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Multiple system atrophy

Abstract

Multiple system atrophy (MSA) is a rare neurodegenerative disease that is characterized by neuronal loss and gliosis in multiple areas of the central nervous system including striatonigral, olivopontocerebellar and central autonomic structures. Oligodendroglial cytoplasmic inclusions containing misfolded and aggregated α-synuclein are the histopathological hallmark of MSA. A firm clinical diagnosis requires the presence of autonomic dysfunction in combination with parkinsonism that responds poorly to levodopa and/or cerebellar ataxia. Clinical diagnostic accuracy is suboptimal in early disease because of phenotypic overlaps with Parkinson disease or other types of degenerative parkinsonism as well as with other cerebellar disorders. The symptomatic management of MSA requires a complex multimodal approach to compensate for autonomic failure, alleviate parkinsonism and cerebellar ataxia and associated disabilities. None of the available treatments significantly slows the aggressive course of MSA. Despite several failed trials in the past, a robust pipeline of putative disease-modifying agents, along with progress towards early diagnosis and the development of sensitive diagnostic and progression biomarkers for MSA, offer new hope for patients.

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Fig. 1: Oligodendroglial and neuronal pathology in MSA.
Fig. 2: Distribution and progression of pathology in subtypes of MSA.
Fig. 3: Pathophysiological mechanisms contributing to glial and neuronal pathology in MSA.
Fig. 4: Natural history of MSA.
Fig. 5: Imaging findings in MSA.

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References

  1. Fanciulli, A. & Wenning, G. K. Multiple-system atrophy. N. Engl. J. Med. 372, 249–263 (2015).

    PubMed  Google Scholar 

  2. Quinn, N. Multiple system atrophy–the nature of the beast. J. Neurol. Neurosurg. Psychiatry https://doi.org/10.1136/jnnp.52.suppl.78 (1989).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Graham, J. G. & Oppenheimer, D. R. Orthostatic hypotension and nicotine sensitivity in a case of multiple system atrophy. J. Neurol. Neurosurg. Psychiatry 32, 28–34 (1969).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Papp, M. I., Kahn, J. E. & Lantos, P. L. Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J. Neurol. Sci. 94, 79–100 (1989). Description of GCIs in patients with striatonigral degeneration, olivopontocerebellar atrophy and Shy–Drager syndrome providing evidence that these three syndromes are different manifestations of MSA.

    CAS  PubMed  Google Scholar 

  5. Spillantini, M. G. et al. Filamentous α-synuclein inclusions link multiple system atrophy with Parkinson’s disease and dementia with Lewy bodies. Neurosci. Lett. 251, 205–208 (1998). This is the first report that α-synuclein is the major component of GCI in MSA.

    CAS  PubMed  Google Scholar 

  6. Bjornsdottir, A., Gudmundsson, G., Blondal, H. & Olafsson, E. Incidence and prevalence of multiple system atrophy: a nationwide study in Iceland. J. Neurol. Neurosurg. Psychiatry 84, 136–140 (2013).

    PubMed  Google Scholar 

  7. Bower, J. H., Maraganore, D. M., McDonnell, S. K. & Rocca, W. A. Incidence of progressive supranuclear palsy and multiple system atrophy in Olmsted County, Minnesota, 1976 to 1990. Neurology 49, 1284–1288 (1997).

    CAS  PubMed  Google Scholar 

  8. Chrysostome, V. et al. Epidemiology of multiple system atrophy: a prevalence and pilot risk factor study in Aquitaine, France. Neuroepidemiology 23, 201–208 (2004).

    CAS  PubMed  Google Scholar 

  9. Schrag, A., Ben-Shlomo, Y. & Quinn, N. P. Prevalence of progressive supranuclear palsy and multiple system atrophy: a cross-sectional study. Lancet 354, 1771–1775 (1999).

    CAS  PubMed  Google Scholar 

  10. GBD 2016 Parkinson’s Disease Collaborators. Global, regional, and national burden of Parkinson’s disease, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 17, 939–953 (2018).

    Google Scholar 

  11. Wenning, G. K. et al. The natural history of multiple system atrophy: a prospective European cohort study. Lancet Neurol. 12, 264–274 (2013).

    PubMed  PubMed Central  Google Scholar 

  12. Low, P. A. et al. Natural history of multiple system atrophy in the USA: a prospective cohort study. Lancet Neurol. 14, 710–719 (2015).

    PubMed  PubMed Central  Google Scholar 

  13. Watanabe, H. et al. Progression and prognosis in multiple system atrophy: an analysis of 230 Japanese patients. Brain 125, 1070–1083 (2002).

    PubMed  Google Scholar 

  14. Gatto, E. et al. Pan-American Consortium of Multiple System Atrophy (PANMSA). A Pan-American multicentre cohort study of multiple system atrophy. J. Parkinsons Dis. 4, 693–698 (2014).

    PubMed  Google Scholar 

  15. Wenning, G. K., Tison, F., Ben Shlomo, Y., Daniel, S. E. & Quinn, N. P. Multiple system atrophy: a review of 203 pathologically proven cases. Mov. Disord. 12, 133–147 (1997).

    CAS  PubMed  Google Scholar 

  16. Batla, A. et al. Young-onset multiple system atrophy: clinical and pathological features. Mov. Disord. 33, 1099–1107 (2018).

    CAS  PubMed  Google Scholar 

  17. Hara, K. et al. Multiplex families with multiple system atrophy. Arch. Neurol. 64, 545–551 (2007).

    PubMed  Google Scholar 

  18. Wullner, U., Schmitt, I., Kammal, M., Kretzschmar, H. A. & Neumann, M. Definite multiple system atrophy in a German family. J. Neurol. Neurosurg. Psychiatry 80, 449–450 (2009).

    CAS  PubMed  Google Scholar 

  19. Multiple-System Atrophy Research Collaborators. Mutations in COQ2 in familial and sporadic multiple-system atrophy. N. Engl. J. Med. 369, 233–244 (2013).

    Google Scholar 

  20. Stankovic, I. et al. Laboratory-supported multiple system atrophy beyond autonomic function testing and imaging: a systematic review by the MoDiMSA Study Group. Mov. Disord. Clin. Pract. 8, 322–340 (2021).

    PubMed  PubMed Central  Google Scholar 

  21. Sailer, A. et al. A genome-wide association study in multiple system atrophy. Neurology 87, 1591–1598 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Gu, X. et al. Analysis of GWAS-linked variants in multiple system atrophy. Neurobiol. Aging 67, 201.e1–201.e4 (2018).

    CAS  Google Scholar 

  23. Sharma, M., Wenning, G. & Kruger, R., European Multiple-System Atrophy Study Group. Mutant COQ2 in multiple-system atrophy. N. Engl. J. Med. 371, 80–81 (2014).

    CAS  PubMed  Google Scholar 

  24. Zhao, Q. et al. Association of the COQ2 V393A variant with risk of multiple system atrophy in East Asians: a case-control study and meta-analysis of the literature. Neurol. Sci. 37, 423–430 (2016).

    PubMed  Google Scholar 

  25. Porto, K. J. et al. COQ2 V393A confers high risk susceptibility for multiple system atrophy in East Asian population. J. Neurol. Sci. 429, 117623 (2021).

    CAS  PubMed  Google Scholar 

  26. Sasaki, H. et al. Copy number loss of (src homology 2 domain containing)-transforming protein 2 (SHC2) gene: discordant loss in monozygotic twins and frequent loss in patients with multiple system atrophy. Mol. Brain 4, 24 (2011).

    PubMed  PubMed Central  Google Scholar 

  27. Ferguson, M. C. et al. SHC2 gene copy number in multiple system atrophy (MSA). Clin. Auton. Res. 24, 25–30 (2014).

    PubMed  Google Scholar 

  28. Bourinaris, T. & Houlden, H. C9orf72 and its relevance in parkinsonism and movement disorders: a comprehensive review of the literature. Mov. Disord. Clin. Pract. 5, 575–585 (2018).

    PubMed  PubMed Central  Google Scholar 

  29. Seo, J. H. et al. A case-control study of multiple system atrophy in Korean patients. Mov. Disord. 25, 1953–1959 (2010).

