Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study

Ronald B Postuma, Alex Iranzo, Michele Hu, Birgit Högl, Bradley F Boeve, Raffaele Manni, Wolfgang H Oertel, Isabelle Arnulf, Luigi Ferini-Strambi, Monica Puligheddu, Elena Antelmi, Valerie Cochen De Cock, Dario Arnaldi, Brit Mollenhauer, Aleksandar Videnovic, Karel Sonka, Ki-Young Jung, Dieter Kunz, Yves Dauvilliers, Federica Provini, Simon J Lewis, Jitka Buskova, Milena Pavlova, Anna Heidbreder, Jacques Y Montplaisir, Joan Santamaria, Thomas R Barber, Ambra Stefani, Erik K St Louis, Michele Terzaghi, Annette Janzen, Smandra Leu-Semenescu, Guiseppe Plazzi, Flavio Nobili, Friederike Sixel-Doering, Petr Dusek, Frederik Bes, Pietro Cortelli, Kaylena Ehgoetz Martens, Jean-Francois Gagnon, Carles Gaig, Marco Zucconi, Claudia Trenkwalder, Ziv Gan-Or, Christine Lo, Michal Rolinski, Philip Mahlknecht, Evi Holzknecht, Angel R Boeve, Luke N Teigen, Gianpaolo Toscano, Geert Mayer, Silvia Morbelli, Benjamin Dawson, Amelie Pelletier, Ronald B Postuma, Alex Iranzo, Michele Hu, Birgit Högl, Bradley F Boeve, Raffaele Manni, Wolfgang H Oertel, Isabelle Arnulf, Luigi Ferini-Strambi, Monica Puligheddu, Elena Antelmi, Valerie Cochen De Cock, Dario Arnaldi, Brit Mollenhauer, Aleksandar Videnovic, Karel Sonka, Ki-Young Jung, Dieter Kunz, Yves Dauvilliers, Federica Provini, Simon J Lewis, Jitka Buskova, Milena Pavlova, Anna Heidbreder, Jacques Y Montplaisir, Joan Santamaria, Thomas R Barber, Ambra Stefani, Erik K St Louis, Michele Terzaghi, Annette Janzen, Smandra Leu-Semenescu, Guiseppe Plazzi, Flavio Nobili, Friederike Sixel-Doering, Petr Dusek, Frederik Bes, Pietro Cortelli, Kaylena Ehgoetz Martens, Jean-Francois Gagnon, Carles Gaig, Marco Zucconi, Claudia Trenkwalder, Ziv Gan-Or, Christine Lo, Michal Rolinski, Philip Mahlknecht, Evi Holzknecht, Angel R Boeve, Luke N Teigen, Gianpaolo Toscano, Geert Mayer, Silvia Morbelli, Benjamin Dawson, Amelie Pelletier

Abstract

Idiopathic REM sleep behaviour disorder (iRBD) is a powerful early sign of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. This provides an unprecedented opportunity to directly observe prodromal neurodegenerative states, and potentially intervene with neuroprotective therapy. For future neuroprotective trials, it is essential to accurately estimate phenoconversion rate and identify potential predictors of phenoconversion. This study assessed the neurodegenerative disease risk and predictors of neurodegeneration in a large multicentre cohort of iRBD. We combined prospective follow-up data from 24 centres of the International RBD Study Group. At baseline, patients with polysomnographically-confirmed iRBD without parkinsonism or dementia underwent sleep, motor, cognitive, autonomic and special sensory testing. Patients were then prospectively followed, during which risk of dementia and parkinsonsim were assessed. The risk of dementia and parkinsonism was estimated with Kaplan-Meier analysis. Predictors of phenoconversion were assessed with Cox proportional hazards analysis, adjusting for age, sex, and centre. Sample size estimates for disease-modifying trials were calculated using a time-to-event analysis. Overall, 1280 patients were recruited. The average age was 66.3 ± 8.4 and 82.5% were male. Average follow-up was 4.6 years (range = 1-19 years). The overall conversion rate from iRBD to an overt neurodegenerative syndrome was 6.3% per year, with 73.5% converting after 12-year follow-up. The rate of phenoconversion was significantly increased with abnormal quantitative motor testing [hazard ratio (HR) = 3.16], objective motor examination (HR = 3.03), olfactory deficit (HR = 2.62), mild cognitive impairment (HR = 1.91-2.37), erectile dysfunction (HR = 2.13), motor symptoms (HR = 2.11), an abnormal DAT scan (HR = 1.98), colour vision abnormalities (HR = 1.69), constipation (HR = 1.67), REM atonia loss (HR = 1.54), and age (HR = 1.54). There was no significant predictive value of sex, daytime somnolence, insomnia, restless legs syndrome, sleep apnoea, urinary dysfunction, orthostatic symptoms, depression, anxiety, or hyperechogenicity on substantia nigra ultrasound. Among predictive markers, only cognitive variables were different at baseline between those converting to primary dementia versus parkinsonism. Sample size estimates for definitive neuroprotective trials ranged from 142 to 366 patients per arm. This large multicentre study documents the high phenoconversion rate from iRBD to an overt neurodegenerative syndrome. Our findings provide estimates of the relative predictive value of prodromal markers, which can be used to stratify patients for neuroprotective trials.

