Alarming signs and biomarkers of isolated rapid eye movement behavior disorder transforming into α-syncleinopathies

doi:10.3969/j.issn.1672-6731.2022.03.002

Abstract

Abstract: α-synucleinopathies are a group of common neurodegenerative diseases. Once diagnosed, the disease's pathology is already in the middle or late stages, and the best timing for disease modification therapy is missed. Thus, it is very important to explore the early warning signs or early markers of α-synucleinopathies. Isolated rapid eye movement behavior disorder (iRBD) is the prodromal phase of α-synucleinopathies and may serve as an early warning for future transforming into α-synucleinopathies at this stage. The early warning mechanisms for the iRBD transforming into α-synucleinopathies in terms of non-motor symptoms, neuroimaging markers, neuro biological markers, and genetics are illustrated through perspective studies.

Key words: REM sleep behavior disorder, α-synuclein, Review

摘要： α-突触核蛋白病是临床常见的神经系统变性疾病，早期诊断困难。为使患者尽早获得疾病修饰治疗的最佳时机，探索α-突触核蛋白病的预警因素或标志物即显得尤为重要。孤立性快速眼动睡眠期行为障碍（iRBD）是α-突触核蛋白病的前驱症状，在此阶段发挥预警作用可阻止或延缓其转化为α-突触核蛋白病。本文从非运动症状、神经影像学标志物、生物学标志物和基因学等方面阐述iRBD转化为α-突触核蛋白病的预警因素及标志物研究进展。

关键词: REM睡眠行为障碍, α突触核蛋白, 综述

ZHU Xue, LIU Jun. Alarming signs and biomarkers of isolated rapid eye movement behavior disorder transforming into α-syncleinopathies[J]. Chinese Journal of Contemporary Neurology and Neurosurgery, 2022, 22(3): 131-136.

朱雪, 刘军. 孤立性快速眼动睡眠期行为障碍转化为α-突触核蛋白病的预警因素及标志物研究进展[J]. 中国现代神经疾病杂志, 2022, 22(3): 131-136.

