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Plasma NfL, clinical subtypes and motor progression in Parkinson's disease

  • Author Footnotes
    1 Andrea Pilotto and Alberto Imarisio equally contributed to this work.
    Andrea Pilotto
    Correspondence
    Corresponding author. Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, P.zale Spedali Civili, 1 - 25123, Brescia, Italy.
    Footnotes
    1 Andrea Pilotto and Alberto Imarisio equally contributed to this work.
    Affiliations
    Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy

    FERB Onlus, Ospedale S. Isidoro, Trescore Balneario, Bergamo, Italy
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  • Author Footnotes
    1 Andrea Pilotto and Alberto Imarisio equally contributed to this work.
    Alberto Imarisio
    Footnotes
    1 Andrea Pilotto and Alberto Imarisio equally contributed to this work.
    Affiliations
    Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
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  • Francesca Conforti
    Affiliations
    Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
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  • Andrea Scalvini
    Affiliations
    Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
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  • Stefano Masciocchi
    Affiliations
    Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
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  • Sara Nocivelli
    Affiliations
    Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
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  • Rosanna Turrone
    Affiliations
    Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
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  • Stefano Gipponi
    Affiliations
    Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
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  • Elisabetta Cottini
    Affiliations
    Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
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  • Barbara Borroni
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    Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
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  • Maria Cristina Rizzetti
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    FERB Onlus, Ospedale S. Isidoro, Trescore Balneario, Bergamo, Italy
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  • Marina Pizzi
    Affiliations
    Division of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
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  • Laura Bonanni
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    Department of Neuroscience Imaging and Clinical Sciences, University G. D'Annunzio of Chieti-Pescara, Chieti, Italy
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  • Andrea Sturchio
    Affiliations
    James J. and Joan A. Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, OH, USA
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  • Alberto J. Espay
    Affiliations
    James J. and Joan A. Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, OH, USA
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  • Henrik Zetterberg
    Affiliations
    Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden

    Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK

    UK Dementia Research Institute at UCL, London, UK
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  • Nicholas J. Ashton
    Affiliations
    Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    Wallenberg Centre for Molecular and Translational Medicine, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden

    King's College London, Institute of Psychiatry, Psychology & Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London, UK

    NIHR Biomedical Research Centre for Mental Health & Biomedical Research Unit for Dementia at South London & Maudsley NHS Foundation, London, UK
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  • Abdul Hye
    Affiliations
    King's College London, Institute of Psychiatry, Psychology & Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London, UK

    NIHR Biomedical Research Centre for Mental Health & Biomedical Research Unit for Dementia at South London & Maudsley NHS Foundation, London, UK
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  • Alessandro Padovani
    Affiliations
    Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
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  • Author Footnotes
    1 Andrea Pilotto and Alberto Imarisio equally contributed to this work.

      Highlights

      • Increased plasma NfL concentrations are associated with malignant PD phenotype.
      • Plasma NfL levels correlate with motor and non-motor symptoms in PD.
      • Plasma NfL is the best predictor of motor progression in PD compared to clinical subtypes.

      Abstract

      Introduction

      neurofilament light chain (NfL) levels have been proposed as reliable biomarkers of neurodegeneration in Parkinson's disease (PD) but the relationship between plasma NfL, clinical subtypes of PD and motor progression is still debated.

      Methods

      plasma NfL concentration was measured in 45 healthy controls and consecutive 92 PD patients who underwent an extensive motor and non-motor assessment at baseline and after 2 years of follow-up. PD malignant phenotype was defined as the combination of at least two out of cognitive impairment, orthostatic hypotension and REM sleep behavior disorder. PD patients were divided according to the age-adjusted cut-offs of plasma NfL levels into high and normal NfL (H-NfL and N-NfL, respectively). A multivariable linear regression model was used to assess the value of plasma NfL as predictor of 2-years progression in PD.

      Results

      NfL was higher in PD patients than in controls (p = 0.037). H-NfL (n = 16) group exhibited more severe motor and non-motor symptoms, higher prevalence of malignant phenotype and worse motor progression (MDS-UPDRS-III 11.3 vs 0.7 points, p = 0.003) compared to N-NfL group (n = 76). In linear regression analyses plasma NfL emerged as the best predictor of 2-year motor progression compared to age, sex, disease duration, baseline motor/non-motor variables.

      Conclusion

      increased plasma NfL concentration is associated with malignant PD phenotype and faster motor progression. These findings support the role of NfL assessment as a useful measure for stratifying patients with different baseline slopes of decline in future clinical trials of putative disease-modifying treatments.

      Keywords

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      References

        • Espay A.J.
        • Schwarzschild M.A.
        • Tanner C.M.
        • Fernandez H.H.
        • Simon D.K.
        • Leverenz J.B.
        • Merola A.
        • Chen-Plotkin A.
        • Brundin P.
        • Kauffman M.A.
        • Erro R.
        • Kieburtz K.
        • Woo D.
        • Macklin E.A.
        • Standaert D.G.
        • Lang A.E.
        Biomarker-driven phenotyping in Parkinson's disease: a translational missing link in disease-modifying clinical trials.
        Mov. Disord. 2017; 32: 319-324https://doi.org/10.1002/mds.26913
        • Fereshtehnejad S.-M.
        • Romenets S.R.
        • Anang J.B.M.
        • Latreille V.
        • Gagnon J.-F.
        • Postuma R.B.
        New clinical subtypes of Parkinson disease and their longitudinal progression.
        JAMA Neurol. 2015; 72: 863https://doi.org/10.1001/jamaneurol.2015.0703
        • Fereshtehnejad S.-M.
        • Zeighami Y.
        • Dagher A.
        • Postuma R.B.
        Clinical criteria for subtyping Parkinson's disease: biomarkers and longitudinal progression.
        Brain. 2017; 140: 1959-1976https://doi.org/10.1093/brain/awx118
        • Pilotto A.
        • Romagnolo A.
        • Tuazon J.A.
        • Vizcarra J.A.
        • Marsili L.
        • Zibetti M.
        • Rosso M.
        • Rodriguez-Porcel F.
        • Borroni B.
        • Rizzetti M.C.
        • Rossi C.
        • Vizcarra-Escobar D.
        • Molano J.R.
        • Lopiano L.
        • Ceravolo R.
        • Masellis M.
        • Espay A.J.
        • Padovani A.
        • Merola A.
        Orthostatic hypotension and REM sleep behaviour disorder: impact on clinical outcomes in α-synucleinopathies.
        J. Neurol. Neurosurg. Psychiatry. 2019; 90: 1257-1263https://doi.org/10.1136/jnnp-2019-320846
        • Espay A.J.
        • Brundin P.
        • Lang A.E.
        Precision medicine for disease modification in Parkinson disease.
        Nat. Rev. Neurol. 2017; 13: 119-126https://doi.org/10.1038/nrneurol.2016.196
        • Ashton N.
        • Janelidze S.
        • Al Khleifat A.
        • Leuzy A.
        • Van Der Ende E.
        • Karikari T.
        • Benedet A.
        • Pascoal T.
        • Lleó A.
        • Galimberti D.
        • Bonanni L.
        • Pilotto A.
        • Padovani A.
        • Lycke J.
        • Novakova L.
        • Axelsson M.
        • Velayudhan L.
        • Rabinovici G.
        • Miller B.
        • Pariante C.
        • Resnick S.
        • Schöll M.
        • Fernandez-Eulate G.
        Diagnostic Value of Plasma Neurolament Light: A Multicentre Validation Study.
        Unpubl. Data, 2021https://doi.org/10.21203/rs.3.rs-63386/v1
        • Mollenhauer B.
        • Dakna M.
        • Kruse N.
        • Galasko D.
        • Foroud T.
        • Zetterberg H.
        • Schade S.
        • Gera R.G.
        • Wang W.
        • Gao F.
        • Frasier M.
        • Chahine L.M.
        • Coffey C.S.
        • Singleton A.B.
        • Simuni T.
        • Weintraub D.
        • Seibyl J.
        • Toga A.W.
        • Tanner C.M.
        • Kieburtz K.
        • Marek K.
        • Siderowf A.
        • Cedarbaum J.M.
        • Hutten S.J.
        • Trenkwalder C.
        • Graham D.
        Validation of serum neurofilament light chain as a biomarker of Parkinson's disease progression.
