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Progression models for iRBD phenoconversion: unity is strength

This multicenter study identified the strongest progressors among predictive biomarkers of neurodegeneration in individuals with iRBD and tried to tackle the best biomarkers for future randomized neuroprotective trials.

The neurodegenerative synucleinopathies, including Parkinson’s disease and dementia with Lewy bodies, are characterized by a typically lengthy prodromal period of progressive subclinical motor and non-motor manifestations. Among these, idiopathic REM sleep behavior disorder is a powerful early predictor of eventual phenoconversion, and therefore represents a critical opportunity to intervene with neuroprotective therapy. To inform the design of randomized trials, it is essential to study the natural progression of clinical markers during the prodromal stages of disease in order to establish optimal clinical end points.

In a recent study, Joza and collaborators (1) collected prospective follow-up data from 28 centres of the International REM Sleep Behavior Disorder Study Group representing 12 countries. Polysomnogram-confirmed REM sleep behavior disorder subjects were assessed for prodromal Parkinson’s disease using the Movement Disorder Society criteria and underwent periodic structured sleep, motor, cognitive, autonomic and olfactory testing. Linear mixed-effect modelling was used to estimate annual rates of clinical marker progression stratified by disease subtype, including prodromal Parkinson’s disease and prodromal dementia with Lewy bodies. In addition, we calculated sample size requirements to demonstrate slowing of progression under different anticipated treatment effects.

Overall, 1160 subjects were followed over an average of 3.3 ± 2.2 years. Among clinical variables assessed continuously, motor variables tended to progress faster and required the lowest sample sizes, ranging from 151 to 560 per group (at 50% drug efficacy and 2-year follow-up). By contrast, cognitive, olfactory and autonomic variables showed modest progression with higher variability, resulting in high sample sizes. The most efficient design was a time-to-event analysis using combined milestones of motor and cognitive decline, estimating 117 per group at 50% drug efficacy and 2-year trial duration. Finally, while phenoconverters showed overall greater progression than non-converters in motor, olfactory, cognitive and certain autonomic markers, the only robust difference in progression between Parkinson’s disease and dementia with Lewy bodies phenoconverters was in cognitive testing.

This large multicentre study demonstrates the evolution of motor and non-motor manifestations in prodromal synucleinopathy. These findings provide optimized clinical end points and sample size estimates to inform future neuroprotective trials.

Key Points:

  • Motor assessment using the MDS-UPDRS-III and quantitative motor testing shows the greatest degree of progression over time in iRBD patients
  • There is moderate progression of other non-motor markers, particularly the MDS-UPDRS-II, MMSE and olfactory scores, and limited to no progression in psychiatric and some autonomic measures
  • While phenoconverters show overall greater progression than non-converters in motor, olfactory, cognitive and certain autonomic markers, the only robust difference in progression between PD and DLB-phenoconverters may be in cognitive testing
  • The most efficient trial design for future randomized trials may be a combined end point of a sustained increase in MDS-UPDRS-III and/or a sustained decrease in MoCA score, while stratifying by MDS prodromal PD criteria and extending trial duration from 1 to 2 years yields the largest reductions in sample size.
  • The study emphasizes the importance of multidisciplinary collaboration in the diagnosis and management of iRBD.


  1. Joza S, Hu MT, Jung KY, Kunz D, Stefani A, Dušek P, Terzaghi M, Arnaldi D, Videnovic A, Schiess MC, Hermann W, Lee JY, Ferini-Strambi L, Lewis SJG, Leclair-Visonneau L, Oertel WH, Antelmi E, Sixel-Döring F, Cochen De Cock V, Liguori C, Liu J, Provini F, Puligheddu M, Nicoletti A, Bassetti CLA, Bušková J, Dauvilliers Y, Ferri R, Montplaisir JY, Lawton M, Kim HJ, Bes F, Högl B, Šonka K, Fiamingo G, Pietro M, Lavadia ML, Suescun J, Woo KA, Marelli S, Ehgoetz Martens K, Janzen A, Plazzi G, Mollenhauer B, Fernandes M, Li Y, Cortelli P, Figorilli M, Cicero CE, Schaefer C, Guiraud L, Lanza G, Gagnon JF, Sunwoo JS, Ibrahim A, Girtler N, Trenkwalder C, Baldelli L, Pelletier A, Postuma RB; International REM Sleep Behavior Disorder Study Group. Progression of clinical markers in prodromal Parkinson's disease and dementia with Lewy bodies: a multicentre study. Brain. 2023 Mar 7:awad072. doi: 10.1093/brain/awad072. Epub ahead of print. PMID: 36881989.
  2. Miglis MG, Adler CH, Antelmi E, Arnaldi D, Baldelli L, Boeve BF, Cesari M, Dall'Antonia I, Diederich NJ, Doppler K, Dušek P, Ferri R, Gagnon JF, Gan-Or Z, Hermann W, Högl B, Hu MT, Iranzo A, Janzen A, Kuzkina A, Lee JY, Leenders KL, Lewis SJG, Liguori C, Liu J, Lo C, Ehgoetz Martens KA, Nepozitek J, Plazzi G, Provini F, Puligheddu M, Rolinski M, Rusz J, Stefani A, Summers RLS, Yoo D, Zitser J, Oertel WH. Biomarkers of conversion to α-synucleinopathy in isolated rapid-eye-movement sleep behaviour disorder. Lancet Neurol. 2021 Aug;20(8):671-684. doi: 10.1016/S1474-4422(21)00176-9. PMID: 34302789; PMCID: PMC8600613.
  3. 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. Brain. 2019 Jul 1;142(7):2051-2067. doi: 10.1093/brain/awz111. PMID: 31111143.

Publish on behalf of the Scientific Panel on Sleep-wake disorders