Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by repeated episodes of REM sleep-related vocalizations and/or complex motor behaviors. Definite diagnosis of RBD is based on history and polysomnography, both of which are less accessible due to the lack of trained specialists and high cost. While RBD may be associated with disorders like narcolepsy, focal brain lesions, and encephalitis, idiopathic RBD (iRBD) may convert to Parkinson's disease (PD) and other synucleinopathies in more than 80% of patients and it is to date the most specific clinical prodromal marker of PD. Identification of individuals at high risk for development of PD is becoming one of the most important topics for current PD-related research as well as for future treatment trials targeting prodromal PD. Furthermore, concomitant clinical symptoms, such as subtle motor impairment, hyposmia, autonomic dysfunction, or cognitive difficulties, in subjects with iRBD may herald its phenoconversion to clinically manifest parkinsonism. The assessment of these motor and non-motor symptoms in iRBD may increase the sensitivity and specificity in identifying prodromal PD subjects. This review evaluates the diagnostic accuracy of individual rating scales and validated single items for screening of RBD and the role and accuracy of available clinical, electrophysiological, imaging, and tissue biomarkers in predicting the phenoconversion from iRBD to clinically manifest synucleinopathies.

Department of Circuit Theory Faculty of Electrical Engineering Czech Technical University Prague Prague Czechia

Department of Neurology Center of Clinical Neuroscience 1st Faculty of Medicine Charles University and General University Hospital Prague Czechia

Department of Neurology Faculty of Medicine P J Safarik University Kosice Slovakia

Department of Neurology University Hospital of L Pasteur Kosice Slovakia

Movement Disorders Unit Department of Neurology Hospital Ruber Internacional Madrid Spain

See more in PubMed

American Academy of Sleep Medicine. International Classification of Sleep Disorders. 3rd ed Darien, IL: American Academy of Sleep Medicine; (2014). 383 p. PubMed PMC

Chiu HKF, Wing YK, Lam LCW, Li SW, Lum CM, Ho CK, et al. Sleep-related injury in the elderly-an epidemiological study in Hong Kong. Sleep (2000) 23:513–7.10.1093/sleep/23.4.1e PubMed DOI

St. Louis EK, McCarter SJ, Boeve BF, Silber MH, Kantarci K, Benaroch EE, et al. Lesional REM sleep behavior disorder localizes to the dorsomedial pons. Neurology (2014) 83:1871–3.10.1212/WNL.0000000000000978 PubMed DOI PMC

Postuma RB, Gagnon JF, Tuineaig M, Bertrand JA, Latreille V, Desjardins C, et al. Antidepressants and REM sleep behavior disorder: isolated side effect or neurodegenerative signal? Sleep (2013) 36:1579–85.10.5665/sleep.3102 PubMed DOI PMC

Boeve BF, Silber MH, Ferman TJ, Lin SC, Benaroch EE, Schmeichel AM, et al. Clinicopathologic correlations in 172 cases of rapid eye movement sleep behavior disorder with or without a coexisting neurologic disorder. Sleep Med (2013) 14:754–62.10.1016/j.sleep.2012.10.015 PubMed DOI PMC

Schenck CH, Boeve BF, Mahowald MW. Delayed emergence of a parkinsonian disorder or dementia in 81% of older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder: a 16-year update on a previously reported series. Sleep Med (2013) 14:744–8.10.1016/j.sleep.2012.10.009 PubMed DOI

Iranzo A, Fernandez-Arcos A, Tolosa E, Serradell M, Molinuevo JL, Valldeoriola F, et al. Neurodegenerative disorder risk in idiopathic REM sleep behavior disorder: study in 174 patients. PLoS One (2014) 9:e89741.10.1371/journal.pone.0089741 PubMed DOI PMC

Kang SH, Yoon IY, Lee SD, Han JW, Kim TH, Kim KW. REM sleep behavior disorder in the Korean elderly population: prevalence and clinical characteristics. Sleep (2013) 36:1147–52.10.5665/sleep.2874 PubMed DOI PMC

Jellinger K. Neuropathology of Sporadic Parkinson’s disease: evaluation and changes of concepts. Mov Disord (2012) 27:8–30.10.1002/mds.23795 PubMed DOI

Koga S, Dickson DW. Recent advances in neuropathology, biomarkers and therapeutic approach of multiple system atrophy. J Neurol Neurosurg Psychiatry (2018) 89:175–84.10.1136/jnnp-2017-315813 PubMed DOI

Berg D, Postuma R, Adler C, Bloem B, Chan P, Dubois B, et al. MDS research criteria for prodromal Parkinson’s disease. Mov Disord (2015) 30:1600–9.10.1002/mds.26431 PubMed DOI

Sixel-Doring F, Schweitzer M, Mollenhauer B, Trenkwalder C. Intraindividual variability of REM sleep behavior disorder in Parkinson’s disease: a comparative assessment using a new REM sleep behavior disorder severity scale (RBDSS) for clinical routine. J Clin Sleep Med (2011) 7:75–80. PubMed PMC

Li SX, Wing YK, Lam SP, Zhang J, Yu MW, Ho CK, et al. Validation of a new REM sleep behavior disorder questionnaire (RBDQ-HK). Sleep Med (2010) 11:43–8.10.1016/j.sleep.2009.06.008 PubMed DOI

