Presynaptic Dopaminergic Imaging Characterizes Patients with REM Sleep Behavior Disorder Due to Synucleinopathy

Dario Arnaldi^{1

2}, Pietro Mattioli¹, Stefano Raffa², Matteo Pardini^{1

2}, Federico Massa^{1

2}, Alex Iranzo³, Andres Perissinotti⁴, Aida Niñerola-Baizán⁴, Carles Gaig³, Monica Serradell³, Amaia Muñoz-Lopetegi³, Gerard Mayà³, Claudio Liguori^{5

6}, Mariana Fernandes⁵, Fabio Placidi^{5

6}, Agostino Chiaravalloti^{7

8}, Karel Šonka⁹, Petr Dušek⁹, David Zogala¹⁰, Jiri Trnka¹⁰, Bradley F Boeve¹¹, Toji Miyagawa¹¹, Val J Lowe¹², Tomoyuki Miyamoto¹³, Masayuki Miyamoto¹⁴, Monica Puligheddu¹⁵, Michela Figorilli¹⁵, Alessandra Serra¹⁶, Michele T Hu¹⁷, Johannes C Klein¹⁷, Frederik Bes^{18

19}, Dieter Kunz^{18

19}, Valérie Cochen De Cock^{20

21}, Delphine de Verbizier²², Giuseppe Plazzi^{23

24}, Elena Antelmi²⁵, Michele Terzaghi^{26

27}, Irene Bossert²⁸, Kristína Kulcsárová^{29

30}, Alessio Martino³¹, Alessandro Giuliani³², Marco Pagani³³, Flavio Nobili^#^{1

2}, Silvia Morbelli^#^{2

34}; International REM Sleep Behavior Disorder Study Group

Affiliations

¹ Department of Neuroscience (DINOGMI), University of Genoa, Genoa, Italy.
² IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
³ Neurology Service, Sleep Disorder Centre, Hospital Clínic Barcelona, Universitat de Barcelona, IDIBAPS, CIBERNED: CB06/05/0018-ISCIII, Barcelona, Spain.
⁴ Nuclear Medicine Service, Hospital Clínic Barcelona, Biomedical Research Networking Centre of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), ISCIII, Barcelona, Spain.
⁵ Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
⁶ Sleep Medicine Center, Neurology Unit, University Hospital of Rome Tor Vergata, Rome, Italy.
⁷ Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.
⁸ IRCCS Neuromed, Pozzilli, Italy.
⁹ Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
¹⁰ Institute of Nuclear Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
¹¹ Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
¹² Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.
¹³ Department of Neurology, Dokkyo Medical University Saitama Medical Center, Saitama, Japan.
¹⁴ Center of Sleep Medicine, Dokkyo Medical University Hospital, Tochigi, Japan.
¹⁵ Sleep Disorder Center, Department of Public Health and Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy.
¹⁶ Nuclear Medicine Unit, Department of Medical Science and Public Health, University of Cagliari, Cagliari, Italy.
¹⁷ Division of Neurology, Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, UK.
¹⁸ Clinic of Sleep & Chronomedicine, St. Hedwig-Hospital, Berlin, Germany.
¹⁹ Institute of Physiology, Sleep Research & Clinical Chronobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
²⁰ Sleep and Neurology Department, Beau Soleil Clinic, Montpellier, France.
²¹ EuroMov Digital Health in Motion, Univ Montpellier, IMT Mines Ales, Montpellier, France.
²² Nuclear Medicine Unit, University Hospital of Montpellier, Montpellier, France.
²³ IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
²⁴ Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio-Emilia, Modena, Italy.
²⁵ Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
²⁶ Sleep Medicine and Epilepsy Unit, IRCCS Mondino Foundation, Pavia, Italy.
²⁷ Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
²⁸ Nuclear Medicine Unit, ICS Maugeri SpA SB IRCCS, Pavia, Italy.
²⁹ Department of Neurology, P. J. Safarik University, Kosice, Slovak Republic.
³⁰ Department of Neurology, University Hospital of L. Pasteur, Kosice, Slovak Republic.
³¹ Department of Business and Management, LUISS University, Rome, Italy.
³² Department of Environment and Health, Istituto Superiore di Sanità (Italian National Institute of Health), Rome, Italy.
³³ Institute of Cognitive Sciences and Technologies, Consiglio Nazionale delle Ricerche, Rome, Italy.
³⁴ Nuclear Medicine Unit, Department of Medical Sciences, University of Turin, Turin, Italy.

^# Contributed equally.

PMID: 38466158
PMCID: PMC11102309
DOI: 10.1002/ana.26902

Multicenter Study

Presynaptic Dopaminergic Imaging Characterizes Patients with REM Sleep Behavior Disorder Due to Synucleinopathy

Dario Arnaldi et al. Ann Neurol. 2024 Jun.

. 2024 Jun;95(6):1178-1192.

doi: 10.1002/ana.26902. Epub 2024 Mar 11.