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References

[1] Postuma RB, Iranzo A, Hu M, Högl B, Boeve BF, Manni R, Oertel WH, Arnulf I, Ferini-Strambi L, Puligheddu M, Antelmi E, Cochen De Cock V, Arnaldi D, Mollenhauer B, Videnovic A, Sonka K, Jung KY, Kunz D, Dauvilliers Y, Provini F, Lewis SJ, Buskova J, Pavlova M, Heidbreder A, Montplaisir JY, Santamaria J, Barber TR, Stefani A, St Louis EK, Terzaghi M, Janzen A, Leu-Semenescu S, Plazzi G, Nobili F, Sixel-Doering F, Dusek P, Bes F, Cortelli P, Ehgoetz Martens K, Gagnon JF, Gaig C, Zucconi M, Trenkwalder C, Gan-Or Z, Lo C, Rolinski M, Mahlknecht P, Holzknecht E, Boeve AR, Teigen LN, Toscano G, Mayer G, Morbelli S, Dawson B, Pelletier A. Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder:a multicentre study[J]. Brain, 2019, 142:744-759.
[2] Ferri R, Aricò D, Cosentino FII, Lanuzza B, Chiaro G, Manconi M. REM sleep without atonia with REM sleep-related motor events:broadening the spectrum of REM sleep behavior disorder[J]. Sleep, 2018, 41:zsy187.
[3] Högl B, Stefani A, Videnovic A. Idiopathic REM sleep behaviour disorder and neurodegeneration:an update[J]. Nat Rev Neurol, 2018, 14:40-55.
[4] Nepozitek J, Dostalova S, Dusek P, Kemlink D, Prihodova I, Ibarburu Lorenzo Y Losada V, Friedrich L, Bezdicek O, Nikolai T, Perinova P, Dall'Antonia I, Dusek P, Ruml M, Ruzicka E, Sonka K. Simultaneous tonic and phasic REM sleep without atonia best predicts early phenoconversion to neurodegenerative disease in idiopathic REM sleep behavior disorder[J]. Sleep, 2019, 42:zsz132.
[5] McCarter SJ, Sandness DJ, McCarter AR, Feemster JC, Teigen LN, Timm PC, Boeve BF, Silber MH, St Louis EK. REM sleep muscle activity in idiopathic REM sleep behavior disorder predicts phenoconversion[J]. Neurology, 2019, 93:e1171-1179.
[6] Lyu Z, Zheng S, Zhang X, Mai Y, Pan J, Hummel T, Hähner A, Zou L. Olfactory impairment as an early marker of Parkinson's disease in REM sleep behaviour disorder:a systematic review and meta-analysis[J]. J Neurol Neurosurg Psychiatry, 2021, 92:271-281.
[7] Dušek P, Ibarburu VLYL, Bezdicek O, Dall'antonia I, Dostálová S, Kovalská P, Krupička R, Nepožitek J, Nikolai T, Novotný M, Peřinová P, Rusz J, Serranová T, Tykalová T, Ulmanová O, Mecková Z, Ptáčník V, Trnka J, Zogala D, Růžička E, Šonka K. Relations of non-motor symptoms and dopamine transporter binding in REM sleep behavior disorder[J]. Sci Rep, 2019, 9:15463.
[8] Fereshtehnejad SM, Yao C, Pelletier A, Montplaisir JY, Gagnon JF, Postuma RB. Evolution of prodromal Parkinson's disease and dementia with Lewy bodies:a prospective study[J]. Brain, 2019, 142:2051-2067.
[9] Jennings D, Siderowf A, Stern M, Seibyl J, Eberly S, Oakes D, Marek K; PARS Investigators. Conversion to Parkinson disease in the PARS hyposmic and dopamine transporter-deficit prodromal cohort[J]. JAMA Neurol, 2017, 74:933-940.
[10] Ashraf-Ganjouei A, Moradi K, Aarabi M, Abdolalizadeh A, Kazemi SZ, Kasaeian A, Vahabi Z. The association between REM sleep behavior disorder and autonomic dysfunction in Parkinson's disease[J]. J Parkinsons Dis, 2021, 11:747-755.
[11] McCarter SJ, Gehrking TL, St Louis EK, Suarez MD, Boeve BF, Silber MH, Low PA, Singer W. Autonomic dysfunction and phenoconversion in idiopathic REM sleep behavior disorder[J]. Clin Auton Res, 2020, 30:207-213.
[12] Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease[J]. Neurobiol Aging, 2003, 24:197-211.
[13] Postuma RB, Gagnon JF, Vendette M, Desjardins C, Montplaisir JY. Olfaction and color vision identify impending neurodegeneration in rapid eye movement sleep behavior disorder[J]. Ann Neurol, 2011, 69:811-818.