    PubMed  Google Scholar 

  30. Vanacore, N. et al. Case-control study of multiple system atrophy. Mov. Disord. 20, 158–163 (2005).

    PubMed  Google Scholar 

  31. Vidal, J. S. et al. Risk factors of multiple system atrophy: a case-control study in French patients. Mov. Disord. 23, 797–803 (2008).

    PubMed  Google Scholar 

  32. Tseng, F. S., Deng, X., Ong, Y. L., Li, H. H. & Tan, E. K. Multiple system atrophy (MSA) and smoking: a meta-analysis and mechanistic insights. Aging 12, 21959–21970 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Jackson, L. et al. Earlier age of onset in multiple system atrophy with smoking and heavy alcohol use. Parkinsonism Relat. Disord. 66, 212–215 (2019).

    PubMed  PubMed Central  Google Scholar 

  34. Starhof, C., Hejl, A. M., Korbo, L., Winge, K. & Friis, S. Risk of multiple system atrophy and the use of anti-inflammatory drugs: a Danish register-based case-control study. Neuroepidemiology 54, 58–63 (2020).

    PubMed  Google Scholar 

  35. Fujiwara, H. et al. α-Synuclein is phosphorylated in synucleinopathy lesions. Nat. Cell Biol. 4, 160–164 (2002).

    CAS  PubMed  Google Scholar 

  36. Trojanowski, J. Q. & Revesz, T., Neuropathology Working Group on MSA. Proposed neuropathological criteria for the post mortem diagnosis of multiple system atrophy. Neuropathol. Appl. Neurobiol. 33, 615–620 (2007).

    CAS  PubMed  Google Scholar 

  37. Ozawa, T. et al. The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations. Brain 127, 2657–2671 (2004).

    PubMed  Google Scholar 

  38. Song, Y. J. et al. p25α relocalizes in oligodendroglia from myelin to cytoplasmic inclusions in multiple system atrophy. Am. J. Pathol. 171, 1291–1303 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Ota, K. et al. Relocation of p25α/tubulin polymerization promoting protein from the nucleus to the perinuclear cytoplasm in the oligodendroglia of sporadic and COQ2 mutant multiple system atrophy. Acta Neuropathol. Commun. 2, 136 (2014).

    PubMed  PubMed Central  Google Scholar 

  40. Lantos, P. L. & Papp, M. I. Cellular pathology of multiple system atrophy: a review. J. Neurol. Neurosurg. Psychiatry 57, 129–133 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Cykowski, M. D. et al. Expanding the spectrum of neuronal pathology in multiple system atrophy. Brain 138, 2293–2309 (2015).

    PubMed  PubMed Central  Google Scholar 

  42. Sekiya, H. et al. Wide distribution of alpha-synuclein oligomers in multiple system atrophy brain detected by proximity ligation. Acta Neuropathol. 137, 455–466 (2019).

    CAS  PubMed  Google Scholar 

  43. Jellinger, K. A., Seppi, K. & Wenning, G. K. Grading of neuropathology in multiple system atrophy: proposal for a novel scale. Mov. Disord. 20, S29–S36 (2005).

    PubMed  Google Scholar 

  44. Schweighauser, M. et al. Structures of α-synuclein filaments from multiple system atrophy. Nature 585, 464–469 (2020). This study demonstrates using cryoelectron microscopy that GCI in MSA are composed of two types of α-synuclein filaments, each consisting of two protofibrils. MSA fibrils are distinct from those in Lewy body dementia.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Shahnawaz, M. et al. Discriminating α-synuclein strains in Parkinson’s disease and multiple system atrophy. Nature 578, 273–277 (2020). This study discriminated between samples of cerebrospinal fluid from patients with PD and those from patients with MSA by α-synuclein protein misfolding cyclic amplification with an overall sensitivity of 95.4%.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Araki, K. et al. The secondary structural difference between Lewy body and glial cytoplasmic inclusion in autopsy brain with synchrotron FTIR micro-spectroscopy. Sci. Rep. 10, 19423 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Van der Perren, A. et al. The structural differences between patient-derived α-synuclein strains dictate characteristics of Parkinson’s disease, multiple system atrophy and dementia with Lewy bodies. Acta Neuropathol. 139, 977–1000 (2020).

    PubMed  PubMed Central  Google Scholar 

  48. Candelise, N., Baiardi, S., Franceschini, A., Rossi, M. & Parchi, P. Towards an improved early diagnosis of neurodegenerative diseases: the emerging role of in vitro conversion assays for protein amyloids. Acta Neuropathol. Commun. 8, 117 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Asi, Y. T. et al. Alpha-synuclein mRNA expression in oligodendrocytes in MSA. Glia 62, 964–970 (2014).

    PubMed  PubMed Central  Google Scholar 

  50. Djelloul, M. et al. Alpha-synuclein expression in the oligodendrocyte lineage: an in vitro and in vivo study using rodent and human models. Stem Cell Rep. 5, 174–184 (2015).

    CAS  Google Scholar 

  51. Hass, E. W. et al. Robust α-synuclein pathology in select brainstem neuronal populations is a potential instigator of multiple system atrophy. Acta Neuropathol. Commun. 9, 80 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Kisos, H., Pukass, K., Ben-Hur, T., Richter-Landsberg, C. & Sharon, R. Increased neuronal alpha-synuclein pathology associates with its accumulation in oligodendrocytes in mice modeling α-synucleinopathies. PLoS ONE 7, e46817 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Reyes, J. F. et al. Alpha-synuclein transfers from neurons to oligodendrocytes. Glia 62, 387–398 (2014).

    PubMed  Google Scholar 

  54. Mavroeidi, P. et al. Endogenous oligodendroglial alpha-synuclein and TPPP/p25α orchestrate alpha-synuclein pathology in experimental multiple system atrophy models. Acta Neuropathol. 138, 415–441 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Peelaerts, W. et al. α-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 522, 340–344 (2015).

    CAS  PubMed  Google Scholar 

  56. Fellner, L. et al. Limited effects of dysfunctional macroautophagy on the accumulation of extracellularly derived α-synuclein in oligodendroglia: implications for MSA pathogenesis. BMC Neurosci. 19, 32 (2018).

    PubMed  PubMed Central  Google Scholar 

  57. Ferreira, N. et al. Multiple system atrophy-associated oligodendroglial protein p25α stimulates formation of novel α-synuclein strain with enhanced neurodegenerative potential. Acta Neuropathol. 142, 87–115 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Yu, Z. et al. Reduced oligodendrocyte exosome secretion in multiple system atrophy involves SNARE dysfunction. Brain 143, 1780–1797 (2020).

    PubMed  PubMed Central  Google Scholar 

  59. Prusiner, S. B. et al. Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism. Proc. Natl Acad. Sci. USA 112, E5308–E5317 (2015). This study shows that inoculation with brain homogenates from patients with MSA induces a progressive neuronal (but not oligodendroglial) synucleinopathy in heterozygous M83+/− transgenic mice that overexpress human A53T-mutated α-synuclein in neurons.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Dhillon, J. S. et al. Comparative analyses of the in vivo induction and transmission of α-synuclein pathology in transgenic mice by MSA brain lysate and recombinant α-synuclein fibrils. Acta Neuropathol. Commun. 7, 80 (2019).

    PubMed  PubMed Central  Google Scholar 

  61. Sargent, D. et al. ‘Prion-like’ propagation of the synucleinopathy of M83 transgenic mice depends on the mouse genotype and type of inoculum. J. Neurochem. 143, 126–135 (2017).

    CAS  PubMed  Google Scholar 

  62. Peng, C. et al. Cellular milieu imparts distinct pathological α-synuclein strains in α-synucleinopathies. Nature 557, 558–563 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Tarutani, A., Arai, T., Murayama, S., Hisanaga, S. I. & Hasegawa, M. Potent prion-like behaviors of pathogenic α-synuclein and evaluation of inactivation methods. Acta Neuropathol. Commun. 6, 29 (2018).

    PubMed  PubMed Central  Google Scholar 

  64. Uemura, N. et al. Slow progressive accumulation of oligodendroglial alpha-synuclein (α-Syn) pathology in synthetic α-Syn fibril-induced mouse models of synucleinopathy. J. Neuropathol. Exp. Neurol. 78, 877–890 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Teil, M. et al. Brain injections of glial cytoplasmic inclusions induce a multiple system atrophy-like pathology. Brain 145, 1001–1017 (2021). This study demonstrates that inoculation with GCI-enriched fractions from patients with MSA induces moderate neuropathological alterations in non-human primates after 2 years of follow-up that recapitulate some early features of MSA.