Chang Y, Gu Z, Zhan S, Zhang H, Li Y, An J, et al. Validation of the Beijing version of the REM sleep behavior disorder questoinnaire (RBDQ-Beijing) in a mainland chinese cohort. Tohoku J Exp Med (2014) 234:7–15.10.1620/tjem.234.7 PubMed DOI

Sasai T, Matsuura M, Wing YK, Inoue Y. Validation of the Japanese version of the REM sleep behavior disorder questionnaire (RBDQ-JP). Sleep Med (2012) 13:913–8.10.1016/j.sleep.2012.04.011 PubMed DOI

Shen SS, Shen Y, Xiong KP, Chen J, Mao CJ, Huang JY, et al. Validation study of REM sleep behavior disorder questionnaire – Hong Kong (RBDQ-HK) in East China. Sleep Med (2014) 15:952–8.10.1016/j.sleep.2014.03.020 PubMed DOI

Li SX, Lam SP, Zhang J, Yu MW, Chan JW, Liu Y, et al. A prospective, naturalistic follow-up study of treatment outcomes with clonazepam in rapid eye movement sleep behavior disorder. Sleep Med (2016) 21:114–20.10.1016/j.sleep.2015.12.020 PubMed DOI

Kashihara K, Nomura T, Maeda T, Tsuboi Y, Mishima T, Takigawa H, et al. Beneficial effects of Ramalteon on rapid eye movement sleep behavior disorder associated with Parkinson’s disease – results of a multicenter open trial. Intern Med (2016) 55:231–6.10.2169/internalmedicine.55.5464 PubMed DOI

Zhou J, Zhang J, Du L, Li Z, Li Y, Lei F, et al. Characteristics of early- and late-onset rapid eye movement sleep behavior disorder in China: a case-control study. Sleep Med (2014) 15:654–60.10.1016/j.sleep.2013.12.020 PubMed DOI

Zhou J, Zhang J, Li Y, Du L, Li Z, Lei F, et al. Gender differences in REM sleep behavior disorder: a clinical and polysomnographic study in China. Sleep Med (2015) 16:414–8.10.1016/j.sleep.2014.10.020 PubMed DOI

Postuma RB, Bertrand JA, Montplaisir J, Desjardins C, Vendette M, Rios Romenets S, et al. Rapid eye movement sleep behavior disorder and risk of dementia in Parkinson’s disease: a prospective study. Mov Disord (2012) 27:720–6.10.1002/mds.24939 PubMed DOI

Neikrug AB, Anconi-Israel S. Diagnostic tools for REM sleep behavior disorder. Sleep Med Rev (2012) 16:415–29.10.1016/j.smrv.2011.08.004 PubMed DOI PMC

Stiasny-Kolster K, Mayer G, Schafer S, Möller JC, Heinzel-Gutenbrunner M, Oertel WH. The REM sleep behavior disorder screening questionnaire – a new diagnostic instrument. Mov Disord (2007) 22:2386–93.10.1002/mds.21740 PubMed DOI

Miyamoto T, Miyamoto M, Iwananmi M, Kobayashi M, Nakamura M, Inoue Y, et al. The REM sleep behavior disorder screening questionnaire: validation study of a Japanese version. Sleep Med (2009) 10:1151–4.10.1016/j.sleep.2009.05.007 PubMed DOI

Wang Y, Wang ZW, Yang YC, WU HJ, Zhao JY, Zhao ZX. Validation of the rapid eye movement sleep behavior disorder screening questionnaire in China. J Clin Neurosci (2015) 22:1420–4.10.1016/j.jocn.2015.03.008 PubMed DOI

Comert IT, Pelin Z, Aricak T, Yapan S. Validation of the Turkish version of the REM sleep behavior disorder screening questionnaire. Behav Neurol (2016) 2016:8341651.10.1155/2016/8341651 PubMed DOI PMC

Marelli S, Rancoita PMV, Giarusso F, Galbiati A, Zucconi M, Oldani A, et al. National validation and proposed revision of REM sleep behavior disorder screening questionnaire. J Neurol (2016) 263:2470–5.10.1007/s00415-016-8285-y PubMed DOI

Stefani A, Mahlknecht P, Seppi K, Nocker M, Mair KJ, Hotter A, et al. Consistency of “Probable RBD” diagnosis with the RBD screening questionnaire: a follow-up study. Mov Disord Clin Pract (2016) 4:403–5.10.1002/mdc3.12448 PubMed DOI PMC

Bjornara KA, Dietrichs E, Toft M. REM sleep behavior disorder in Parkinson’s disease – is there a gender difference? Parkinsonism Relat Disord (2013) 19:120–2.10.1016/j.parkreldis.2012.05.027 PubMed DOI

Stiasny-Kolster K, Sixel-Doring F, Trenkwalder K, Heinzel-Gutenbrunner M, Seppi K, Poewe W, et al. Diagnostic value of the REM sleep behavior disorder screening questionnaire in Parkinson’s disease. Sleep Med (2015) 16:186–9.10.1016/j.sleep.2014.08.014 PubMed DOI

Li K, Li SH, Su W, Chen HB. Diagnostic accuracy of REM sleep behavior disorder screening questionnaire: a meta-analysis. Neurol Sci (2017) 38:1039–46.10.1007/s10072-017-2886-9 PubMed DOI

Lee HG, Choi JW, Lee YJ, Jeong DU. Depressed REM sleep behavior disorder patients are less likely to recall enacted dreams than non-depressed ones. Psychiatry Investig (2016) 13:227–31.10.4306/pi.2016.13.2.227 PubMed DOI PMC