Keywords: Parkinson’s disease; REM sleep behaviour disorder; dementia with Lewy bodies; multiple system atrophy.

© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.

Figures

Figure 1
Figure 1
Kaplan-Meier plot of disease-free survival (i.e. free of parkinsonism or dementia) among patients with iRBD..
Figure 2
Figure 2
Kaplan-Meier plot of disease-free survival of patients with iRBD stratified according to presence of motor and cognitive markers. Results are presented according to baseline assessment (i.e. patients who develop a de novo marker abnormality over the course of the follow-up remain in the ‘marker-free’ group). Solid line indicates patients with normal values, dashed line abnormal values. Hazard ratios (HRs) are with Cox proportional hazards, adjusting for age, sex, and centre, with 95% confidence intervals in parentheses.
Figure 3
Figure 3
Kaplan-Meier plot of disease-free survival of patients with iRBD stratified according to presence of sleep and psychiatric markers. Solid line indicates patients with normal values, dashed line abnormal values. Hazard ratios (HRs) are with Cox proportional hazards, adjusting for age, sex, and centre, with 95% confidence intervals in parentheses.
Figure 4
Figure 4
Kaplan-Meier plot of disease-free survival of patients with iRBD stratified according to presence of special sensory and autonomic markers. Solid line indicates patients with normal values, dashed line abnormal values. Hazard ratios (HRs) are with Cox proportional hazards, adjusting for age, sex, and centre, with 95% confidence intervals in parentheses.