    Google Scholar 

  66. Compta, Y. et al. Cerebrospinal fluid levels of coenzyme Q10 are reduced in multiple system atrophy. Parkinsonism Relat. Disord. 46, 16–23 (2018).

    PubMed  Google Scholar 

  67. Barca, E. et al. Decreased coenzyme Q10 levels in multiple system atrophy cerebellum. J. Neuropathol. Exp. Neurol. 75, 663–672 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Perez-Rodriguez, D. et al. Investigation of somatic CNVs in brains of synucleinopathy cases using targeted SNCA analysis and single cell sequencing. Acta Neuropathol. Commun. 7, 219 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Perez-Soriano, A. & Marti, M. J. Mini-review: the MSA transcriptome. Neurosci. Lett. 743, 135586 (2021).

    CAS  PubMed  Google Scholar 

  70. Rydbirk, R. et al. Epigenetic modulation of AREL1 and increased HLA expression in brains of multiple system atrophy patients. Acta Neuropathol. Commun. 8, 29 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Bettencourt, C. et al. White matter DNA methylation profiling reveals deregulation of HIP1, LMAN2, MOBP, and other loci in multiple system atrophy. Acta Neuropathol. 139, 135–156 (2020).

    CAS  PubMed  Google Scholar 

  72. Todorich, B., Pasquini, J. M., Garcia, C. I., Paez, P. M. & Connor, J. R. Oligodendrocytes and myelination: the role of iron. Glia 57, 467–478 (2009).

    PubMed  Google Scholar 

  73. Dexter, D. T. et al. Alterations in the levels of iron, ferritin and other trace metals in Parkinson’s disease and other neurodegenerative diseases affecting the basal ganglia. Brain 114, 1953–1975 (1991).

    PubMed  Google Scholar 

  74. Visanji, N. P. et al. Iron deficiency in parkinsonism: region-specific iron dysregulation in Parkinson’s disease and multiple system atrophy. J. Parkinsons Dis. 3, 523–537 (2013).

    CAS  PubMed  Google Scholar 

  75. Lee, J. H., Kim, T. H., Mun, C. W., Kim, T. H. & Han, Y. H. Progression of subcortical atrophy and iron deposition in multiple system atrophy: a comparison between clinical subtypes. J. Neurol. 262, 1876–1882 (2015).

    PubMed  Google Scholar 

  76. Wang, Y. et al. Different iron-deposition patterns of multiple system atrophy with predominant parkinsonism and idiopathetic Parkinson diseases demonstrated by phase-corrected susceptibility-weighted imaging. AJNR Am. J. Neuroradiol. 33, 266–273 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Peran, P. et al. MRI supervised and unsupervised classification of Parkinson’s disease and multiple system atrophy. Mov. Disord. 33, 600–608 (2018).

    PubMed  Google Scholar 

  78. Seki, M. et al. Diagnostic potential of multimodal MRI markers in atypical parkinsonian disorders. J. Parkinsons Dis. 9, 681–691 (2019).

    CAS  PubMed  Google Scholar 

  79. Mills, J. D., Kim, W. S., Halliday, G. M. & Janitz, M. Transcriptome analysis of grey and white matter cortical tissue in multiple system atrophy. Neurogenetics 16, 107–122 (2015).

    CAS  PubMed  Google Scholar 

  80. Finkelstein, D. I. et al. The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease. Acta Neuropathol. Commun. 5, 53 (2017).

    PubMed  PubMed Central  Google Scholar 

  81. Shukla, J. J. et al. Therapeutic potential of iron modulating drugs in a mouse model of multiple system atrophy. Neurobiol. Dis. 159, 105509 (2021).

    CAS  PubMed  Google Scholar 

  82. Heras-Garvin, A. et al. ATH434 reduces α-synuclein-related neurodegeneration in a murine model of multiple system atrophy. Mov. Disord. https://doi.org/10.1002/mds.28714 (2021).

    Article  PubMed  Google Scholar 

  83. Schwarz, L., Goldbaum, O., Bergmann, M., Probst-Cousin, S. & Richter-Landsberg, C. Involvement of macroautophagy in multiple system atrophy and protein aggregate formation in oligodendrocytes. J. Mol. Neurosci. 47, 256–266 (2012).

    CAS  PubMed  Google Scholar 

  84. Tanji, K. et al. Alteration of autophagosomal proteins in the brain of multiple system atrophy. Neurobiol. Dis. 49, 190–198 (2013).

    CAS  PubMed  Google Scholar 

  85. Miki, Y. et al. AMBRA1, a novel α-synuclein-binding protein, is implicated in the pathogenesis of multiple system atrophy. Brain Pathol. 28, 28–42 (2018).

    CAS  PubMed  Google Scholar 

  86. Odagiri, S. et al. Autophagic adapter protein NBR1 is localized in Lewy bodies and glial cytoplasmic inclusions and is involved in aggregate formation in α-synucleinopathy. Acta Neuropathol. 124, 173–186 (2012).

    CAS  PubMed  Google Scholar 

  87. Monzio Compagnoni, G. et al. Mitochondrial dysregulation and impaired autophagy in iPSC-derived dopaminergic neurons of multiple system atrophy. Stem Cell Rep. 11, 1185–1198 (2018).

    CAS  Google Scholar 

  88. Kaji, S. et al. Pathological endogenous α-synuclein accumulation in oligodendrocyte precursor cells potentially induces inclusions in multiple system atrophy. Stem Cell Rep. 10, 356–365 (2018).

    CAS  Google Scholar 

  89. Arotcarena, M. L. et al. Transcription factor EB overexpression prevents neurodegeneration in experimental synucleinopathies. JCI Insight https://doi.org/10.1172/jci.insight.129719 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Nykjaer, C. H., Brudek, T., Salvesen, L. & Pakkenberg, B. Changes in the cell population in brain white matter in multiple system atrophy. Mov. Disord. 32, 1074–1082 (2017).

    CAS  PubMed  Google Scholar 

  91. Salvesen, L. et al. Changes in total cell numbers of the basal ganglia in patients with multiple system atrophy – a stereological study. Neurobiol. Dis. 74, 104–113 (2015).

    PubMed  Google Scholar 

  92. Ahmed, Z., Asi, Y. T., Lees, A. J., Revesz, T. & Holton, J. L. Identification and quantification of oligodendrocyte precursor cells in multiple system atrophy, progressive supranuclear palsy and Parkinson’s disease. Brain Pathol. 23, 263–273 (2013).

    PubMed  Google Scholar 

  93. May, V. E. et al. α-Synuclein impairs oligodendrocyte progenitor maturation in multiple system atrophy. Neurobiol. Aging 35, 2357–2368 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Del Campo, N. et al. Broad white matter impairment in multiple system atrophy. Hum. Brain Mapp. 42, 357–366 (2021).

    PubMed  Google Scholar 

  95. Santaella, A. et al. Cerebrospinal fluid myelin basic protein is elevated in multiple system atrophy. Parkinsonism Relat. Disord. 76, 80–84 (2020).

    PubMed  Google Scholar 

  96. Song, Y. J. et al. Degeneration in different parkinsonian syndromes relates to astrocyte type and astrocyte protein expression. J. Neuropathol. Exp. Neurol. 68, 1073–1083 (2009).

    CAS  PubMed  Google Scholar 

  97. Ishizawa, K. et al. Microglial activation parallels system degeneration in multiple system atrophy. J. Neuropathol. Exp. Neurol. 63, 43–52 (2004).

    PubMed  Google Scholar 

  98. Li, F., Ayaki, T., Maki, T., Sawamoto, N. & Takahashi, R. NLRP3 inflammasome-related proteins are upregulated in the putamen of patients with multiple system atrophy. J. Neuropathol. Exp. Neurol. 77, 1055–1065 (2018).