[14] Holec SAM, Woerman AL. Evidence of distinct alpha-synuclein strains underlying disease heterogeneity[J]. Acta Neuropathol, 2021, 142:73-86.
[15] Pereira JB, Weintraub D, Chahine L, Aarsland D, Hansson O, Westman E. Cortical thinning in patients with REM sleep behavior disorder is associated with clinical progression[J]. NPJ Parkinsons Dis, 2019, 5:7.
[16] Zhou L, Li G, Zhang Y, Zhang M, Chen Z, Zhang L, Wang X, Zhang M, Ye G, Li Y, Chen S, Li B, Wei H, Liu J. Increased free water in the substantia nigra in idiopathic REM sleep behaviour disorder[J]. Brain, 2021, 144:1488-1497.
[17] Iranzo A, Santamaría J, Valldeoriola F, Serradell M, Salamero M, Gaig C, Niñerola-Baizán A, Sánchez-Valle R, Lladó A, De Marzi R, Stefani A, Seppi K, Pavia J, Högl B, Poewe W, Tolosa E, Lomeña F. Dopamine transporter imaging deficit predicts early transition to synucleinopathy in idiopathic rapid eye movement sleep behavior disorder[J]. Ann Neurol, 2017, 82:419-428.
[18] Shin JH, Lee JY, Kim YK, Shin SA, Kim H, Nam H, Jeon B. Longitudinal change in dopamine transporter availability in idiopathic REM sleep behavior disorder[J]. Neurology, 2020, 95:e3081-3092.
[19] Arnaldi D, Chincarini A, Hu MT, Sonka K, Boeve B, Miyamoto T, Puligheddu M, De Cock VC, Terzaghi M, Plazzi G, Tachibana N, Morbelli S, Rolinski M, Dusek P, Lowe V, Miyamoto M, Figorilli M, Verbizier D, Bossert I, Antelmi E, Meli R, Barber TR, Trnka J, Miyagawa T, Serra A, Pizza F, Bauckneht M, Bradley KM, Zogala D, McGowan DR, Jordan L, Manni R, Nobili F. Dopaminergic imaging and clinical predictors for phenoconversion of REM sleep behaviour disorder[J]. Brain, 2021, 144:278-287.
[20] Videnovic A, Ju YS, Arnulf I, Cochen-De Cock V, Högl B, Kunz D, Provini F, Ratti PL, Schiess MC, Schenck CH, Trenkwalder C; Treatment and Trials Working Group of the International RBD Study Group. Clinical trials in REM sleep behavioural disorder:challenges and opportunities[J]. J Neurol Neurosurg Psychiatry, 2020, 91:740-749.
[21] Li Y, Zhang H, Mao W, Liu X, Hao S, Zhou Y, Ma J, Gu Z, Chan P. Visual dysfunction in patients with idiopathic rapid eye movement sleep behavior disorder[J]. Neurosci Lett, 2019, 709:134360.
[22] Rossi M, Candelise N, Baiardi S, Capellari S, Giannini G, Orrù CD, Antelmi E, Mammana A, Hughson AG, Calandra-Buonaura G, Ladogana A, Plazzi G, Cortelli P, Caughey B, Parchi P. Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies[J]. Acta Neuropathol, 2020, 140:49-62.
[23] Iranzo A, Fairfoul G, Ayudhaya ACN, Serradell M, Gelpi E, Vilaseca I, Sanchez-Valle R, Gaig C, Santamaria J, Tolosa E, Riha RL, Green AJE. Detection of α-synuclein in CSF by RT-QuIC in patients with isolated rapid-eye-movement sleep behaviour disorder:a longitudinal observational study[J]. Lancet Neurol, 2021, 20:203-212.
[24] Stefani A, Iranzo A, Holzknecht E, Perra D, Bongianni M, Gaig C, Heim B, Serradell M, Sacchetto L, Garrido A, Capaldi S, Sánchez-Gómez A, Cecchini MP, Mariotto S, Ferrari S, Fiorini M, Schmutzhard J, Cocchiara P, Vilaseca I, Brozzetti L, Monaco S, Jose Marti M, Seppi K, Tolosa E, Santamaria J, Högl B, Poewe W, Zanusso G; SINBAR (Sleep Innsbruck Barcelona) group. Alpha-synuclein seeds in olfactory mucosa of patients with isolated REM sleep behaviour disorder[J]. Brain, 2021, 144:1118-1126.
[25] Niu M, Li Y, Li G, Zhou L, Luo N, Yao M, Kang W, Liu J. A longitudinal study on α-synuclein in plasma neuronal exosomes as a biomarker for Parkinson's disease development and progression[J]. Eur J Neurol, 2020, 27:967-974.
[26] Jiang C, Hopfner F, Katsikoudi A, Hein R, Catli C, Evetts S, Huang Y, Wang H, Ryder JW, Kuhlenbaeumer G, Deuschl G, Padovani A, Berg D, Borroni B, Hu MT, Davis JJ, Tofaris GK. Serum neuronal exosomes predict and differentiate Parkinson's disease from atypical parkinsonism[J]. J Neurol Neurosurg Psychiatry, 2020, 91:720-729.
[27] Beach TG, Adler CH, Sue LI, Vedders L, Lue L, White Iii CL, Akiyama H, Caviness JN, Shill HA, Sabbagh MN, Walker DG; Arizona Parkinson's Disease Consortium. Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders[J]. Acta Neuropathol, 2010, 119:689-702.
[28] Zitser J, Gibbons C, Miglis MG. The role of tissue biopsy as a biomarker in REM sleep behavior disorder[J]. Sleep Med Rev, 2020, 51:101283.
[29] Sprenger FS, Stefanova N, Gelpi E, Seppi K, Navarro-Otano J, Offner F, Vilas D, Valldeoriola F, Pont-Sunyer C, Aldecoa I, Gaig C, Gines A, Cuatrecasas M, Högl B, Frauscher B, Iranzo A, Wenning GK, Vogel W, Tolosa E, Poewe W. Enteric nervous system α-synuclein immunoreactivity in idiopathic REM sleep behavior disorder[J]. Neurology, 2015, 85:1761-1768.
[30] Iranzo A, Borrego S, Vilaseca I, Martí C, Serradell M, Sánchez-Valle R, Kovacs GG, Valldeoriola F, Gaig C, Santamaria J, Tolosa E, Gelpi E. α-Synuclein aggregates in labial salivary glands of idiopathic rapid eye movement sleep behavior disorder[J]. Sleep, 2018, 41:zsy101.
[31] Doppler K, Jentschke HM, Schulmeyer L, Vadasz D, Janzen A, Luster M, Höffken H, Mayer G, Brumberg J, Booij J, Musacchio T, Klebe S, Sittig-Wiegand E, Volkmann J, Sommer C, Oertel WH. Dermal phospho-alpha-synuclein deposits confirm REM sleep behaviour disorder as prodromal Parkinson's disease[J]. Acta Neuropathol, 2017, 133:535-545.
[32] Antelmi E, Donadio V, Incensi A, Plazzi G, Liguori R. Skin nerve phosphorylated α-synuclein deposits in idiopathic REM sleep behavior disorder[J]. Neurology, 2017, 88:2128-2131.
[33] Antelmi E, Pizza F, Donadio V, Filardi M, Sosero YL, Incensi A, Vandi S, Moresco M, Ferri R, Marelli S, Ferini-Strambi L, Liguori R, Plazzi G. Biomarkers for REM sleep behavior disorder in idiopathic and narcoleptic patients[J]. Ann Clin Transl Neurol, 2019, 6:1872-1876.
[34] Al-Qassabi A, Tsao TS, Racolta A, Kremer T, Cañamero M, Belousov A, Santana MA, Beck RC, Zhang H, Meridew J, Pugh J, Lian F, Robida MD, Ritter M, Czech C, Beach TG, Pestic-Dragovich L, Taylor KI, Zago W, Tang L, Dziadek S, Postuma RB. Immunohistochemical detection of synuclein pathology in skin in idiopathic rapid eye movement sleep behavior disorder and parkinsonism[J]. Mov Disord, 2021, 36:895-904.
[35] Donadio V, Doppler K, Incensi A, Kuzkina A, Janzen A, Mayer G, Volkmann J, Rizzo G, Antelmi E, Plazzi G, Sommer C, Liguori R, Oertel WH. Abnormal α-synuclein deposits in skin nerves:intra-and inter-laboratory reproducibility[J]. Eur J Neurol, 2019, 26:1245-1251.
[36] Wilke C, Dos Santos MCT, Schulte C, Deuschle C, Scheller D, Verbelen M, Brockmann K, von Thaler AK, Sünkel U, Roeben B, Bujac S, Metzger FG, Maetzler W, da Costa AN, Synofzik M, Berg D. Intraindividual neurofilament dynamics in serum mark the conversion to sporadic Parkinson's disease[J]. Mov Disord, 2020, 35:1233-1238.
[37] Fernández-Santiago R, Iranzo A, Gaig C, Serradell M, Fernández M, Tolosa E, Santamaría J, Ezquerra M. MicroRNA association with synucleinopathy conversion in rapid eye movement behavior disorder[J]. Ann Neurol, 2015, 77:895-901.
[38] Mondello S, Kobeissy F, Mechref Y, Zhao J, Talih FR, Cosentino F, Antelmi E, Moresco M, Plazzi G, Ferri R. Novel biomarker signatures for idiopathic REM sleep behavior disorder:a proteomic and system biology approach[J]. Neurology, 2018, 91:e1710-1715.
[39] Dong X, Mondello S, Kobeissy F, Talih F, Ferri R, Mechref Y. LC-MS/MS glycomics of idiopathic rapid eye movement sleep behavior disorder[J]. Electrophoresis, 2018, 39:3096-3103.
[40] Ouled Amar Bencheikh B, Ruskey JA, Arnulf I, Dauvilliers Y, Monaca CC, De Cock VC, Gagnon JF, Spiegelman D, Hu MTM, Högl B, Stefani A, Ferini-Strambi L, Plazzi G, Antelmi E, Young P, Heidbreder A, Mollenhauer B, Sixel-Döring F, Trenkwalder C, Oertel W, Montplaisir JY, Postuma RB, Rouleau GA, Gan-Or Z. LRRK2 protective haplotype and full sequencing study in REM sleep behavior disorder[J]. Parkinsonism Relat Disord, 2018, 52:98-101.
[41] Li J, Ruskey JA, Arnulf I, Dauvilliers Y, Hu MTM, Högl B, Leblond CS, Zhou S, Ambalavanan A, Ross JP, Bourassa CV, Spiegelman D, Laurent SB, Stefani A, Charley Monaca C, Cochen De Cock V, Boivin M, Ferini-Strambi L, Plazzi G, Antelmi E, Young P, Heidbreder A, Labbe C, Ferman TJ, Dion PA, Fan D, Desautels A, Gagnon JF, Dupré N, Fon EA, Montplaisir JY, Boeve BF, Postuma RB, Rouleau GA, Ross OA, Gan-Or Z. Full sequencing and haplotype analysis of MAPT in Parkinson's disease and rapid eye movement sleep behavior disorder[J]. Mov Disord, 2018, 33:1016-1020.
[42] Gan-Or Z, Montplaisir JY, Ross JP, Poirier J, Warby SC, Arnulf I, Strong S, Dauvilliers Y, Leblond CS, Hu MTM, Högl B, Stefani A, Monaca CC, De Cock VC, Boivin M, Ferini-Strambi L, Plazzi G, Antelmi E, Young P, Heidbreder A, Barber TR, Evetts SG, Rolinski M, Dion PA, Desautels A, Gagnon JF, Dupré N, Postuma RB, Rouleau GA. The dementia-associated APOE ε4 allele is not associated with rapid eye movement sleep behavior disorder[J]. Neurobiol Aging, 2017, 49:218.e13-15.
[43] Gan-Or Z, Mirelman A, Postuma RB, Arnulf I, Bar-Shira A, Dauvilliers Y, Desautels A, Gagnon JF, Leblond CS, Frauscher B, Alcalay RN, Saunders-Pullman R, Bressman SB, Marder K, Monaca C, Högl B, Orr-Urtreger A, Dion PA, Montplaisir JY, Giladi N, Rouleau GA. GBA mutations are associated with rapid eye movement sleep behavior disorder[J]. Ann Clin Transl Neurol, 2015, 2:941-945.
[44] Krohn L, Ruskey JA, Rudakou U, Leveille E, Asayesh F, Hu MTM, Arnulf I, Dauvilliers Y, Högl B, Stefani A, Monaca CC, Abril B, Plazzi G, Antelmi E, Ferini-Strambi L, Heidbreder A, Boeve BF, Espay AJ, De Cock VC, Mollenhauer B, Sixel-Döring F, Trenkwalder C, Sonka K, Kemlink D, Figorilli M, Puligheddu M, Dijkstra F, Viaene M, Oertel W, Toffoli M, Gigli GL, Valente M, Gagnon JF, Desautels A, Montplaisir JY, Postuma RB, Rouleau GA, Gan-Or Z. GBA variants in REM sleep behavior disorder:a multicenter study[J]. Neurology, 2020, 95:e1008-1016.
[45] Krohn L, Wu RYJ, Heilbron K, Ruskey JA, Laurent SB, Blauwendraat C, Alam A, Arnulf I, Hu MTM, Dauvilliers Y, Högl B, Toft M, Bjørnarå KA, Stefani A, Holzknecht E, Monaca CC, Abril B, Plazzi G, Antelmi E, Ferini-Strambi L, Young P, Heidbreder A, Cochen De Cock V, Mollenhauer B, Sixel-Döring F, Trenkwalder C, Sonka K, Kemlink D, Figorilli M, Puligheddu M, Dijkstra F, Viaene M, Oertel W, Toffoli M, Gigli GL, Valente M, Gagnon JF, Nalls MA, Singleton AB, Desautels A, Montplaisir JY, Cannon P, Ross OA, Boeve BF, Dupré N, Fon EA, Postuma RB, Pihlstrøm L, Rouleau GA, Gan-Or Z; 23andMe Research Team. Fine-mapping of SNCA in rapid eye movement sleep behavior disorder and overt synucleinopathies[J]. Ann Neurol, 2020, 87:584-598.
[46] Krohn L, Öztürk TN, Vanderperre B, Ouled Amar Bencheikh B, Ruskey JA, Laurent SB, Spiegelman D, Postuma RB, Arnulf I, Hu MTM, Dauvilliers Y, Högl B, Stefani A, Monaca CC, Plazzi G, Antelmi E, Ferini-Strambi L, Heidbreder A, Rudakou U, Cochen De Cock V, Young P, Wolf P, Oliva P, Zhang XK, Greenbaum L, Liong C, Gagnon JF, Desautels A, Hassin-Baer S, Montplaisir JY, Dupré N, Rouleau GA, Fon EA, Trempe JF, Lamoureux G, Alcalay RN, Gan-Or Z. Genetic, structural, and functional evidence link TMEM175 to synucleinopathies[J]. Ann Neurol, 2020, 87:139-153.

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