References

    1. Adler CH, Beach TG. Neuropathological basis of nonmotor manifestations of Parkinson’s disease. Mov Disord 2016; 31: 1114–9.
    1. American Academy of Sleep Medicine TFC, Hauri PJC. The international classification of sleep disorders: diagnostic and coding manual. 2nd edn. Westchester, IL: American Academy of Sleep Medicine; 2007.
    1. 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.
    1. Barber TR, Lawton M, Rolinski M, Evetts S, Baig F, Ruffmann C, et al.Prodromal Parkinsonism and neurodegenerative risk stratification in REM sleep behaviour disorder. Sleep 2017; 40. doi: 10.1093/sleep/zsx071.
    1. Bastien CH, Vallieres A, Morin CM. Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med 2001; 2: 297–307.
    1. Beck AT, Epstein N, Brown G, Steer RA. An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol 1988; 56: 893–7.
    1. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry 1961; 4: 561–71.
    1. Berg D, Postuma RB, Adler CH, Bloem BR, Chan P, Dubois B, et al.MDS research criteria for prodromal Parkinson’s disease. Mov Disord 2015; 30: 1600–11.
    1. Bertrand JA, Bedetti C, Postuma RB, Monchi O, Genier Marchand D, Jubault T, et al.Color discrimination deficits in Parkinson’s disease are related to cognitive impairment and white-matter alterations. Mov Disord 2012; 27: 1781–8.
    1. Chaudhuri KR, Martinez-Martin P, Schapira AH, 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.
    1. Chetelat G, La Joie R, Villain N, Perrotin A, de La Sayette V, Eustache F, et al.Amyloid imaging in cognitively normal individuals, at-risk populations and preclinical Alzheimer’s disease. Neuroimage Clin 2013; 2: 356–65.
    1. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994; 44: 2308–14.
    1. Desrosiers J, Hebert R, Bravo G, Dutil E. The Purdue Pegboard Test: normative data for people aged 60 and over. Disabil Rehabil 1995; 17: 217–24.
    1. Doty RL, Shaman P, Dann M. Development of the University of Pennsylvania Smell Identification Test: a standardized microencapsulated test of olfactory function. Physiol Behav 1984; 32: 489–502.
    1. Dubois B, Burn D, Goetz C, Aarsland D, Brown RG, Broe GA, et al.Diagnostic procedures for Parkinson’s disease dementia: recommendations from the movement disorder society task force. Mov Disord 2007; 22: 2314–24.
    1. Fahn S, Elton R; Members of the UDC. The Unified Parkinson’s Disease Rating Scale. In: Fahn S, Marsden CD, Calne D, Goldstein M, editors. Recent developments in Parkinson’s disease. Florham Park, NJ: MacMillan HealthCare Information; 1987. p. 153–63.
    1. Farnsworth D. The Farnsworth 100-hue test and dichotomous tests for color vision. J Opt Soc Am 1943; 33: 568–78.
    1. Fereshtehnejad SM, Romenets SR, Anang JB, Latreille V, Gagnon JF, Postuma RB. New clinical subtypes of Parkinson disease and their longitudinal progression: a prospective cohort comparison with other phenotypes. JAMA Neurol 2015; 72: 863–73.
    1. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189–98.
    1. Frauscher B, Iranzo A, Gaig C, Gschliesser V, Guaita M, Raffelseder V, et al.Normative EMG values during REM sleep for the diagnosis of REM sleep behavior disorder. Sleep 2012; 35: 835–47.
    1. Gaudry E, Vagg P, Spielberger CD. Validation of the state-trait distinction in anxiety research. Multivariate Behav Res 1975; 10: 331–41.
    1. Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, et al.Movement Disorder 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.
    1. Goldman JG, Postuma R. Premotor and nonmotor features of Parkinson’s disease. Curr Opin Neurol 2014; 27: 434–41.
    1. Haba-Rubio J, Frauscher B, Marques-Vidal P, Toriel J, Tobback N, Andries D, et al.Prevalence and determinants of REM sleep behavior disorder in the general population. Sleep 2018; 41. doi: 10.1093/sleep/zsx197.
    1. Higgins PD, Johanson JF. Epidemiology of constipation in North America: a systematic review. Am J Gastroenterol 2004; 99: 750–9.
    1. Hogl B, Stefani A, Videnovic A. Idiopathic REM sleep behaviour disorder and neurodegeneration—an update. Nat Rev Neurol 2018; 14: 40–55.
    1. Hummel T, Sekinger B, Wolf SR, Pauli E, Kobal G. ‘Sniffin’ Sticks’: olfactory performance assessed by the combined testing of odour identification, odor discrimination and olfactory threshold. Chem Senses 1997; 22: 39–52.
    1. 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.
    1. Jennings D, Siderowf A, Stern M, Seibyl J, Eberly S, Oakes D, et al.Conversion to Parkinson’s disease in the PARS Prodromal Cohort. JAMA Neurol 2017; 74: 933–40.
    1. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991; 14: 540–5.
    1. 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.
    1. Keezer MR, Wolfson C, Postuma RB. Age, gender, comorbidity, and the MDS-UPDRS: results from a population-based study. Neuroepidemiology 2016; 46: 222–7.
