagnostic imaging ; REM Sleep Behavior Disorder*/metabolism ; Positron-Emission Tomography*; Humans ; Male ; Female ; Aged ; Middle Aged ; Parkinson Disease/diagnostic imaging ; Parkinson Disease/metabolism ; Disease Progression ; Lewy Body Disease/diagnostic imaging ; Lewy Body Disease/metabolism ; Donepezil ; Dihydroxyphenylalanine/analogs & derivatives ; Dihydroxyphenylalanine/pharmacokinetics ; Polysomnography

Background and Purpose: Most patients with isolated rapid eye movement sleep behaviour disorder (iRBD) progress to a parkinsonian alpha-synucleinopathy. However, time to phenoconversion shows great variation. The aim of this study was to investigate whether cholinergic and dopaminergic dysfunction in iRBD patients was associated with impending phenoconversion.
Methods: Twenty-one polysomnography-confirmed iRBD patients underwent baseline ¹¹ C-donepezil and 6-Fluoro-( ¹⁸ F)-l-3,4-dihydroxyphenylalanine ( ¹⁸ F-DOPA) positron emission tomography (PET). Potential phenoconversion was monitored for up to 8 years. PET images were analysed according to patients' diagnoses after 3 and 8 years using linear regression. Time-to-event analysis was made with Cox regression, dividing patients into low and high tracer uptake groups.
Results: Follow-up was accomplished in 17 patients. Eight patients progressed to either Parkinson's disease (n = 4) or dementia with Lewy bodies (n = 4), while nine remained non-phenoconverters. Compared with non-phenoconverters, 8-year phenoconverters had lower mean ¹¹ C-donepezil uptake in the parietal (p = 0.032) and frontal cortex (p = 0.042), whereas mean ¹¹ C-donepezil uptake in 3-year phenoconverters was lower in the parietal cortex (p = 0.005), frontal cortex (p = 0.025), thalamus (p = 0.043) and putamen (p = 0.049). Phenoconverters within 3 years and 8 years had lower ¹⁸ F-DOPA uptake in the putamen (p < 0.001). iRBD patients with low parietal ¹¹ C-donepezil uptake had a 13.46 (95% confidence interval 1.42;127.21) times higher rate of phenoconversion compared with those with higher uptake (p = 0.023). iRBD patients with low ¹⁸ F-DOPA uptake in the most affected putamen were all phenoconverters with higher rate of phenoconversion (p = 0.0002).
Conclusions: These findings suggest that cortical cholinergic dysfunction, particularly within the parietal cortex, could be a biomarker candidate for predicting short-term phenoconversion in iRBD patients. This study aligns with previous reports suggesting dopaminergic dysfunction is associated with forthcoming phenoconversion.
(© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Neurology. 2017 Jul 4;89(1):88-100. (PMID: 28592453)
Mov Disord Clin Pract. 2021 Aug 23;8(7):1012-1026. (PMID: 34631936)
Neurology. 2008 Aug 26;71(9):670-6. (PMID: 18725592)
Alzheimers Dement. 2011 May;7(3):270-9. (PMID: 21514249)
J Cereb Blood Flow Metab. 1985 Dec;5(4):584-90. (PMID: 4055928)
J Neurol Neurosurg Psychiatry. 1992 Mar;55(3):181-4. (PMID: 1564476)
Lancet Neurol. 2010 Nov;9(11):1070-7. (PMID: 20846908)
Cell Mol Neurobiol. 1991 Feb;11(1):55-77. (PMID: 2013059)
Mov Disord. 2004 Nov;19(11):1306-12. (PMID: 15390007)
Neuroimage. 2011 Jun 1;56(3):1463-8. (PMID: 21396455)
Lancet Neurol. 2016 Apr;15(4):405-19. (PMID: 26971662)
Mov Disord. 2011 Mar;26(4):644-52. (PMID: 21312275)
J Parkinsons Dis. 2023;13(4):515-523. (PMID: 37212074)
Neurosci Lett. 1999 Jan 22;260(1):5-8. (PMID: 10027686)
Eur J Neurol. 2020 Apr;27(4):644-652. (PMID: 31725927)
J Cereb Blood Flow Metab. 1996 Sep;16(5):834-40. (PMID: 8784228)
PLoS One. 2014 Feb 26;9(2):e89741. (PMID: 24587002)
Sleep Med. 2019 Jun;58:35-41. (PMID: 31078078)
Mov Disord. 2008 Nov 15;23(15):2129-70. (PMID: 19025984)
Mov Disord. 2015 Oct;30(12):1591-601. (PMID: 26474316)
Eur J Neurol. 2024 Dec;31(12):e16503. (PMID: 39360592)
Mov Disord. 2006 Jul;21(7):916-23. (PMID: 16547944)
Ann Clin Transl Neurol. 2021 Jan;8(1):201-212. (PMID: 33321002)
Mov Disord. 2024 Aug;39(8):1323-1328. (PMID: 38477376)
J Am Geriatr Soc. 2005 Apr;53(4):695-9. (PMID: 15817019)
Mov Disord. 2007 Oct 15;22(13):1901-11. (PMID: 17674410)
Eur J Neurol. 2024 Jan;31(1):e16101. (PMID: 37847229)
Nat Rev Neurol. 2018 Jan;14(1):40-55. (PMID: 29170501)
Ann Neurol. 2017 Sep;82(3):419-428. (PMID: 28833467)
Lancet Neurol. 2017 Oct;16(10):789-796. (PMID: 28684245)

R4-A104-B60 Danish Parkinson's Association (Parkinsonforeningen); CB06/05/0018 Instituto de Salud Carlos III; 23-0916 Augustinus Fonden; 4004-00480B Danmarks Frie Forskningsfond; 8020-00260B Danmarks Frie Forskningsfond

Keywords: REM sleep behavior disorder; cholinergic neurons/abnormalities; dopaminergic imaging; positron emission tomography

2C598205QX (fluorodopa F 18)
8SSC91326P (Donepezil)
63-84-3 (Dihydroxyphenylalanine)

Date Created: 20241003 Date Completed: 20241112 Latest Revision: 20241114

20241114

PMC11554850

10.1111/ene.16503

39360592