    CAS  PubMed  Google Scholar 

  99. Williams, G. P. et al. T cell infiltration in both human multiple system atrophy and a novel mouse model of the disease. Acta Neuropathol. 139, 855–874 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Rydbirk, R. et al. Cytokine profiling in the prefrontal cortex of Parkinson’s disease and multiple system atrophy patients. Neurobiol. Dis. 106, 269–278 (2017).

    CAS  PubMed  Google Scholar 

  101. Jucaite, A. et al. Glia imaging differentiates multiple system atrophy from Parkinson’s disease: a positron emission tomography study with [(11)C]PBR28 and machine learning analysis. Mov. Disord. https://doi.org/10.1002/mds.28814 (2021). This is the first report of a machine learning analysis of glial PET imaging with [11C]PBR28 discriminating patients with MSA from those with PD with high diagnostic accuracy.

    Article  PubMed  Google Scholar 

  102. Compta, Y. et al. Cerebrospinal fluid cytokines in multiple system atrophy: a cross-sectional Catalan MSA registry study. Parkinsonism Relat. Disord. 65, 3–12 (2019).

    PubMed  Google Scholar 

  103. Radford, R. et al. The degree of astrocyte activation in multiple system atrophy is inversely proportional to the distance to α-synuclein inclusions. Mol. Cell Neurosci. 65, 68–81 (2015).

    CAS  PubMed  Google Scholar 

  104. Pike, A. F. et al. α-Synuclein evokes NLRP3 inflammasome-mediated IL-1β secretion from primary human microglia. Glia 69, 1413–1428 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Trudler, D. et al. Soluble α-synuclein-antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2025847118 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Wang, W. et al. Caspase-1 causes truncation and aggregation of the Parkinson’s disease-associated protein α-synuclein. Proc. Natl Acad. Sci. USA 113, 9587–9592 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Bassil, F. et al. Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy. Proc. Natl Acad. Sci. USA 113, 9593–9598 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Perez-Soriano, A. et al. Transcriptomic differences in MSA clinical variants. Sci. Rep. 10, 10310 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Inoue, Y. et al. The stimulator of interferon genes (STING) pathway is upregulated in striatal astrocytes of patients with multiple system atrophy. Neurosci. Lett. 757, 135972 (2021).

    CAS  PubMed  Google Scholar 

  110. Rizzo, G. et al. Accuracy of clinical diagnosis of Parkinson disease: a systematic review and meta-analysis. Neurology 86, 566–576 (2016).

    PubMed  Google Scholar 

  111. Wenning, G. K. et al. What clinical features are most useful to distinguish definite multiple system atrophy from Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 68, 434–440 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Miki, Y. et al. Identification of multiple system atrophy mimicking Parkinson’s disease or progressive supranuclear palsy. Brain 144, 1138–1151 (2021). This large clinicopathological study analysing clinical pointers distinguished patients with atypical MSA from those with typical PD or progressive supranuclear palsy.

    PubMed  PubMed Central  Google Scholar 

  113. Lin, D. J., Hermann, K. L. & Schmahmann, J. D. Multiple system atrophy of the cerebellar type: clinical state of the art. Mov. Disord. 29, 294–304 (2014).

    PubMed  Google Scholar 

  114. Abele, M. et al. The aetiology of sporadic adult-onset ataxia. Brain 125, 961–968 (2002).

    CAS  PubMed  Google Scholar 

  115. Kim, H. J. et al. Should genetic testing for SCAs be included in the diagnostic workup for MSA? Neurology 83, 1733–1738 (2014).

    PubMed  Google Scholar 

  116. Miki, Y. et al. Improving diagnostic accuracy of multiple system atrophy: a clinicopathological study. Brain 142, 2813–2827 (2019).

    PubMed  Google Scholar 

  117. Gilman, S. et al. Consensus statement on the diagnosis of multiple system atrophy. J. Auton. Nerv. Syst. 74, 189–192 (1998).

    CAS  PubMed  Google Scholar 

  118. Gilman, S. et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71, 670–676 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Osaki, Y., Ben-Shlomo, Y., Lees, A. J., Wenning, G. K. & Quinn, N. P. A validation exercise on the new consensus criteria for multiple system atrophy. Mov. Disord. 24, 2272–2276 (2009).

    PubMed  Google Scholar 

  120. Koga, S. et al. When DLB, PD, and PSP masquerade as MSA: an autopsy study of 134 patients. Neurology 85, 404–412 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Wenning, G. K. et al. The Movement Disorder Society criteria for the diagnosis of multiple system atrophy. Mov. Disord. 37, 1131–1148 (2022). This paper presents revised clinical diagnostic criteria for MSA developed by a task force commissioned by the International Movement Disorder Society (MDS MSA criteria) aiming for enhanced clinical diagnostic accuracy.

    PubMed  PubMed Central  Google Scholar 

  122. O’Sullivan, S. S. et al. Clinical outcomes of progressive supranuclear palsy and multiple system atrophy. Brain 131, 1362–1372 (2008).

    PubMed  Google Scholar 

  123. Ben-Shlomo, Y., Wenning, G. K., Tison, F. & Quinn, N. P. Survival of patients with pathologically proven multiple system atrophy: a meta-analysis. Neurology 48, 384–393 (1997).

    CAS  PubMed  Google Scholar 

  124. Savica, R., Turcano, P., Bower, J. H., Ahlskog, J. E. & Mielke, M. M. Survival and progression in synucleinopathy phenotypes with parkinsonism: a population-based study. Mayo Clin. Proc. 94, 1825–1831 (2019).

    PubMed  Google Scholar 

  125. Giannini, G. et al. Progression and prognosis in multiple system atrophy presenting with REM behavior disorder. Neurology 94, e1828–e1834 (2020).

    PubMed  Google Scholar 

  126. Giannini, G. et al. Early stridor onset and stridor treatment predict survival in 136 patients with MSA. Neurology 87, 1375–1383 (2016).

    PubMed  Google Scholar 

  127. Calandra-Buonaura, G. et al. Dysphagia in multiple system atrophy consensus statement on diagnosis, prognosis and treatment. Parkinsonism Relat. Disord. 86, 124–132 (2021).

    CAS  PubMed  Google Scholar 

  128. Foubert-Samier, A. et al. Disease progression and prognostic factors in multiple system atrophy: a prospective cohort study. Neurobiol. Dis. 139, 104813 (2020).

    PubMed  Google Scholar 

  129. Kim, H. J., Jeon, B. S., Lee, J. Y. & Yun, J. Y. Survival of Korean patients with multiple system atrophy. Mov. Disord. 26, 909–912 (2011).

    PubMed  Google Scholar 

  130. Petrovic, I. N. et al. Multiple system atrophy-parkinsonism with slow progression and prolonged survival: a diagnostic catch. Mov. Disord. 27, 1186–1190 (2012).

    PubMed  Google Scholar 

  131. Papapetropoulos, S. et al. Causes of death in multiple system atrophy. J. Neurol. Neurosurg. Psychiatry 78, 327–329 (2007).

    PubMed  PubMed Central  Google Scholar 

  132. Krismer, F. et al. Sniffing the diagnosis: olfactory testing in neurodegenerative parkinsonism. Parkinsonism Relat. Disord. 35, 36–41 (2017).

    CAS  PubMed  Google Scholar 

  133. Fujita, H. et al. Usefulness of cardiac MIBG scintigraphy, olfactory testing and substantia nigra hyperechogenicity as additional diagnostic markers for distinguishing between Parkinson’s disease and atypical Parkinsonian syndromes. PLoS ONE 11, e0165869 (2016).

    PubMed  PubMed Central  Google Scholar 

  134. Yamamoto, T. et al. The utility of post-void residual volume versus sphincter electromyography to distinguish between multiple system atrophy and Parkinson’s disease. PLoS ONE 12, e0169405 (2017).

    PubMed  PubMed Central  Google Scholar 

  135. Yamamoto, T. et al. Postvoid residual predicts the diagnosis of multiple system atrophy in Parkinsonian syndrome. J. Neurol. Sci. 381, 230–234 (2017).

    PubMed  Google Scholar 

  136. Hahn, K. & Ebersbach, G. Sonographic assessment of urinary retention in multiple system atrophy and idiopathic Parkinson’s disease. Mov. Disord. 20, 1499–1502 (2005).