        Mov. Disord. 2020; https://doi.org/10.1002/mds.28206
        • Hansson O.
        • Janelidze S.
        • Hall S.
        • Magdalinou N.
        • Lees A.J.
        • Andreasson U.
        • Norgren N.
        • Linder J.
        • Forsgren L.
        • Constantinescu R.
        • Zetterberg H.
        • Blennow K.
        Blood-based NfL: a biomarker for differential diagnosis of parkinsonian disorder.
        Neurology. 2017; 88: 930-937https://doi.org/10.1212/WNL.0000000000003680
        • Lin C.H.
        • Li C.H.
        • Yang K.C.
        • Lin F.J.
        • Wu C.C.
        • Chieh J.J.
        • Chiu M.J.
        Blood NfL: a biomarker for disease severity and progression in Parkinson disease.
        Neurology. 2019; 93 (e1104–e1111)https://doi.org/10.1212/WNL.0000000000008088
        • Postuma R.B.
        • Berg D.
        • Stern M.
        • Poewe W.
        • Olanow C.W.
        • Oertel W.
        • Obeso J.
        • Marek K.
        • Litvan I.
        • Lang A.E.
        • Halliday G.
        • Goetz C.G.
        • Gasser T.
        • Dubois B.
        • Chan P.
        • Bloem B.R.
        • Adler C.H.
        • Deuschl G.
        MDS clinical diagnostic criteria for Parkinson's disease.
        Mov. Disord. 2015; 30: 1591-1601https://doi.org/10.1002/mds.26424
        • Tomlinson C.L.
        • Stowe R.
        • Patel S.
        • Rick C.
        • Gray R.
        • Clarke C.E.
        Systematic review of levodopa dose equivalency reporting in Parkinson's disease.
        Mov. Disord. 2010; 25: 2649-2653https://doi.org/10.1002/mds.23429
        • Emre M.
        • Aarsland D.
        • Brown R.
        • Burn D.J.
        • Duyckaerts C.
        • Mizuno Y.
        • Broe G.A.
        • Cummings J.
        • Dickson D.W.
        • Gauthier S.
        • Goldman J.
        • Goetz C.
        • Korczyn A.
        • Lees A.
        • Levy R.
        • Litvan I.
        • McKeith I.
        • Olanow W.
        • Poewe W.
        • Quinn N.
        • Sampaio C.
        • Tolosa E.
        • Dubois B.
        Clinical diagnostic criteria for dementia associated with Parkinson's disease.
        Mov. Disord. 2007; 22: 1689-1707https://doi.org/10.1002/mds.21507
        • Goetz C.G.
        • Tilley B.C.
        • Shaftman S.R.
        • Stebbins G.T.
        • Fahn S.
        • Martinez-Martin P.
        • Poewe W.
        • Sampaio C.
        • Stern M.B.
        • Dodel R.
        • Dubois B.
        • Holloway R.
        • Jankovic J.
        • Kulisevsky J.
        • Lang A.E.
        • Lees A.
        • Leurgans S.
        • LeWitt P.A.
        • Nyenhuis D.
        • Olanow C.W.
        • Rascol O.
        • Schrag A.
        • Teresi J.A.
        • van Hilten J.J.
        • LaPelle N.
        Movement disorder society UPDRS revision task force, 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: 2129-2170https://doi.org/10.1002/mds.22340
        • Goetz C.G.
        • Poewe W.
        • Rascol O.
        • Sampaio C.
        • Stebbins G.T.
        • Counsell C.
        • Giladi N.
        • Holloway R.G.
        • Moore C.G.
        • Wenning G.K.
        • Yahr M.D.
        • Seidl L.
        Movement disorder society task force on rating scales for Parkinson's disease, movement disorder society task force report on the Hoehn and Yahr staging scale: status and recommendations.
        Mov. Disord. 2004; 19: 1020-1028https://doi.org/10.1002/mds.20213
        • Chaudhuri K.R.
        • Martinez-Martin P.
        • Brown R.G.
        • Sethi K.
        • Stocchi F.
        • Odin P.
        • Ondo W.
        • Abe K.
        • Macphee G.
        • Macmahon D.
        • Barone P.