    1. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 2001; 16: 606–13.
    1. Li Y, Kang WK, 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.
    1. Mahlknecht P, Iranzo A, Hogl B, Frauscher B, Muller C, Santamaria J, et al.Olfactory dysfunction predicts early transition to a Lewy body disease in idiopathic RBD. Neurology 2015; 84: 654–8.
    1. McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D, et al.Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the dementia with Lewy bodies Consortium. Neurology 2017; 89: 88–100.
    1. Montplaisir J, Gagnon JF, Fantini ML, Postuma RB, Dauvilliers Y, Desautels A, et al.Polysomnographic diagnosis of idiopathic REM sleep behavior disorder. Mov Disord 2010; 25: 2044–51.
    1. Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, et al.The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005; 53: 695–9.
    1. Nutt JG, Lea ES, Van HL, Schuff RA, Sexton GJ. Determinants of tapping speed in normal control subjects and subjects with Parkinson’s disease: differing effects of brief and continued practice. Mov Disord 2000; 15: 843–9.
    1. Podsiadlo D, Richardson S. The timed “Up & Go”: a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc 1991; 39: 142–8.
    1. Postuma RB, Adler CH, Dugger BN, Hentz JG, Shill HA, Driver-Dunckley E, et al.REM sleep behavior disorder and neuropathology in Parkinson’s disease. Mov Disord 2015a; 30: 1413–7.
    1. Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, et al.MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord 2015b; 30: 1591–600.
    1. Postuma RB, Gagnon JF, Bertrand JA, Genier Marchand D, Montplaisir JY. Parkinson risk in idiopathic REM sleep behavior disorder: preparing for neuroprotective trials. Neurology 2015c; 84: 1104–13.
    1. Postuma RB, Gagnon JF, Vendette M, Desjardins C, Montplaisir J. Olfaction and color vision identify impending neurodegeneration in REM behavior disorder. Ann Neurol 2011; 69: 811–8.
    1. Postuma RB, Gagnon JF, Vendette M, Fantini ML, Massicotte-Marquez J, Montplaisir J. Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder. Neurology 2009; 72: 1296–300.
    1. 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 2015d; 77: 830–9.
    1. Postuma RB, Lang AE, Gagnon JF, Pelletier A, Montplaisir JY. How does parkinsonism start? Prodromal parkinsonism motor changes in idiopathic REM sleep behaviour disorder. Brain 2012; 135(Pt 6): 1860–70.
    1. Pujol M, Pujol J, Alonso T, Fuentes A, Pallerola M, Freixenet J, et al.Idiopathic REM sleep behavior disorder in the elderly Spanish community: a primary care center study with a two-stage design using video-polysomnography. Sleep Med 2017; 40: 116–21.
    1. 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 2013a; 14: 744–8.
    1. Schenck CH, Montplaisir JY, Frauscher B, Hogl B, Gagnon JF, Postuma R, et al.Rapid eye movement sleep behavior disorder: devising controlled active treatment studies for symptomatic and neuroprotective therapy—a consensus statement from the International Rapid Eye Movement Sleep Behavior Disorder Study Group. Sleep Med 2013b; 14: 795–806.
    1. Snaith RP, Bridge GW, Hamilton M. The Leeds scales for the self-assessment of anxiety and depression. Br J Psychiatry 1976; 128: 156–65.
    1. Soldatos CR, Dikeos DG, Paparrigopoulos TJ. Athens Insomnia Scale: validation of an instrument based on ICD-10 criteria. J Psychosom Res 2000; 48: 555–60.
    1. Spitzer RL, Kroenke K, Williams JB, Lowe B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med 2006; 166: 1092–7.
    1. Valencia Garcia S, Brischoux F, Clement O, Libourel PA, Arthaud S, Lazarus M, et al.Ventromedial medulla inhibitory neuron inactivation induces REM sleep without atonia and REM sleep behavior disorder. Nat Commun 2018; 9: 504.
    1. Visser M, Marinus J, Stiggelbout AM, van Hilten JJ. Assessment of autonomic dysfunction in Parkinson’s disease: the SCOPA-AUT. Mov Disord 2004; 19: 1306–12.
    1. Wenning GK, Tison F, Seppi K, Sampaio C, Diem A, Yekhlef F, et al.Development and validation of the Unified Multiple System Atrophy Rating Scale (UMSARS). Mov Disord 2004; 19: 1391–402.
    1. Wing YK, Li SX, Mok V, Lam SP, Tsoh J, Chan A, et al.Prospective outcome of rapid eye movement sleep behaviour disorder: psychiatric disorders as a potential early marker of Parkinson’s disease. J Neurol Neurosurg Psychiatry 2012; 83: 470–2.
    1. Yesavage JA, Brink TL, Rose TL, Lum O, Huang V, Adey M, et al.Development and validation of a geriatric depression screening scale: a preliminary report. Journal of psychiatric research 1982; 17: 37–49.
    1. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983; 67: 361–70.

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