    PubMed  Google Scholar 

  137. Pellecchia, M. T. et al. Can autonomic testing and imaging contribute to the early diagnosis of multiple system atrophy? A systematic review and recommendations by the Movement Disorder Society Multiple System Atrophy Study Group. Mov. Disord. Clin. Pract. 7, 750–762 (2020). This is a comprehensive and up-to-date systematic review of the utility of brain imaging and autonomic function testing in supporting a diagnosis of MSA.

    PubMed  PubMed Central  Google Scholar 

  138. Pellecchia, M. T. et al. Multiple system atrophy is distinguished from idiopathic Parkinson’s disease by the arginine growth hormone stimulation test. Ann. Neurol. 60, 611–615 (2006).

    CAS  PubMed  Google Scholar 

  139. Pellecchia, M. T. et al. The arginine growth hormone stimulation test in bradykinetic-rigid parkinsonisms. Mov. Disord. 23, 190–194 (2008).

    PubMed  Google Scholar 

  140. Gardner, R. C. & Schmahmann, J. D. Arginine test is not reliable for diagnosing cerebellar multiple system atrophy. Ann. Neurol. 67, 404–408 (2010).

    CAS  PubMed  Google Scholar 

  141. Lee, E. A., Kim, B. J. & Lee, W. Y. Diagnosing multiple system atrophy with greater accuracy: combined analysis of the clonidine-growth hormone test and external anal sphincter electromyography. Mov. Disord. 17, 1242–1247 (2002).

    PubMed  Google Scholar 

  142. Strijks, E. et al. Stimulation of growth-hormone release with clonidine does not distinguish individual cases of idiopathic Parkinson’s disease from those with striatonigral degeneration. J. Neurol. 249, 1206–1210 (2002).

    CAS  PubMed  Google Scholar 

  143. Traschutz, A. et al. Natural history, phenotypic spectrum, and discriminative features of multisystemic RFC1 disease. Neurology 96, e1369–e1382 (2021).

    PubMed  PubMed Central  Google Scholar 

  144. Mollenhauer, B. et al. α-Synuclein and tau concentrations in cerebrospinal fluid of patients presenting with parkinsonism: a cohort study. Lancet Neurol. 10, 230–240 (2011).

    CAS  PubMed  Google Scholar 

  145. Magdalinou, N. K. et al. A panel of nine cerebrospinal fluid biomarkers may identify patients with atypical parkinsonian syndromes. J. Neurol. Neurosurg. Psychiatry 86, 1240–1247 (2015).

    CAS  PubMed  Google Scholar 

  146. Aerts, M. B., Esselink, R. A., Abdo, W. F., Bloem, B. R. & Verbeek, M. M. CSF α-synuclein does not differentiate between parkinsonian disorders. Neurobiol. Aging 33, 430.e1–430.e3 (2012).

    CAS  Google Scholar 

  147. Hall, S. et al. Accuracy of a panel of 5 cerebrospinal fluid biomarkers in the differential diagnosis of patients with dementia and/or parkinsonian disorders. Arch. Neurol. 69, 1445–1452 (2012).

    PubMed  Google Scholar 

  148. Singer, W. et al. Alpha-synuclein oligomers and neurofilament light chain in spinal fluid differentiate multiple system atrophy from Lewy body synucleinopathies. Ann. Neurol. 88, 503–512 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Poggiolini, I. et al. Diagnostic value of cerebrospinal fluid alpha-synuclein seed quantification in synucleinopathies. Brain https://doi.org/10.1093/brain/awab431 (2021).

    Article  PubMed Central  Google Scholar 

  150. Hansson, O. et al. Blood-based NfL: a biomarker for differential diagnosis of parkinsonian disorder. Neurology 88, 930–937 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Du, J. et al. Clinical correlates of decreased plasma coenzyme Q10 levels in patients with multiple system atrophy. Parkinsonism Relat. Disord. 57, 58–62 (2018).

    PubMed  Google Scholar 

  152. Doppler, K. et al. Distinctive distribution of phospho-alpha-synuclein in dermal nerves in multiple system atrophy. Mov. Disord. 30, 1688–1692 (2015).

    CAS  PubMed  Google Scholar 

  153. Brumberg, J. et al. Dermal and cardiac autonomic fiber involvement in Parkinson’s disease and multiple system atrophy. Neurobiol. Dis. 153, 105332 (2021).

    CAS  PubMed  Google Scholar 

  154. Wang, Z. et al. Skin α-synuclein aggregation seeding activity as a novel biomarker for Parkinson disease. JAMA Neurol. https://doi.org/10.1001/jamaneurol.2020.3311 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Bargar, C. et al. Discrimination of MSA-P and MSA-C by RT-QuIC analysis of olfactory mucosa: the first assessment of assay reproducibility between two specialized laboratories. Mol. Neurodegener. 16, 82 (2021). This paper provides preliminary evidence for differential aggregation seeding activity among patients with PD, MSA-P and MSA-C using α-synuclein RT-QuIC analysis of the olfactory mucosa.

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Thijs, R. D. et al. Recommendations for tilt table testing and other provocative cardiovascular autonomic tests in conditions that may cause transient loss of consciousness: consensus statement of the European Federation of Autonomic Societies (EFAS) endorsed by the American Autonomic Society (AAS) and the European Academy of Neurology (EAN). Auton. Neurosci. 233, 102792 (2021).

    PubMed  Google Scholar 

  157. Goldstein, D. S., Isonaka, R., Lamotte, G. & Kaufmann, H. Different phenoconversion pathways in pure autonomic failure with versus without Lewy bodies. Clin. Auton. Res. 31, 677–684 (2021).

    PubMed  Google Scholar 

  158. Fanciulli, A. et al. Urinary retention discriminates multiple system atrophy from Parkinson’s disease. Mov. Disord. 34, 1926–1928 (2019).

    PubMed  Google Scholar 

  159. Gandor, F. et al. Laryngeal movement disorders in multiple system atrophy: a diagnostic biomarker? Mov. Disord. 35, 2174–2183 (2020).

    PubMed  PubMed Central  Google Scholar 

  160. Wan, L. et al. Biallelic intronic AAGGG expansion of RFC1 is related to multiple system atrophy. Ann. Neurol. 88, 1132–1143 (2020).

    CAS  PubMed  Google Scholar 

  161. Heim, B., Krismer, F., De Marzi, R. & Seppi, K. Magnetic resonance imaging for the diagnosis of Parkinson’s disease. J. Neural Transm. 124, 915–964 (2017).

    PubMed  Google Scholar 

  162. Massey, L. A. et al. Conventional magnetic resonance imaging in confirmed progressive supranuclear palsy and multiple system atrophy. Mov. Disord. 27, 1754–1762 (2012).

    PubMed  Google Scholar 

  163. Krismer, F. et al. Automated analysis of diffusion-weighted magnetic resonance imaging for the differential diagnosis of multiple system atrophy from Parkinson’s disease. Mov. Disord. 36, 241–245 (2021). This paper reports the finding that automated analysis of microstructural integrity within the middle cerebellar peduncle and putamen has high diagnostic accuracy in discriminating patients with MSA from those with PD in the early to moderate disease stages.

    PubMed  Google Scholar 

  164. Scherfler, C. et al. Diagnostic potential of automated subcortical volume segmentation in atypical parkinsonism. Neurology 86, 1242–1249 (2016).

    PubMed  Google Scholar 

  165. Archer, D. B. et al. Development and validation of the automated imaging differentiation in Parkinsonism (AID-P): a multi-site machine learning study. Lancet Digit. Health 1, e222–e231 (2019).

    PubMed  PubMed Central  Google Scholar 

  166. Meissner, W. G. et al. Multiple system atrophy: recent developments and future perspectives. Mov. Disord. 34, 1629–1642 (2019).

    PubMed  Google Scholar 

  167. Brooks, D. J. & Seppi, K., Neuroimaging Working Group on MSA. Proposed neuroimaging criteria for the diagnosis of multiple system atrophy. Mov. Disord. 24, 949–964 (2009).

    PubMed  Google Scholar 

  168. Gu, S. C., Ye, Q. & Yuan, C. X. Metabolic pattern analysis of (18)F-FDG PET as a marker for Parkinson’s disease: a systematic review and meta-analysis. Rev. Neurosci. 30, 743–756 (2019).