        • Rabey M.
        • Forbes A.
        • Breen K.
        • Tluk S.
        • Naidu Y.
        • Olanow W.
        • Williams A.J.
        • Thomas S.
        • Rye D.
        • Tsuboi Y.
        • Hand A.
        • Schapira A.H.V.
        The metric properties of a novel non-motor symptoms scale for Parkinson's disease: results from an international pilot study.
        Mov. Disord. 2007; 22: 1901-1911https://doi.org/10.1002/mds.21596
        • Hummel T.
        • Konnerth C.G.
        • Rosenheim K.
        • Kobal G.
        Screening of olfactory function with a four-minute odor identification test: reliability, normative data, and investigations in patients with olfactory loss.
        Ann. Otol. Rhinol. Laryngol. 2001; 110: 976-981
        • Stiasny-Kolster K.
        • Mayer G.
        • Schäfer S.
        • Möller J.C.
        • Heinzel-Gutenbrunner M.
        • Oertel W.H.
        The REM sleep behavior disorder screening questionnaire - a new diagnostic instrument.
        Mov. Disord. 2007; 22: 2386-2393https://doi.org/10.1002/mds.21740
        • Lahrmann H.
        • Cortelli P.
        • Hilz M.
        • Mathias C.J.
        • Struhal W.
        • Tassinari M.
        EFNS guidelines on the diagnosis and management of orthostatic hypotension.
        Eur. J. Neurol. 2006; 13: 930-936https://doi.org/10.1111/j.1468-1331.2006.01512.x
        • Kaufmann H.
        • Goldstein D.S.
        Autonomic dysfunction in Parkinson disease.
        in: Handb. Clin. Neurol. Elsevier B.V., 2013: 259-278https://doi.org/10.1016/B978-0-444-53491-0.00021-3
        • Wenning G.K.
        • Tison F.
        • Seppi K.
        • Sampiao C.
        • Diem A.
        • Yekhlef F.
        • Ghorayeb I.
        • Ory F.
        • Galitzky M.
        • Scaravilli T.
        • Bozi M.
        • Colosimo C.
        • Gilman S.
        • Shults C.W.
        • Quinn N.P.
        • Rascol O.
        • Poewe W.
        • Dupont E.
        • Ostergaard K.
        • Tolosa E.
        • Klockgether T.
        • Dodel R.
        • Abele M.
        • Pollak P.
        • Geser F.
        • Stamfer M.
        • Deuschl G.
        • Daniels C.
        • Coelho M.
        • Pirtosek Z.
        • Brooks D.J.
        • Fowler C.
        • Lees A.
        • Mathias C.J.
        • Revesz T.
        • Gerhard A.
        • Holton J.
        • Schrag A.
        • Wood N.
        • Lindvall O.
        • Widner H.
        • Grabowski M.
        • Nilsson C.F.
        • Oertel W.
        • Eggert K.M.
        • Schimke N.
        • Albanese A.
        • del Sorbo F.
        • Barone P.
        • Carella F.
        • Djaljetti R.
        • Meco G.
        • Berciano J.
        • Gonzalez-Mandly A.
        • Giladi N.
        • Gurevich T.
        • Gasser T.
        • Kamm C.
        • Aquilonius S.M.
        • Bergquist J.
        Development and validation of the unified multiple System Atrophy rating scale (UMSARS).
        Mov. Disord. 2004; 19: 1391-1402https://doi.org/10.1002/mds.20255
        • Pilotto A.
        • Turrone R.
        • Liepelt-Scarfone I.
        • Bianchi M.
        • Poli L.
        • Borroni B.
        • Alberici A.
        • Premi E.
        • Formenti A.
        • Bigni B.
        • Cosseddu M.
        • Cottini E.
        • Berg D.
        • Padovani A.
        Vascular risk factors and cognition in Parkinson's disease.
        J. Alzheim. Dis. 2016; 51: 563-570https://doi.org/10.3233/JAD-150610
        • Cummings J.L.
        The Neuropsychiatric Inventory: assessing psychopathology in dementia patients.
        Neurology. 1997; 48https://doi.org/10.1212/wnl.48.5_suppl_6.10s
        • Beck At B.G.
        • Steer R.A.
        Beck Depression Inventory.