Chahine LM, Daley J, Horn S, Colcher A, Hurtig H, Cantor C, et al. Questionnaire-based diagnosis of REM sleep behavior disorder in Parkinson’s disease. Mov Disord (2013) 28:1146–9.10.1002/mds.25438 PubMed DOI

Nomura T, Inoue Y, Hogl B, Uemura Y, Kitayama M, Abe T, et al. Relationship between (123)I-MIBG scintigrams and REM sleep behavior disorder in Parkinson’s disease. Parkinsonism Relat Disord (2010) 16:683–5.10.1016/j.parkreldis.2010.08.011 PubMed DOI

Boeve B, Silber M, Ferman T, Smith G, Petersen R. Validation of a questionnaire for the diagnosis of REM sleep behavior disorder. Neurology (2002) 58:A509.

Boeve BF, Molano JR, Ferman TJ, Smith GE, Lin S-C, Bieniek K, et al. Validation of the Mayo Sleep Questionnaire to screen for REM sleep behavior disorder in an aging and dementia cohort. Sleep Med (2011) 12:445–53.10.1016/j.sleep.2010.12.009 PubMed DOI PMC

Boeve BF, Molano JR, Ferman TJ, Lin S-C, Bieniek K, Tippmann-Peikert M, et al. Validation of the Mayo Sleep Questionnaire to screen for REM sleep behavior disorder in a community-based sample. J Clin Sleep Med (2013) 9:475–80.10.5664/jcsm.2670 PubMed DOI PMC

Bolitho SJ, Naismith SL, Terpening Z, Grunstein RR, Melehan K, Yee BJ, et al. Investigating rapid eye movement sleep without atonia in Parkinson’s disease using the rapid eye movement sleep behavior disorder screening questionnaire. Mov Disord (2014) 29:736–42.10.1002/mds.25832 PubMed DOI

Frauscher B, Ehrmann L, Zamarian L, Auer F, Mitterling T, Gabelia D, et al. Validation of the Innsbruck REM sleep behavior disorder inventory. Mov Disord (2012) 27:1673–8.10.1002/mds.25223 PubMed DOI

Frauscher B, Nomura T, Duerr S, Ehrmann L, Gschliesser V, Wenning GK, et al. Investigation of autonomic function in idiopathic REM sleep behavior disorder. J Neurol (2012) 259:1056–61.10.1007/s00415-011-6298-0 PubMed DOI

Postuma RB, Arnulf I, Hogl B, Iranzo A, Miyamoto T, Dauvilliers Y, et al. A single-question screen for rapid eye movement sleep behavior disorder: a multicenter validation study. Mov Disord (2012) 27:913–6.10.1002/mds.25037 PubMed DOI PMC

Postuma RB, Lang AE, Gagnon JF, Pelletier A, Montplaisir JY. How does parkinsonism start? Prodromal parksonism motor changes in idiopathic REM sleep behaviour disorder. Brain (2012) 135:1860–70.10.1093/brain/aws093 PubMed DOI

Ma JF, Hou MM, Tang HD, Gao X, Liang L, Zhu LF, et al. REM sleep behavior disorder was associated with Parkinson’s disease: a community-based study. BMC Neurol (2016) 16:123.10.1186/s12883-016-0640-1 PubMed DOI PMC

Chaudhuri KR, Martinez-Martin P, Schapira AHV, Stocchi F, Sethi K, Odin P, et al. International multicenter pilot study of the first comprehensive self-completed nonmotor symptoms questionnaire for Parkinson’s disease: the NMSQuest study. Mov Disord (2006) 21:916–23.10.1002/mds.20844 PubMed DOI

Romenets S, Wolfson C, Galatas C, Pelletier A, Altman R, Wadup L, et al. Validation of the non-motor symptoms questionnaire (NMS-Quest). Parkinsonism Relat Disord (2012) 18:54–8.10.1016/j.parkreldis.2011.08.013 PubMed DOI

Chaudhuri K, Rojo JM, Schapira AHV, Brooks DJ, Stocchi F, Odin P, et al. A proposal for a comprehensive grading of Parkinson’s disease severity combining motor and non-motor assessments: meeting an unmet need. PLoS One (2013) 8:e0150130.10.1371/journal.pone.0150130 PubMed DOI PMC

Evatt ML, Chaudhuri KR, Chou KL, Cubo E, Hinson V, Kompoliti K, et al. Dysautonomia rating scales in Parkinson’s disease: sialorrhea, dysphagia, and constipation – critique and recommendations by movement disorders task force on rating scales for Parkinson’s disease. Mov Disord (2009) 24:635–46.10.1002/mds.22260 PubMed DOI PMC

Chaudhuri KR, Weintraub D, Schrag A, Martinez-Martin P, On Behalf of EUROPAR, The MDS Non-Motor PD Study Group The International Parkinson and Movement Disorder Society–Non-Motor Rating Scale (MDS-NMS): results from the cognitive pre-testing and phases 1 and 2 of an international validation. Mov Disord (2016) 31:S516.