    CAS  PubMed  Google Scholar 

  169. Wilson, D., Hallett, M. & Anderson, T. An eye on movement disorders. Mov. Disord. Clin. Pract. 8, 1168–1180 (2021).

    PubMed  PubMed Central  Google Scholar 

  170. Fanciulli, A. et al. Multiple system atrophy. Int. Rev. Neurobiol. 149, 137–192 (2019).

    CAS  PubMed  Google Scholar 

  171. Poewe, W. et al. Parkinson disease. Nat. Rev. Dis. Prim. 3, 17013 (2017).

    PubMed  Google Scholar 

  172. Brumberg, J. & Isaias, I. U. SPECT molecular imaging in atypical parkinsonism. Int. Rev. Neurobiol. 142, 37–65 (2018).

    PubMed  Google Scholar 

  173. Goldstein, D. S. & Cheshire, W. P. Jr. Roles of cardiac sympathetic neuroimaging in autonomic medicine. Clin. Auton. Res. 28, 397–410 (2018).

    PubMed  PubMed Central  Google Scholar 

  174. Heim, B., Krismer, F. & Seppi, K. Structural imaging in atypical parkinsonism. Int. Rev. Neurobiol. 142, 67–148 (2018).

    PubMed  Google Scholar 

  175. Saeed, U. et al. Imaging biomarkers in Parkinson’s disease and parkinsonian syndromes: current and emerging concepts. Transl. Neurodegener. 6, 8 (2017).

    PubMed  PubMed Central  Google Scholar 

  176. Xu, Z., Arbizu, J. & Pavese, N. PET molecular imaging in atypical parkinsonism. Int. Rev. Neurobiol. 142, 3–36 (2018).

    PubMed  Google Scholar 

  177. Chougar, L., Pyatigorskaya, N. & Lehericy, S. Update on neuroimaging for categorization of Parkinson’s disease and atypical parkinsonism. Curr. Opin. Neurol. 34, 514–524 (2021).

    PubMed  Google Scholar 

  178. Arribarat, G., De Barros, A. & Peran, P. Modern brainstem MRI techniques for the diagnosis of Parkinson’s disease and parkinsonisms. Front. Neurol. 11, 791 (2020).

    PubMed  PubMed Central  Google Scholar 

  179. Lee, J. H. & Lee, M. S. Brain iron accumulation in atypical parkinsonian syndromes: in vivo MRI evidences for distinctive patterns. Front. Neurol. 10, 74 (2019).

    PubMed  PubMed Central  Google Scholar 

  180. Heim, B., Krismer, F., Poewe, W. & Seppi, K. Imaging markers of disease progression in multiple system atrophy. Future Neurol. 14, FNL24 (2019).

    Google Scholar 

  181. Tinaz, S. Functional connectome in Parkinson’s disease and parkinsonism. Curr. Neurol. Neurosci. Rep. 21, 24 (2021).

    PubMed  PubMed Central  Google Scholar 

  182. Haghshomar, M. et al. Cerebellar microstructural abnormalities in Parkinson’s disease: a systematic review of diffusion tensor imaging studies. Cerebellum https://doi.org/10.1007/s12311-021-01355-3 (2022).

    Article  PubMed  Google Scholar 

  183. Abos, A. et al. Differentiation of multiple system atrophy from Parkinson’s disease by structural connectivity derived from probabilistic tractography. Sci. Rep. 9, 16488 (2019).

    PubMed  PubMed Central  Google Scholar 

  184. Iranzo, A. et al. Decreased striatal dopamine transporter uptake and substantia nigra hyperechogenicity as risk markers of synucleinopathy in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a prospective study [corrected]. Lancet Neurol. 9, 1070–1077 (2010).

    CAS  PubMed  Google Scholar 

  185. Lee, P. H. et al. A randomized trial of mesenchymal stem cells in multiple system atrophy. Ann. Neurol. 72, 32–40 (2012).

    PubMed  Google Scholar 

  186. Parnetti, L. et al. CSF and blood biomarkers for Parkinson’s disease. Lancet Neurol. 18, 573–586 (2019).

    CAS  PubMed  Google Scholar 

  187. Rossi, M. et al. Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies. Acta Neuropathol. 140, 49–62 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Martinez-Valbuena, I. et al. Combining skin α-synuclein real-time quaking-induced conversion and circulating neurofilament light chain to distinguish multiple system atrophy and Parkinson’s disease. Mov. Disord. 37, 648–650 (2022).

    CAS  PubMed  Google Scholar 

  189. Mangesius, S. et al. Novel decision algorithm to discriminate Parkinsonism with combined blood and imaging biomarkers. Parkinsonism Relat. Disord. 77, 57–63 (2020).

    PubMed  Google Scholar 

  190. Giannini, G., Provini, F., Cortelli, P. & Calandra-Buonaura, G. REM sleep behaviour disorder in multiple system atrophy: from prodromal to progression of disease. Front. Neurol. 12, 677213 (2021).

    PubMed  PubMed Central  Google Scholar 

  191. Munoz-Lopetegi, A. et al. Magnetic resonance imaging abnormalities as a marker of multiple system atrophy in isolated rapid eye movement sleep behavior disorder. Sleep https://doi.org/10.1093/sleep/zsaa089 (2021).

    Article  PubMed  Google Scholar 

  192. Kaufmann, H. et al. Natural history of pure autonomic failure: a United States prospective cohort. Ann. Neurol. 81, 287–297 (2017). This is a prospective follow-up study in patients presenting with PAF reporting predictors and rates of conversion to MSA or Lewy body disorders.

    PubMed  PubMed Central  Google Scholar 

  193. Singer, W. et al. Pure autonomic failure: predictors of conversion to clinical CNS involvement. Neurology 88, 1129–1136 (2017).

    PubMed  PubMed Central  Google Scholar 

  194. Heim, B. et al. Diagnostic accuracy of MR planimetry in clinically unclassifiable parkinsonism. Parkinsonism Relat. Disord. 82, 87–91 (2021).

    CAS  PubMed  Google Scholar 

  195. Carre, G. et al. Brain MRI of multiple system atrophy of cerebellar type: a prospective study with implications for diagnosis criteria. J. Neurol. 267, 1269–1277 (2020).

    CAS  PubMed  Google Scholar 

  196. Burns, M. R. & McFarland, N. R. Current management and emerging therapies in multiple system atrophy. Neurotherapeutics 17, 1582–1602 (2020).

    PubMed  PubMed Central  Google Scholar 

  197. Wenning, G. K., Ben Shlomo, Y., Magalhaes, M., Daniel, S. E. & Quinn, N. P. Clinical features and natural history of multiple system atrophy. An analysis of 100 cases. Brain 117, 835–845 (1994).

    PubMed  Google Scholar 

  198. Hughes, A. J., Colosimo, C., Kleedorfer, B., Daniel, S. E. & Lees, A. J. The dopaminergic response in multiple system atrophy. J. Neurol. Neurosurg. Psychiatry 55, 1009–1013 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Boesch, S. M., Wenning, G. K., Ransmayr, G. & Poewe, W. Dystonia in multiple system atrophy. J. Neurol. Neurosurg. Psychiatry 72, 300–303 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Kollensperger, M. et al. Presentation, diagnosis, and management of multiple system atrophy in Europe: final analysis of the European Multiple System Atrophy Registry. Mov. Disord. 25, 2604–2612 (2010).

    PubMed  Google Scholar 

  201. Poewe, W. et al. Efficacy of rasagiline in patients with the parkinsonian variant of multiple system atrophy: a randomised, placebo-controlled trial. Lancet Neurol. 14, 145–152 (2015).

    CAS  PubMed  Google Scholar 

  202. Rascol, O., Fabbri, M. & Poewe, W. Amantadine in the treatment of Parkinson’s disease and other movement disorders. Lancet Neurol. 20, 1048–1056 (2021).

    CAS  PubMed  Google Scholar 

  203. Meissner, W. G. et al. Outcome of deep brain stimulation in slowly progressive multiple system atrophy: a clinico-pathological series and review of the literature. Parkinsonism Relat. Disord. 24, 69–75 (2016).