        second ed. manual. The Psychological Corporation, San Antonio (TX)1996
        • Litvan I.
        • Goldman J.G.
        • Tröster A.I.
        • Schmand B.A.
        • Weintraub D.
        • Petersen R.C.
        • Mollenhauer B.
        • Adler C.H.
        • Marder K.
        • Williams-Gray C.H.
        • Aarsland D.
        • Kulisevsky J.
        • Rodriguez-Oroz M.C.
        • Burn D.J.
        • Barker R.A.
        • Emre M.
        Diagnostic criteria for mild cognitive impairment in Parkinson's disease: Movement Disorder Society Task Force guidelines.
        Mov. Disord. 2012; 27: 349-356https://doi.org/10.1002/mds.24893
        • Hodge V.J.
        • Hodge V.J.
        • Austin J.
        A survey of outlier detection methodologies.
        Artif. Intell. Rev. 2004; 22 (2004): 85-126
        • Disanto G.
        • Barro C.
        • Benkert P.
        • Naegelin Y.
        • Schädelin S.
        • Giardiello A.
        • Zecca C.
        • Blennow K.
        • Zetterberg H.
        • Leppert D.
        • Kappos L.
        • Gobbi C.
        • Kuhle J.
        Serum Neurofilament light: a biomarker of neuronal damage in multiple sclerosis.
        Ann. Neurol. 2017; 81: 857-870https://doi.org/10.1002/ana.24954
        • Gaetani L.
        • Blennow K.
        • Calabresi P.
        • Di Filippo M.
        • Parnetti L.
        • Zetterberg H.
        Neurofilament light chain as a biomarker in neurological disorders.
        J. Neurol. Neurosurg. Psychiatry. 2019; 90https://doi.org/10.1136/jnnp-2018-320106
        • Bäckström D.C.
        • Domellöf M.E.
        • Linder J.
        • Olsson B.
        • Öhrfelt A.
        • Trupp M.
        • Zetterberg H.
        • Blennow K.
        • Forsgren L.
        Cerebrospinal fluid patterns and the risk of future dementia in early, incident Parkinson disease.
        JAMA Neurol. 2015; 72: 1175-1182https://doi.org/10.1001/jamaneurol.2015.1449
        • Marques T.M.
        • Van Rumund A.
        • Oeckl P.
        • Kuiperij H.B.
        • Esselink R.A.J.
        • Bloem B.R.
        • Otto M.
        • Verbeek M.M.
        Serum NFL discriminates Parkinson disease from atypical parkinsonisms.
        Neurology. 2019; 92 (E1479–E1486)https://doi.org/10.1212/WNL.0000000000007179
        • Zetterberg H.
        Is there a value of neurofilament light as a biomarker for neurodegeneration in Parkinson's disease?.
        Mov. Disord. 2020; 35: 1111-1112https://doi.org/10.1002/mds.28101
        • Sampedro F.
        • Pérez-González R.
        • Martínez-Horta S.
        • Marín-Lahoz J.
        • Pagonabarraga J.
        • Kulisevsky J.
        Serum neurofilament light chain levels reflect cortical neurodegeneration in de novo Parkinson's disease.
        Park. Relat. Disord. 2020; 74: 43-49https://doi.org/10.1016/j.parkreldis.2020.04.009
        • Pilotto A.
        • Premi E.
        • Caminiti S.P.
        • Presotto L.
        • Turrone R.
        • Alberici A.
        • Paghera B.
        • Borroni B.
        • Padovani A.
        • Perani D.
        Single-subject SPM FDG-PET patterns predict risk of dementia progression in Parkinson disease.
        Neurology. 2018; 90: e1029-e1037https://doi.org/10.1212/WNL.0000000000005161
        • Lerche S.
        • Wurster I.
        • Röben B.
        • Zimmermann M.
        • Machetanz G.
        • Wiethoff S.
        • Dehnert M.
        • Rietschel L.
        • Riebenbauer B.
        • Deuschle C.
        • Stransky E.
        • Lieplt-Scarfone I.
        • Gasser T.
        • Brockmann K.
        CSF NFL in a longitudinally assessed PD cohort: age effects and cognitive trajectories.
        Mov. Disord. 2020; https://doi.org/10.1002/mds.28056