Postuma RB, Gagnon JF, Bertrand JA, Genier Marchand D, Montplaisir J. Parkinson risk in idiopathic REM sleep behavior disorder: preparing for neuroprotective trials. Neurology (2015) 84:1104–13.10.1212/WNL.0000000000001364 PubMed DOI PMC

Postuma RB, Gagnon JF, Vendette M, Montplaisir JY. Markers of neurodegeneration in idiopathic rapid eye movement sleep behaviour disorder and Parkinson’s disease. Brain (2009) 132:3298–307.10.1093/brain/awp244 PubMed DOI

McDade EM, Boot BP, Christianson TJH, Pankratz VS, Boeve BF, Ferman TJ, et al. Subtle gait changes in patients with REM sleep behavior disorder. Mov Disord (2013) 28:1847–53.10.1002/mds.25653 PubMed DOI PMC

Alibiglou L, Videnovic A, Planetta PJ, Vaillancourt DE, MacKinnon CD. Subliminal gait initiation deficits in rapid eye movement sleep behavior disorder: a harbinger of freezing of gait? Mov Disord (2016) 31:1711–9.10.1002/mds.26665 PubMed DOI PMC

Hlavnicka J, Cmejla R, Tykalova T, Sonka K, Ruzicka E, Rusz J. Automated analysis of connected speech reveals early biomarkers of Parkinson’s disease in patients with rapid eye movement sleep behaviour disorder. Sci Rep (2017) 7:12.10.1038/s41598-017-00047-5 PubMed DOI PMC

Rusz J, Hlavnicka J, Tykalova T, Buskova J, Ulmanova O, Ruzicka E, et al. Quantitative assessment of motor speech abnormalities in idiopathic REM sleep behaviour disorder. Sleep Med (2016) 19:141–7.10.1016/j.sleep.2015.07.030 PubMed DOI

Fahn S, Elton RL. Members of the UPDRS Development Committee. Unified Parkinson’s Disease Rating Scale. In: Fahn S, Marsden CD, Calne DB, Lieberman A, editors. Recent Developments in Parkinson’s Disease. (Vol. 2), Florham Park, NJ: MacMillan Healthcare Information; (1987). p. 153–63.

Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, et al. Movement Disorders Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord (2008) 23:2129–70.10.1002/mds.22340 PubMed DOI

Skorvanek M, Ladomirjakova Z, Han V, Lesko N, Feketeova E, Jarcuskova D, et al. Prevalence of prodromal Parkinson’s disease as defined by MDS research criteria among elderly patients undergoing colonoscopy. J Parkinsons Dis (2017) 7:481–9.10.3233/JPD-161036 PubMed DOI

Fantini ML, Postuma RB, Montplaisir J, Ferini-Strambi L. Olfactory deficit in idiopathic rapid eye movements sleep behavior disorder. Brain Res Bull (2006) 70:386–90.10.1016/j.brainresbull.2006.07.008 PubMed DOI

Shin HY, Joo EY, Kim ST, Dhong HJ, Cho JW. Comparison study of olfactory function and substantia nigra hyperechogenicity in idiopathic REM sleep behavior disorder, Parkinson’s disease and normal control. Neurol Sci (2013) 34(6):935–40.10.1007/s10072-012-1164-0 PubMed DOI

Iranzo A, Stefani A, Serradell M, Martí MJ, Lomeña F, Mahlknecht P, et al. Characterization of patients with longstanding idiopathic REM sleep behavior disorder. Neurology (2017) 89:242–8.10.1212/WNL.0000000000004121 PubMed DOI

Barber TR, Lawton M, Rolinski M, Evetts S, Baig F, Ruffmann C, et al. Prodromal Parkinsonism and neurodegenerative risk stratification in REM sleep behavior disorder. Sleep (2017) 40(8):zsx071.10.1093/sleep/zsx071 PubMed DOI PMC

Mahlknecht P, Iranzo A, Högl B, Frauscher B, Müller C, Santamaría J, et al. Olfactory dysfunction predicts early transition to a Lewy body disease in idiopathic RBD. Neurology (2015) 84:654–8.10.1212/WNL.0000000000001265 PubMed DOI

Fereshtehnejad SM, Montplaisir JY, Pelletier A, Gagnon JF, Berg D, Postuma RB. Validation of the MDS research criteria for prodromal Parkinson’s disease: longitudinal assessment in a REM sleep behavior disorder (RBD) cohort. Mov Disord (2017) 32:865–73.10.1002/mds.26989 PubMed DOI

Li Y, Kang W, Yang Q, Zhang L, Zhang L, Dong F, et al. Predictive markers for early conversion of iRBD to neurodegenerative synucleinopathy diseases. Neurology (2017) 88:1493–500.10.1212/WNL.0000000000003838 PubMed DOI PMC

Ferrini-Strambi L, Oertel W, Dauvilliers Y, Postuma RB, Marelli S, Iranzo A, et al. Autonomic symptoms in idiopathic REM behavior disorder: a multicentre case-control study. J Neurol (2014) 261:1112–8.10.1007/s00415-014-7317-8 PubMed DOI

Postuma RB, Gagnon JF, Pelletier A, Montplaisir J. Prodromal autonomic symptoms and signs in Parkinson’s disease and dementia with Lewy bodies. Mov Disord (2013) 28:597–604.10.1002/mds.25445 PubMed DOI

Postuma RB, Iranzo A, Hogl B, Arnulf I, Ferini-Strambi L, Manni R, et al. Risk factors for neurodegeneration in idiopathic rapid eye movement sleep behavior disorder: a multicenter study. Ann Neurol (2015) 77:830–9.10.1002/ana.24385 PubMed DOI PMC