Authors

Affiliations

¹ Department of Neuroscience (DINOGMI), University of Genoa, Genoa, Italy.
² IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
³ Neurology Service, Sleep Disorder Centre, Hospital Clínic Barcelona, Universitat de Barcelona, IDIBAPS, CIBERNED: CB06/05/0018-ISCIII, Barcelona, Spain.
⁴ Nuclear Medicine Service, Hospital Clínic Barcelona, Biomedical Research Networking Centre of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), ISCIII, Barcelona, Spain.
⁵ Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
⁶ Sleep Medicine Center, Neurology Unit, University Hospital of Rome Tor Vergata, Rome, Italy.
⁷ Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.
⁸ IRCCS Neuromed, Pozzilli, Italy.
⁹ Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
¹⁰ Institute of Nuclear Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
¹¹ Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
¹² Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.
¹³ Department of Neurology, Dokkyo Medical University Saitama Medical Center, Saitama, Japan.
¹⁴ Center of Sleep Medicine, Dokkyo Medical University Hospital, Tochigi, Japan.
¹⁵ Sleep Disorder Center, Department of Public Health and Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy.
¹⁶ Nuclear Medicine Unit, Department of Medical Science and Public Health, University of Cagliari, Cagliari, Italy.
¹⁷ Division of Neurology, Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, UK.
¹⁸ Clinic of Sleep & Chronomedicine, St. Hedwig-Hospital, Berlin, Germany.
¹⁹ Institute of Physiology, Sleep Research & Clinical Chronobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
²⁰ Sleep and Neurology Department, Beau Soleil Clinic, Montpellier, France.
²¹ EuroMov Digital Health in Motion, Univ Montpellier, IMT Mines Ales, Montpellier, France.
²² Nuclear Medicine Unit, University Hospital of Montpellier, Montpellier, France.
²³ IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
²⁴ Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio-Emilia, Modena, Italy.
²⁵ Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
²⁶ Sleep Medicine and Epilepsy Unit, IRCCS Mondino Foundation, Pavia, Italy.
²⁷ Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
²⁸ Nuclear Medicine Unit, ICS Maugeri SpA SB IRCCS, Pavia, Italy.
²⁹ Department of Neurology, P. J. Safarik University, Kosice, Slovak Republic.
³⁰ Department of Neurology, University Hospital of L. Pasteur, Kosice, Slovak Republic.
³¹ Department of Business and Management, LUISS University, Rome, Italy.
³² Department of Environment and Health, Istituto Superiore di Sanità (Italian National Institute of Health), Rome, Italy.
³³ Institute of Cognitive Sciences and Technologies, Consiglio Nazionale delle Ricerche, Rome, Italy.
³⁴ Nuclear Medicine Unit, Department of Medical Sciences, University of Turin, Turin, Italy.

^# Contributed equally.

PMID: 38466158
PMCID: PMC11102309
DOI: 10.1002/ana.26902

Abstract

Objective: To apply a machine learning analysis to clinical and presynaptic dopaminergic imaging data of patients with rapid eye movement (REM) sleep behavior disorder (RBD) to predict the development of Parkinson disease (PD) and dementia with Lewy bodies (DLB).

Methods: In this multicenter study of the International RBD study group, 173 patients (mean age 70.5 ± 6.3 years, 70.5% males) with polysomnography-confirmed RBD who eventually phenoconverted to overt alpha-synucleinopathy (RBD due to synucleinopathy) were enrolled, and underwent baseline presynaptic dopaminergic imaging and clinical assessment, including motor, cognitive, olfaction, and constipation evaluation. For comparison, 232 RBD non-phenoconvertor patients (67.6 ± 7.1 years, 78.4% males) and 160 controls (68.2 ± 7.2 years, 53.1% males) were enrolled. Imaging and clinical features were analyzed by machine learning to determine predictors of phenoconversion.

Results: Machine learning analysis showed that clinical data alone poorly predicted phenoconversion. Presynaptic dopaminergic imaging significantly improved the prediction, especially in combination with clinical data, with 77% sensitivity and 85% specificity in differentiating RBD due to synucleinopathy from non phenoconverted RBD patients, and 85% sensitivity and 86% specificity in discriminating PD-converters from DLB-converters. Quantification of presynaptic dopaminergic imaging showed that an empirical z-score cutoff of -1.0 at the most affected hemisphere putamen characterized RBD due to synucleinopathy patients, while a cutoff of -1.0 at the most affected hemisphere putamen/caudate ratio characterized PD-converters.

Interpretation: Clinical data alone poorly predicted phenoconversion in RBD due to synucleinopathy patients. Conversely, presynaptic dopaminergic imaging allows a good prediction of forthcoming phenoconversion diagnosis. This finding may be used in designing future disease-modifying trials. ANN NEUROL 2024;95:1178-1192.

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Figures

**Figure 1.**
A) Relevance of the 14 DaT-SPECT variables in the support vector machine classification between RBD due synucleinopathy (i.e. phenoconverted on a short term) from RBD patients not yet phenoconverted at last follow-up. B) Relevance of the six clinical variables and of the 14 DaT-SPECT variables in the support vector machine classification between RBD due synucleinopathy from RBD patients not yet phenoconverted at last follow-up.

**Figure 2.**
A) Relevance of the 14 DaT-SPECT variables in the support vector machine classification between PD-converters and DLB-converters. B) Relevance of the six clinical variables and of the 14 DaT-SPECT variables in the support vector machine classification between PD-converters and DLB-converters.

See this image and copyright information in PMC

References

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1. Doppler K, Antelmi E, Kuzkina A, et al. Consistent skin α-synuclein positivity in REM sleep behavior disorder - A two center two-to-four-year follow-up study. Parkinsonism Relat Disord. 2021. May;86:108–13. - PubMed
1. Iranzo A, Fairfoul G, Ayudhaya ACN, et al. Detection of α-synuclein in CSF by RT-QuIC in patients with isolated rapid-eye-movement sleep behaviour disorder: a longitudinal observational study. Lancet Neurol. 2021. Mar;20(3):203–12. - PubMed
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Presynaptic Dopaminergic Imaging Characterizes Patients with REM Sleep Behavior Disorder Due to Synucleinopathy

Affiliations

Presynaptic Dopaminergic Imaging Characterizes Patients with REM Sleep Behavior Disorder Due to Synucleinopathy

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical