Progression of clinical markers in prodromal Parkinson’s disease and dementia with Lewy bodies: a multicentre study
Stephen Joza
(1)
,
Michele Hu
(2)
,
Ki-Young Jung
(3)
,
Dieter Kunz
,
Ambra Stefani
(4)
,
Petr Dušek
(5)
,
Michele Terzaghi
(6, 7)
,
Dario Arnaldi
(8, 9)
,
Aleksandar Videnovic
(10)
,
Mya Schiess
(11)
,
Wiebke Hermann
(12)
,
Jee-Young Lee
(13)
,
Luigi Ferini-Strambi
(14)
,
Simon Lewis
(15)
,
Laurène Leclair-Visonneau
(16, 17)
,
Wolfgang Oertel
(18, 19)
,
Elena Antelmi
(20)
,
Friederike Sixel-Döring
(18, 21)
,
Valérie Cochen de Cock
(22, 23)
,
Claudio Liguori
(24)
,
Jun Liu
(25)
,
Federica Provini
(26, 27)
,
Monica Puligheddu
(28)
,
Alessandra Nicoletti
(29)
,
Claudio Bassetti
(30)
,
Jitka Bušková
(5)
,
Yves Dauvilliers
(31)
,
Raffaele Ferri
(32)
,
Jacques Montplaisir
(33, 34)
,
Michael Lawton
(35)
,
Han-Joon Kim
(3)
,
Frederik Bes
(36)
,
Birgit Högl
(4)
,
Karel Šonka
(5)
,
Giuseppe Fiamingo
(6, 7)
,
Pietro Mattioli
(8)
,
Maria Lorena Lavadia
(10)
,
Jessika Suescun
(11)
,
Kyung Ah Woo
(13)
,
Sara Marelli
(14)
,
Kaylena Ehgoetz Martens
(37)
,
Annette Janzen
(18)
,
Giuseppe Plazzi
(38, 27)
,
Brit Mollenhauer
(21, 38)
,
Mariana Fernandes
(24)
,
Yuanyuan Li
(25)
,
Pietro Cortelli
(26, 27)
,
Michela Figorilli
(39)
,
Calogero Edoardo Cicero
(29)
,
Carolin Schaefer
(30)
,
Lily Guiraud
(31)
,
Giuseppe Lanza
(29)
,
Jean-François Gagnon
(40, 34)
,
Jun-Sang Sunwoo
(41)
,
Abubaker Ibrahim
(4)
,
Nicola Girtler
(8)
,
Claudia Trenkwalder
(21)
,
Luca Baldelli
(26, 27)
,
Amelie Pelletier
(1, 33)
,
Ronald Postuma
(1, 33)