Ferrini-Strambi L, Oldani A, Zucconi M, Smirne S. Cardiac autonomic activity during wakefulness and sleep in REM sleep behavior disorder. Sleep (1996) 19:367–9.10.1093/sleep/19.5.367 PubMed DOI

Postuma RB, Lanfranchi PA, Blais H, Gagnon JF, Montplaisir JY. Cardiac autonomic dysfunction in idiopathic REM sleep behavior disorder. Mov Disord (2010) 25:2304–10.10.1002/mds.23347 PubMed DOI

Lanfranchi PA, Fradette L, Gagnon JF, Colombo R, Montplaisir J. Cardiac autonomic regulation during sleep in idiopathic REM sleep behavior disorder. Sleep (2007) 30:1019–25.10.1093/sleep/30.8.1019 PubMed DOI PMC

Sorensen GL, Mehlsen J, Jennum P. Reduced sympathetic activity in idiopathic rapid-eye-movement sleep behavior disorder and Parkinson’s disease. Auton Neurosci (2013) 179:138–41.10.1016/j.autneu.2013.08.067 PubMed DOI

Sorensen GL, Kempfner J, Zoetmulder M, Sorensen HB, Jennum P. Attenuated heart rate response in REM sleep behavior disorder and Parkinson’s disease. Mov Disord (2012) 27:888–94.10.1002/mds.25012 PubMed DOI

Postuma RB, Berg D. Advances in markers of prodromal Parkinson disease. Nat Rev Neurol (2016) 12:622–34.10.1038/nrneurol.2016.152 PubMed DOI

Arnulf I, Neutel D, Herlin B, Golmard JL, Leu-Semenescu S, Cochen de Cock V, et al. Sleepiness in idiopathic REM sleep behavior disorder and Parkinson disease. Sleep (2015) 38:1529–35.10.5665/sleep.5040 PubMed DOI PMC

Zhou J, Zhang J, Lam SP, Chan JW, Mok V, Chan A, et al. Excessive daytime sleepiness predicts neurodegeneration in idiopathic REM sleep behavior disorder. Sleep (2017) 40:zsx041.10.1093/sleep/zsx041 PubMed DOI

Postuma RB, Gagnon JF, Pelletier A, Montplaisir JY. Insomnia and somnolence in idiopathic RBD: a prospective cohort study. NPJ Parkinsons Dis (2017) 3:9.10.1038/s41531-017-0011-7 PubMed DOI PMC

Frauscher B, Jennum P, Ju YE, Postuma RB, Arnulf I, Cochen De Cock V, et al. Comorbidity and medication in REM sleep behavior disorder: a multicenter case-control study. Neurology (2014) 82:1076–9.10.1212/WNL.0000000000000247 PubMed DOI PMC

Aguirre-Mardones C, Iranzo A, Vilas D, Serradell M, Gaig C, Santamaría J, et al. Prevalence and timeline of nonmotor symptoms in idiopathic rapid eye movement sleep behavior disorder. J Neurol (2015) 262:1568–78.10.1007/s00415-015-7742-3 PubMed DOI

Lam SP, Zhang J, Tsoh J, Li SX, Ho CK, Mok V, et al. REM sleep behavior disorder in psychiatric populations. J Clin Psychiatry (2010) 71:1101–3.10.4088/JCP.l05877gry PubMed DOI

Rutten S, van der Ven PM, Weintraub D, Pontone GM, Leentjens AFG, Berendse HW, et al. Predictors of anxiety in early-stage Parkinson’s disease – results from the first two years of a prospective cohort study. Parkinsonism Relat Disord (2017) 43:49–55.10.1016/j.parkreldis.2017.06.024 PubMed DOI PMC

Oh YS, Kim JS, Chung SW, Song IU, Kim YD, Kim YI, et al. Color vision in Parkinson’s disease and essential tremor. Eur J Neurol (2011) 18:577–83.10.1111/j.1468-1331.2010.03206.x PubMed DOI

Postuma RB, Gagnon JF, Vendette M, Desjardins C, Montplaisir JY. Olfaction and color vision identify impending neurodegeneration in rapid eye movement sleep behavior disorder. Ann Neurol (2011) 69:811–8.10.1002/ana.22282 PubMed DOI

Ferrini-Strambi L, Di Gioia MR, Castronovo V, Oldani A, Zucconi M, Cappa SF. Neuropsychological assessment in idiopathic REM sleep behavior disorder (RBD): does the idiopathic form of RBD really exist? Neurology (2004) 62:41–5.10.1212/01.WNL.0000101726.69701.FA PubMed DOI

Massicotte-Marquez J, Decary A, Gagnon JF, Vendette M, Mathieu A, Postuma RB, et al. Executive dysfunction and memory impairment in idiopathic REM sleep behavior disorder. Neurology (2008) 70:1250–7.10.1212/01.wnl.0000286943.79593.a6 PubMed DOI

Terzaghi M, Zucchella C, Rustioni V, Sinforiani E, Manni R. Cognitive performances and mild cognitive impairment in idiopathic rapid eye movement sleep behavior disorder: results of a longitudinal follow-up study. Sleep (2013) 36:1527–32.10.5665/sleep.3050 PubMed DOI PMC

Bezdíček O, Nikolai T, Nepožitek J, Peřinová P, Kemlink D, Dušek P, et al. Prospective memory impairment in idiopathic REM sleep behavior disorder. Clin Neuropsychol (2017) 26:1–19.10.1080/13854046.2017.1394493 PubMed DOI