    PubMed  Google Scholar 

  204. Artusi, C. A., Rinaldi, D., Balestrino, R. & Lopiano, L. Deep brain stimulation for atypical parkinsonism: a systematic review on efficacy and safety. Parkinsonism Relat. Disord. 96, 109–118 (2022).

    PubMed  Google Scholar 

  205. Raccagni, C. et al. Physiotherapy improves motor function in patients with the Parkinson variant of multiple system atrophy: a prospective trial. Parkinsonism Relat. Disord. 67, 60–65 (2019).

    CAS  PubMed  Google Scholar 

  206. Perez-Lloret, S. et al. Current concepts in the treatment of multiple system atrophy. Mov. Disord. Clin. Pract. 2, 6–16 (2015).

    PubMed  PubMed Central  Google Scholar 

  207. Thobois, S., Broussolle, E., Toureille, L. & Vial, C. Severe dysphagia after botulinum toxin injection for cervical dystonia in multiple system atrophy. Mov. Disord. 16, 764–765 (2001).

    CAS  PubMed  Google Scholar 

  208. Grossauer, A., Sidoroff, V., Heim, B. & Seppi, K. Symptomatic care in multiple system atrophy: state of the art. Cerebellum https://doi.org/10.1007/s12311-022-01411-6 (2022).

    Article  PubMed  Google Scholar 

  209. Song, P. et al. Repetitive transcranial magnetic stimulation of the cerebellum improves ataxia and cerebello-fronto plasticity in multiple system atrophy: a randomized, double-blind, sham-controlled and TMS-EEG study. Aging 12, 20611–20622 (2020).

    PubMed  PubMed Central  Google Scholar 

  210. Wang, H. et al. Increased cerebellar activation after repetitive transcranial magnetic stimulation over the primary motor cortex in patients with multiple system atrophy. Ann. Transl. Med. 4, 103 (2016).

    PubMed  PubMed Central  Google Scholar 

  211. Jain, S., Dawson, J., Quinn, N. P. & Playford, E. D. Occupational therapy in multiple system atrophy: a pilot randomized controlled trial. Mov. Disord. 19, 1360–1364 (2004).

    PubMed  Google Scholar 

  212. Wedge, F. The impact of resistance training on balance and functional ability of a patient with multiple system atrophy. J. Geriatr. Phys. Ther. 31, 79–83 (2008).

    PubMed  Google Scholar 

  213. Sonoda, Y. et al. Amelioration of motor and nonmotor symptoms in cortical cerebellar atrophy and multiple system atrophy-cerebellar type by inpatient rehabilitation: a retrospective study. Int. J. Rehabil. Res. 44, 104–109 (2021).

    PubMed  Google Scholar 

  214. Ueha, R. et al. Post-operative swallowing in multiple system atrophy. Eur. J. Neurol. 23, 393–400 (2016).

    CAS  PubMed  Google Scholar 

  215. Palma, J. A. & Kaufmann, H. Treatment of autonomic dysfunction in Parkinson disease and other synucleinopathies. Mov. Disord. 33, 372–390 (2018).

    PubMed  PubMed Central  Google Scholar 

  216. Gomez-Caravaca, M. T. et al. The use of botulinum toxin in the treatment of sialorrhea in parkinsonian disorders. Neurol. Sci. 36, 275–279 (2015).

    PubMed  Google Scholar 

  217. Sonoda, Y. et al. Short-term effect of intensive speech therapy on dysarthria in patients with sporadic spinocerebellar degeneration. J. Speech Lang. Hear. Res. 64, 725–733 (2021).

    PubMed  Google Scholar 

  218. Theravance Biopharma. Theravance Biopharma, inc. announces results from study 0170, a second phase 3 study of ampreloxetine, in patients with symptomatic neurogenic orthostatic hypotension (NOH). Theravance Biopharma https://investor.theravance.com/news-releases/news-release-details/theravance-biopharma-inc-announces-results-study-0170-second (2022).

  219. Wright, R. A. et al. A double-blind, dose-response study of midodrine in neurogenic orthostatic hypotension. Neurology 51, 120–124 (1998).

    CAS  PubMed  Google Scholar 

  220. Kaufmann, H. et al. Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial. Neurology 83, 328–335 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Kaufmann, H., Norcliffe-Kaufmann, L. & Palma, J. A. Droxidopa in neurogenic orthostatic hypotension. Expert. Rev. Cardiovasc. Ther. 13, 875–891 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. Squair, J. W. et al. Implanted system for orthostatic hypotension in multiple-system atrophy. N. Engl. J. Med. 386, 1339–1344 (2022).

    PubMed  Google Scholar 

  223. Fanciulli, A. et al. Consensus statement on the definition of neurogenic supine hypertension in cardiovascular autonomic failure by the American Autonomic Society (AAS) and the European Federation of Autonomic Societies (EFAS): endorsed by the European Academy of Neurology (EAN) and the European Society of Hypertension (ESH). Clin. Auton. Res. 28, 355–362 (2018).

    PubMed  PubMed Central  Google Scholar 

  224. Palma, J.-A. et al. The impact of supine hypertension on target organ damage and survival in patients with synucleinopathies and neurogenic orthostatic hypotension. Parkinsonism Relat. Disord. 75, 97–104 (2020).

    PubMed  PubMed Central  Google Scholar 

  225. Park, J. W., Okamoto, L. E. & Biaggioni, I. Advances in the pathophysiology and management of supine hypertension in patients with neurogenic orthostatic hypotension. Curr. Hypertens. Rep. 24, 45–54 (2022).

    PubMed  Google Scholar 

  226. Jordan, J. et al. Management of supine hypertension in patients with neurogenic orthostatic hypotension: scientific statement of the American Autonomic Society, European Federation of Autonomic Societies, and the European Society of Hypertension. J. Hypertens. 37, 1541–1546 (2019).

    CAS  PubMed  Google Scholar 

  227. Giannantoni, A. et al. Botulinum toxin A for overactive bladder and detrusor muscle overactivity in patients with Parkinson’s disease and multiple system atrophy. J. Urol. 182, 1453–1457 (2009).

    PubMed  Google Scholar 

  228. Hussain, I. F., Brady, C. M., Swinn, M. J., Mathias, C. J. & Fowler, C. J. Treatment of erectile dysfunction with sildenafil citrate (Viagra) in parkinsonism due to Parkinson’s disease or multiple system atrophy with observations on orthostatic hypotension. J. Neurol. Neurosurg. Psychiatry 71, 371–374 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  229. Krzastek, S. C., Bopp, J., Smith, R. P. & Kovac, J. R. Recent advances in the understanding and management of erectile dysfunction. F1000Res. https://doi.org/10.12688/f1000research.16576.1 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  230. Palma, J. A. et al. Prevalence of REM sleep behavior disorder in multiple system atrophy: a multicenter study and meta-analysis. Clin. Auton. Res. 25, 69–75 (2015).

    PubMed  PubMed Central  Google Scholar 

  231. Dauvilliers, Y. et al. REM sleep behaviour disorder. Nat. Rev. Dis. Primers 4, 19 (2018).

    PubMed  Google Scholar 

  232. Ghorayeb, I., Bioulac, B. & Tison, F. Sleep disorders in multiple system atrophy. J. Neural Transm. 112, 1669–1675 (2005).

    CAS  PubMed  Google Scholar 

  233. Cortelli, P. et al. Stridor in multiple system atrophy: consensus statement on diagnosis, prognosis, and treatment. Neurology 93, 630–639 (2019).

    PubMed  PubMed Central  Google Scholar 

  234. Rascol, O. et al. Fluoxetine for the symptomatic treatment of multiple system atrophy: the MSA-FLUO trial. Mov. Disord. 36, 1704–1711 (2021).

    CAS  PubMed  Google Scholar 

  235. Martinez, J., Palma, J. A., Norcliffe-Kaufmann, L., Garakani, A. & Kaufmann, H. Impact of depressive symptoms on self-perceived severity of autonomic dysfunction in multiple system atrophy: relevance for patient-reported outcomes in clinical trials. Clin. Auton. Res. 30, 215–221 (2020).

    PubMed  PubMed Central  Google Scholar 

  236. Yust-Katz, S., Hershkovitz, R., Gurevich, T. & Djaldetti, R. Pain in extrapyramidal neurodegenerative diseases. Clin. J. Pain. 33, 635–639 (2017).