1
Montreal Neurological Institute and Hospital
2 Nuffield Department of Clinical Neurosciences [Oxford]
3 Seoul National University Hospital
4 IMU - Innsbruck Medical University = Medizinische Universität Innsbruck
5 UK - Univerzita Karlova [Praha, Česká republika] = Charles University [Prague, Czech Republic]
6 IRCCS Mondino Foundation
7 UNIPV - Università degli Studi di Pavia [Italia] = University of Pavia [Italy] = Université de Pavie [Italie]
8 DINOGMI - Dipartimento di Neuroscienze, riabilitazione, oftalmologia, genetica e scienze materno-infantili [Genova]
9 Ospedale Policlinico San Martino [Genoa]
10 Massachusetts General Hospital [Boston]
11 University of Texas Health Science Center
12 University of Rostock
13 SNU - Seoul National University [Seoul]
14 UniSR - Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie]
15 The University of Sydney
16 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
17 TENS - The Enteric Nervous System in gut and brain disorders [U1235]
18 Philipps Universität Marburg = Philipps University of Marburg
19 HMGU - Helmholtz Zentrum München = German Research Center for Environmental Health
20 UNIVR - Università degli studi di Verona = University of Verona
21 Paracelsus-Elena-Klinik, Kassel, Germany.
22 Euromov DHM - EuroMov - Digital Health in Motion
23 Clinique Beau Soleil [Montpellier]
24 Università degli Studi di Roma Tor Vergata [Roma, Italia] = University of Rome Tor Vergata [Rome, Italy] = Université de Rome Tor Vergata [Rome, Italie]
25 Shangaï Jiao Tong University [Shangaï]
26 UNIBO - Alma Mater Studiorum Università di Bologna = University of Bologna
27 AOUB - IRCCS Azienda Ospedaliero-Universitaria di Bologna
28 UniCa - Università degli Studi di Cagliari = University of Cagliari
29 Unict - Università degli studi di Catania = University of Catania
30 Inselspital - Bern University Hospital [Berne]
31 CHU Montpellier = Montpellier University Hospital
32 I.R.C.C.S. - "Oasi Maria Santissima" Institute for Research and Prevention of Mental Retardation
33 CEAMS - Centre d'études avancées en Médecine du Sommeil
34 UQAM - Université du Québec à Montréal = University of Québec in Montréal
35 University of Bristol [Bristol]
36 Alexianer Krankenhaus Hedwigshoehe, St. Hedwig Kliniken
37 University of Waterloo [Waterloo]
38 UNIMORE - Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia
39 University of Cagliari
40 Hôpital du Sacré-Coeur de Montréal
41 Kangbuk Samsung Hospital [Seoul, Republic of Korea]
2 Nuffield Department of Clinical Neurosciences [Oxford]
3 Seoul National University Hospital
4 IMU - Innsbruck Medical University = Medizinische Universität Innsbruck
5 UK - Univerzita Karlova [Praha, Česká republika] = Charles University [Prague, Czech Republic]
6 IRCCS Mondino Foundation
7 UNIPV - Università degli Studi di Pavia [Italia] = University of Pavia [Italy] = Université de Pavie [Italie]
8 DINOGMI - Dipartimento di Neuroscienze, riabilitazione, oftalmologia, genetica e scienze materno-infantili [Genova]
9 Ospedale Policlinico San Martino [Genoa]
10 Massachusetts General Hospital [Boston]
11 University of Texas Health Science Center
12 University of Rostock
13 SNU - Seoul National University [Seoul]
14 UniSR - Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie]
15 The University of Sydney
16 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
17 TENS - The Enteric Nervous System in gut and brain disorders [U1235]
18 Philipps Universität Marburg = Philipps University of Marburg
19 HMGU - Helmholtz Zentrum München = German Research Center for Environmental Health
20 UNIVR - Università degli studi di Verona = University of Verona
21 Paracelsus-Elena-Klinik, Kassel, Germany.
22 Euromov DHM - EuroMov - Digital Health in Motion
23 Clinique Beau Soleil [Montpellier]
24 Università degli Studi di Roma Tor Vergata [Roma, Italia] = University of Rome Tor Vergata [Rome, Italy] = Université de Rome Tor Vergata [Rome, Italie]
25 Shangaï Jiao Tong University [Shangaï]
26 UNIBO - Alma Mater Studiorum Università di Bologna = University of Bologna
27 AOUB - IRCCS Azienda Ospedaliero-Universitaria di Bologna
28 UniCa - Università degli Studi di Cagliari = University of Cagliari
29 Unict - Università degli studi di Catania = University of Catania
30 Inselspital - Bern University Hospital [Berne]
31 CHU Montpellier = Montpellier University Hospital
32 I.R.C.C.S. - "Oasi Maria Santissima" Institute for Research and Prevention of Mental Retardation
33 CEAMS - Centre d'études avancées en Médecine du Sommeil
34 UQAM - Université du Québec à Montréal = University of Québec in Montréal
35 University of Bristol [Bristol]
36 Alexianer Krankenhaus Hedwigshoehe, St. Hedwig Kliniken
37 University of Waterloo [Waterloo]
38 UNIMORE - Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia
39 University of Cagliari
40 Hôpital du Sacré-Coeur de Montréal
41 Kangbuk Samsung Hospital [Seoul, Republic of Korea]
Stephen Joza
- Fonction : Auteur
- PersonId : 1347651
- ORCID : 0000-0002-5598-4110
Ki-Young Jung
- Fonction : Auteur
- PersonId : 1471398
- ORCID : 0000-0001-5528-9081
Dieter Kunz
- Fonction : Auteur
- PersonId : 1407408
- ORCID : 0000-0002-0430-5878
Ambra Stefani
- Fonction : Auteur
- PersonId : 791695
- ORCID : 0000-0003-4259-8824
Michele Terzaghi
- Fonction : Auteur
- PersonId : 1407409
- ORCID : 0000-0001-9692-2218
Dario Arnaldi
- Fonction : Auteur
- PersonId : 1329087
- ORCID : 0000-0001-6823-6069
Jee-Young Lee
- Fonction : Auteur
- PersonId : 1471399
- ORCID : 0000-0002-9120-2075
Federica Provini
- Fonction : Auteur
- PersonId : 1159259
- ORCID : 0000-0001-9063-2658
Yves Dauvilliers
- Fonction : Auteur
- PersonId : 758941
- ORCID : 0000-0003-0683-6506
Raffaele Ferri
- Fonction : Auteur
- PersonId : 767723
- ORCID : 0000-0001-6937-3065
Annette Janzen
- Fonction : Auteur
- PersonId : 1364076
- ORCID : 0000-0001-8907-5831
Giuseppe Lanza
- Fonction : Auteur
- PersonId : 1471400
- ORCID : 0000-0002-5659-662X
Jun-Sang Sunwoo
- Fonction : Auteur
- PersonId : 1471401
- ORCID : 0000-0001-8834-0568
Résumé
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 behaviour 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 this study, we combined prospective follow-up data from 28 centres of the International REM Sleep Behavior Disorder Study Group representing 12 countries. Polysomnogram-confirmed REM sleep behaviour 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. We used linear mixed-effect modelling 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.