Zhang JR, Chen J, Yang ZJ, Zhang HJ, Fu YT, Shen Y, et al. Rapid eye movement sleep behavior disorder symptoms correlate with domains of cognitive impairment in Parkinson’s disease. Chin Med J (Engl) (2016) 129:379–85.10.4103/0366-6999.176077 PubMed DOI PMC

Boot BP, Boeve BF, Roberts RO, Ferman TJ, Geda YE, Pankratz VS, et al. Probable rapid eye movement sleep behavior disorder increases risk for mild cognitive impairment and Parkinson disease: a population-based study. Ann Neurol (2012) 71:49–56.10.1002/ana.22655 PubMed DOI PMC

Marchand D, Montplaisir J, Postuma RB, Rahayel S, Gagnon JF. Detecting the cognitive prodrome of dementia with lewy bodies: a prospective study of REM sleep behavior disorder. Sleep (2017) 40:zsw014.10.1093/sleep/zsw014 PubMed DOI

Manni R, Sinforiani E, Pacchetti C, Zucchella C, Cremascoli R, Terzaghi M. Cognitive dysfunction and REM sleep behavior disorder: key findings in the literature and preliminary longitudinal findings. Int J Psychophysiol (2013) 89:213–7.10.1016/j.ijpsycho.2013.04.003 PubMed DOI

Boeve BF, Silber MH, Ferman TJ, Kokmen E, Smith GE, Ivnik RJ, et al. REM sleep behavior disorder and degenerative dementia: an association likely reflecting Lewy body disease. Neurology (1998) 51:363–70.10.1212/WNL.51.2.363 PubMed DOI

Fantini ML, Farini E, Ortelli P, Zucconi M, Manconi M, Cappa S, et al. Longitudinal study of cognitive function in idiopathic REM sleep behavior disorder. Sleep (2011) 34:619–25. PubMed PMC

Iranzo A, Molinuevo JL, Santamaria J, Serradell M, Marti MJ, Valldeoriola F, et al. Rapid-eye-movement sleep behaviour disorder as an early marker for a neurodegenerative disorder: a descriptive study. Lancet Neurol (2006) 5:572–7.10.1016/S1474-4422(06)70476-8 PubMed DOI

Molano J, Boeve B, Ferman T, Smith G, Parisi J, Dickson D, et al. Mild cognitive impairment associated with limbic and neocortical Lewy body disease: a clinicopathological study. Brain (2010) 133:540–56.10.1093/brain/awp280 PubMed DOI PMC

Shen LH, Liao MH, Tseng YC. Recent advances in imaging of dopaminergic neurons for evaluation of neuropsychiatric disorders. J Biomed Biotechnol (2012) 2012:259349.10.1155/2012/259349 PubMed DOI PMC

Eisensehr I, Linke R, Tatsch K, Kharraz B, Gildehaus JF, Wetter CT, et al. Increased muscle activity during rapid eye movement sleep correlates with decrease of striatal presynaptic dopamine transporters. IPT and IBZM SPECT imaging in subclinical and clinically manifest idiopathic REM sleep behavior disorder, Parkinson’s disease, and controls. Sleep (2003) 26:507–12. PubMed

Uribe-San Martin R, Venegas Francke P, Lopez Illanes F, Jones Gazmuri A, Salazar Rivera J, Godoy Fernndez J, et al. Plasma urate in REM sleep behavior disorder. Mov Disord (2013) 28:1150–1.10.1002/mds.25441 PubMed DOI

Iranzo A, Valldeoriola F, Lomena F, Molinuevo JL, Serradell M, Salamero M, et al. Serial dopamine transporter imaging of nigrostriatal function in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a prospective study. Lancet Neurol (2011) 10:797–805.10.1016/S1474-4422(11)70152-1 PubMed DOI

Miyamoto M, Miyamoto T, Iwanami M, Muramatsu S, Asari S, Nakano I, et al. Preclinical substantia nigra dysfunction in rapid eye movement sleep behaviour disorder. Sleep Med (2012) 13:102–6.10.1016/j.sleep.2011.03.024 PubMed DOI

Iranzo A, Santamaria J, Valldeoriola F, Serradell M, Salamero M, Gaig C, et al. Dopamine transporter imaging deficit predicts early transition to synucleinopathy in idiopathic rapid eye movement sleep behavior disorder. Ann Neurol (2017) 82:419–28.10.1002/ana.25026 PubMed DOI

Heller J, Brcina N, Dogan I, Holtbernd F, Romanzetti S, Schulz JB, et al. Brain imaging findings in idiopathic REM sleep behavior disorder (RBD) – a systematic review on potential biomarkers for neurodegeneration. Sleep Med Rev (2017) 34:23–33.10.1016/j.smrv.2016.06.006 PubMed DOI

Wu P, Yu H, Peng S, Dauvilliers Y, Wang J, Ge J, et al. Consistent abnormalities in metabolic network activity in idiopathic rapid eye movement sleep behaviour disorder. Brain (2014) 137:3122–8.10.1093/brain/awu290 PubMed DOI PMC

Ge J, Wu P, Peng S, Yu H, Zhang H, Guan Y, et al. Assessing cerebral glucose metabolism in patients with idiopathic rapid eye movement sleep behavior disorder. J Cereb Blood Flow Metab (2015) 35:2062–9.10.1038/jcbfm.2015.173 PubMed DOI PMC

Holtbernd F, Gagnon JF, Postuma RB, Ma Y, Tang CC, Feigin A, et al. Abnormal metabolic network activity in REM sleep behavior disorder. Neurology (2014) 82:620–7.10.1212/WNL.0000000000000130 PubMed DOI PMC

Rolinski M, Griffanti L, Piccini P, Roussakis AA, Szewczyk-Krolikowski K, Menke RA, et al. Basal ganglia dysfunction in idiopathic REM sleep behaviour disorder parallels that in early Parkinson’s disease. Brain (2016) 139:2224–34.10.1093/brain/aww124 PubMed DOI PMC

Iranzo A, Lomena F, Stockner H, Valldeoriola F, Vilaseca I, Salamero M, et al. Decreased striatal dopamine transporter uptake and substantia nigra hyperechogenicity as risk markers of synucleinopathy in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a prospective study [corrected]. Lancet Neurol (2010) 9:1070–7.10.1016/S1474-4422(10)70216-7 PubMed DOI

Iranzo A, Stockner H, Serradell M, Seppi K, Valldeoriola F, Frauscher B, et al. Five-year follow-up of substantia nigra echogenicity in idiopathic REM sleep behavior disorder. Mov Disord (2014) 29:1774–80.10.1002/mds.26055 PubMed DOI

Rupprecht S, Walther B, Gudziol H, Steenbeck J, Freesmeyer M, Witte OW, et al. Clinical markers of early nigrostriatal neurodegeneration in idiopathic rapid eye movement sleep behavior disorder. Sleep Med (2013) 14:1064–70.10.1016/j.sleep.2013.06.008 PubMed DOI

Iwanami M, Miyamoto T, Miyamoto M, Hirata K, Takada E. Relevance of substantia nigra hyperechogenicity and reduced odor identification in idiopathic REM sleep behavior disorder. Sleep Med (2010) 11:361–5.10.1016/j.sleep.2009.12.006 PubMed DOI

Miyamoto T, Miyamoto M, Suzuki K, Nishibayashi M, Iwanami M, Hirata K. 123I-MIBG cardiac scintigraphy provides clues to the underlying neurodegenerative disorder in idiopathic REM sleep behavior disorder. Sleep (2008) 31:717–23.10.1093/sleep/31.5.717 PubMed DOI PMC

Ferri R, Rundo F, Silvani A, Zucconi M, Bruni O, Ferini-Strambi L, et al. REM sleep EEG instability in REM sleep behavior disorder and clonazepam effects. Sleep (2017) 40(8):zsx080.10.1093/sleep/zsx080 PubMed DOI

Bang YR, Jeon HJ, Youn S, Yoon IY. Alterations of awake EEG in idiopathic REM sleep behavior disorder without cognitive impairment. Neurosci Lett (2017) 637:64–9.10.1016/j.neulet.2016.11.052 PubMed DOI

Sunwoo JS, Lee S, Kim JH, Lim JA, Kim TJ, Byun JI, et al. Altered functional connectivity in idiopathic rapid eye movement sleep behavior disorder: a resting-state EEG study. Sleep (2017) 40(6):zsx058.10.1093/sleep/zsx058 PubMed DOI

Rodrigues Brazete J, Gagnon JF, Postuma RB, Bertrand JA, Petit D, Montplaisir J. Electroencephalogram slowing predicts neurodegeneration in rapid eye movement sleep behavior disorder. Neurobiol Aging (2016) 37:74–81.10.1016/j.neurobiolaging.2015.10.007 PubMed DOI

Gan-Or Z, Mirelman A, Postuma RB, Arnulf I, Bar-Shira A, Dauvilliers Y, et al. GBA mutations are associated with rapid eye movement sleep behavior disorder. Ann Clin Transl Neurol (2015) 2:941–5.10.1002/acn3.228 PubMed DOI PMC

Fernández-Santiago R, Iranzo A, Gaig C, Serradell M, Fernández M, Tolosa E, et al. Absence of LRRK2 mutations in a cohort of patients with idiopathic REM sleep behavior disorder. Neurology (2016) 86:1072–3.10.1212/WNL.0000000000002304 PubMed DOI

Gan-Or Z, Montplaisir JY, Ross JP, Poirier J, Warby SC, Arnulf I, et al. The dementia-associated APOE ε4 allele is not associated with rapid eye movement sleep behavior disorder. Neurobiol Aging (2017) 49:218.e13–e15.10.1016/j.neurobiolaging.2016.10.002 PubMed DOI

Gan-Or Z, Mohsin N, Girard SL, Montplaisir JY, Ambalavanan A, Strong S, et al. The role of the melanoma gene MC1R in Parkinson disease and REM sleep behavior disorder. Neurobiol Aging (2016) 43:180.e7–13.10.1016/j.neurobiolaging.2016.03.029 PubMed DOI PMC

Toffoli M, Dreussi E, Cecchin E, Valente E, Sanvilli N, Montico M, et al. SNCA 3’UTR genetic variants in patients with Parkinson’s disease and REM sleep behavior disorder. Neurol Sci (2017) 38:1233–40.10.1007/s10072-017-2945-2 PubMed DOI

Gan-Or Z, Girard SL, Noreau A, Leblond CS, Gagnon JF, Arnulf I, et al. Parkinson’s disease genetic loci in rapid eye movement sleep behavior disorder. J Mol Neurosci (2015) 56:617–22.10.1007/s12031-015-0569-7 PubMed DOI

Anderson KN, Vincent A, Smith IE, Shneerson JM. Cerebrospinal fluid hypocretin levels are normal in idiopathic REM sleep behavior disorder. Eur J Neurol (2010) 17:1105–7.10.1111/j.1468-1331.2010.02954.x PubMed DOI

Zhang WJ, Shang XL, Peng J, Zhou MH, Sun WJ. Expression of prion protein in the cerebrospinal fluid of patients with Parkinson’s disease complicated with rapid eye movement sleep behavior disorder. Genet Mol Res (2017) 16:16019022.10.4238/gmr16019022 PubMed DOI

Mollenhauer B, Zimmermann J, Sixel-Doring F, Focke NK, Wicke T, Ebentheuer J, et al. Monitoring of 30 marker candidates in early Parkinson disease as progression markers. Neurology (2016) 87:168–77.10.1212/WNL.0000000000002651 PubMed DOI PMC

Beach T, Adler CH, Sue L, Vedders L, Lue L, White CL, III, et al. Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol (2010) 119:689–702.10.1007/s00401-010-0664-3 PubMed DOI PMC

Gelpi E, Navarro-Otano J, Tolosa E, Gaig C, Compta Y, Rey MJ, et al. Multiple organ involvement by alpha-synuclein pathology in Lewy body disorders. Mov Disord (2014) 29:1010–8.10.1002/mds.25776 PubMed DOI

Shannon KM, Keshavarzian A, Dodiya H, Jakate S, Kordower JH. Is alpha-synuclein in the colon a biomarker for premotor Parkinson disease? Evidence from 3 cases. Mov Disord (2012) 27:716–9.10.1002/mds.25020 PubMed DOI

Stockholm MG, Danielsen EH, Hamilton-Dutoit SJ, Borghammer P. Pathological α-synuclein in gastrointestinal tissues from prodromal Parkinson disease patients. Ann Neurol (2016) 79:940–9.10.1002/ana.24648 PubMed DOI

Sprenger FS, Stefanova N, Gelpi E, Seppi K, Navarro-Otano J, Offner F, et al. Enteric nervous system alpha-synuclein immunoreactivitiy in idiopathic REM sleep behavior disorders. Neurology (2015) 85:1761–8.10.1212/WNL.0000000000002126 PubMed DOI PMC

Leclair-Visonneau L, Clairembault T, Coron E, Le Dily S, Vavasseur F, Dalichampt M, et al. REM sleep behavior disorder is related to enteric neuropathology in Parkinson disease. Neurology (2017) 89:1612–8.10.1212/WNL.0000000000004496 PubMed DOI

Vilas D, Iranzo A, Tolosa E, Aldecoa I, Berenguer J, Vilaseca I, et al. Assessment of α-synuclein in submandibular glands of patients with idiopathic rapid-eye-movement sleep behavior disorder: a case-control study. Lancet Neurol (2016) 15:708–18.10.1016/S1474-4422(16)00080-6 PubMed DOI

Antelmi E, Donadio V, Incensi A, Plazzi G, Liguori R. Skin nerve phosphorylated a-synclein deposits in idiopathic REM sleep behavior disorder. Neurology (2017) 88:2128–31.10.1212/WNL.0000000000003989 PubMed DOI

Doppler K, Jentschke HM, Schulmeyer L, Vadasz D, Janzen A, Luster M, et al. Dermal phospho-alpha-synuclein deposits confirm REM sleep behavior disorder as prodromal Parkinson’s disease. Acta Neuropathol (2017) 133:535–45.10.1007/s00401-017-1684-z PubMed DOI PMC

Schrempf W, Katona I, Dogan I, Felbert VV, Wienecke M, Heller J, et al. Reduced nerve fiber density in patients with REM sleep behavior disorder. Parkinsonism Relat Disord (2016) 29:10–6.10.1016/j.parkreldis.2016.06.003 PubMed DOI

Braczynski AK, Schulz JB, Bach JP. Vaccination strategies in tauopathies and synucleinopathies. J Neurochem (2017) 143:467–88.10.1111/jnc.14207 PubMed DOI

Athauda D, Maclagan K, Skene SS, Bajwa-Joseph M, Letchford D, Chowdhury K, et al. Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet (2017) 390:1664–75.10.1016/S0140-6736(17)31585-4 PubMed DOI PMC

Frauscher B, Mitterling T, Bode A, Ehrmann L, Gabelia D, Biermayr M, et al. A prospective questionnaire study in 100 healthy sleepers: non-bothersome forms of recognizable sleep disorders are still present. J Clin Sleep Med (2014) 10:623–9.10.5664/jcsm.3784 PubMed DOI PMC

Mahlknecht P, Seppi K, Frauscher B, Kiechl S, Willeit J, Stockner H, et al. Probable RBD and association with neurodegenerative disease markers: a population-based study. Mov Disord (2015) 30:1417–21.10.1002/mds.26350 PubMed DOI

Postuma R, Pelletier A, Berg D, Gagnon JF, Escudier F, Montplaisir J. Screening for prodromal Parkinson’s disease in the general community: a sleep-based approach. Sleep Med (2016) 21:101–5.10.1016/j.sleep.2015.12.016 PubMed DOI

Buskova J, Ibarburu V, Sonka K, Ruzicka E. Screening for REM sleep behavior disorder in the general population. Sleep Med (2016) 24:147.10.1016/j.sleep.2016.07.003 PubMed DOI

Genome-wide association study of REM sleep behavior disorder identifies polygenic risk and brain expression effects