    PubMed  Google Scholar 

  237. Leys, F. et al. Effects of self-administered cannabidiol in a patient with multiple system atrophy. Clin. Auton. Res. 30, 355–356 (2020).

    PubMed  Google Scholar 

  238. Wiblin, L., Lee, M. & Burn, D. Palliative care and its emerging role in multiple system atrophy and progressive supranuclear palsy. Parkinsonism Relat. Disord. 34, 7–14 (2017).

    PubMed  Google Scholar 

  239. Dayal, A. M. et al. Palliative care discussions in multiple system atrophy: a retrospective review. Can. J. Neurol. Sci. 44, 276–282 (2017).

    PubMed  Google Scholar 

  240. Saranza, G., Villanueva, E. Q. III & Lang, A. E. Preferences for communication about end-of-life care in atypical Parkinsonism. Mov. Disord. 36, 2116–2125 (2021).

    PubMed  Google Scholar 

  241. Gao, W. et al. Effect of short-term integrated palliative care on patient-reported outcomes among patients severely affected with long-term neurological conditions: a randomized clinical trial. JAMA Netw. Open 3, e2015061 (2020).

    PubMed  PubMed Central  Google Scholar 

  242. Meissner, W. G. et al. Assessment of quality of life with the multiple system atrophy health-related quality of life scale. Mov. Disord. 27, 1574–1577 (2012).

    PubMed  Google Scholar 

  243. Benrud-Larson, L. M., Sandroni, P., Schrag, A. & Low, P. A. Depressive symptoms and life satisfaction in patients with multiple system atrophy. Mov. Disord. 20, 951–957 (2005).

    PubMed  Google Scholar 

  244. Schrag, A. et al. Measuring health-related quality of life in MSA: the MSA-QoL. Mov. Disord. 22, 2332–2338 (2007).

    PubMed  Google Scholar 

  245. Park, A. et al. Swallowing outcomes following voice therapy in multiple system atrophy with dysphagia: comparison of treatment efficacy with Parkinson’s disease. Dysphagia https://doi.org/10.1007/s00455-021-10265-9 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  246. Schrag, A., Bohlken, J. & Kostev, K. Pre-diagnostic presentations of multiple system atrophy case control study in a primary care dataset. Parkinsonism Relat. Disord. https://doi.org/10.1016/j.parkreldis.2022.02.003 (2022).

    Article  PubMed  Google Scholar 

  247. Postuma, R. B. et al. Risk factors for neurodegeneration in idiopathic rapid eye movement sleep behavior disorder: a multicenter study. Ann. Neurol. 77, 830–839 (2015).

    PubMed  PubMed Central  Google Scholar 

  248. Postuma, R. B. et al. Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study. Brain 142, 744–759 (2019).

    PubMed  PubMed Central  Google Scholar 

  249. Iranzo, A. et al. Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder: an observational cohort study. Lancet Neurol. 12, 443–453 (2013).

    PubMed  Google Scholar 

  250. Saeed, U., Lang, A. E. & Masellis, M. Neuroimaging advances in Parkinson’s disease and atypical Parkinsonian syndromes. Front. Neurol. 11, 572976 (2020).

    PubMed  PubMed Central  Google Scholar 

  251. Beliveau, V. et al. Characterization and diagnostic potential of diffusion tractography in multiple system atrophy. Parkinsonism Relat. Disord. 85, 30–36 (2021).

    CAS  PubMed  Google Scholar 

  252. AC Immune. AC immune reports first live images of alpha-synuclein in human brain with new pet tracer for neurodegenerative disease at AD/PDTM conference. AC Immune https://ir.acimmune.com/news-releases/news-release-details/ac-immune-reports-first-live-images-alpha-synuclein-human-brain (2022).

  253. Iranzo, A. 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. 20, 203–212 (2021).

    CAS  PubMed  Google Scholar 

  254. Stefani, A. et al. Alpha-synuclein seeds in olfactory mucosa of patients with isolated REM sleep behaviour disorder. Brain 144, 1118–1126 (2021).

    PubMed  Google Scholar 

  255. Martinez-Valbuena, I. et al. Alpha-synuclein seeding shows a wide heterogeneity in multiple system atrophy. Transl. Neurodegener. 11, 7 (2022). This is the first study to show between-patient heterogeneity of α-synuclein seeding activity of brain tissue samples as well as heterogeneity of seeding activity between different brain regions in MSA.

    CAS  PubMed  PubMed Central  Google Scholar 

  256. Singer, W. et al. Alpha-synuclein oligomers and neurofilament light chain predict phenoconversion of pure autonomic failure. Ann. Neurol. 89, 1212–1220 (2021). This paper reports the finding that α-synuclein oligomers and NfL in the cerebrospinal fluid might predict future phenoconversion to MSA in patients with PAF.

    CAS  PubMed  PubMed Central  Google Scholar 

  257. Krismer, F., Seppi, K., Stefanova, N. & Wenning, G. K. Toward disease modification in multiple system atrophy: pitfalls, bottlenecks, and possible remedies. Mov. Disord. 31, 235–240 (2016).

    PubMed  Google Scholar 

  258. Sidoroff, V. et al. Disease-modifying therapies for multiple system atrophy: where are we in 2022? J. Parkinsons Dis. 12, 1369–1387 (2022).

    PubMed  Google Scholar 

  259. Singer, W. et al. Intrathecal administration of autologous mesenchymal stem cells in multiple system atrophy. Neurology 93, e77–e87 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  260. Biohaven. Biohaven provides update on phase 3 trial and multiple system atrophy (MSA) program. Biohaven https://www.biohavenpharma.com/investors/news-events/press-releases/09-27-2021 (2021).

  261. Palma, J. A. et al. mTOR inhibition with sirolimus in multiple system atrophy: a randomized, double-blind, placebo-controlled futility trial and 1-year biomarker longitudinal analysis. Mov. Disord. https://doi.org/10.1002/mds.28923 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  262. Mitsui, J. et al. High-dose ubiquinol supplementation in multiple-system atrophy: a multicentre, randomised, double-blinded, placebo-controlled phase 2 trial. Preprint at Lancet https://doi.org/10.2139/ssrn.4117370 (2022).

  263. MSA Coalition. MSA treatment pipeline. MSA Coalition https://www.multiplesystematrophy.org/msa-research/msa-treatment-pipeline/ (2021).

  264. Meissner, W. G. et al. A phase 1 randomized trial of specific active α-synuclein immunotherapies PD01A and PD03A in multiple aystem atrophy. Mov. Disord. 35, 1957–1965 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  265. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT05104476 (2022).

  266. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04165486 (2021).

  267. Heras-Garvin, A. et al. Anle138b modulates α-synuclein oligomerization and prevents motor decline and neurodegeneration in a mouse model of multiple system atrophy. Mov. Disord. 34, 255–263 (2019).

    CAS  PubMed  Google Scholar 

  268. Price, D. L. et al. The small molecule alpha-synuclein misfolding inhibitor, NPT200-11, produces multiple benefits in an animal model of Parkinson’s disease. Sci. Rep. 8, 16165 (2018).

    PubMed  PubMed Central  Google Scholar 

  269. Vidal-Martinez, G. et al. FTY720-Mitoxy reduces synucleinopathy and neuroinflammation, restores behavior and mitochondria function, and increases GDNF expression in Multiple System Atrophy mouse models. Exp. Neurol. 325, 113120 (2020).

    CAS  PubMed  Google Scholar 

  270. Gordon, R. et al. Inflammasome inhibition prevents αα-synuclein pathology and dopaminergic neurodegeneration in mice. Sci. Transl Med. https://doi.org/10.1126/scitranslmed.aah4066 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  271. de Araujo, F. M. et al. Role of microgliosis and NLRP3 inflammasome in Parkinson’s disease pathogenesis and therapy. Cell Mol. Neurobiol. https://doi.org/10.1007/s10571-020-01027-6 (2021).

    Article  PubMed  Google Scholar 

  272. Overk, C. et al. Multiple system atrophy: experimental models and reality. Acta Neuropathol. 135, 33–47 (2018).

    PubMed  Google Scholar 

  273. Krismer, F. et al. Abnormalities on structural MRI associate with faster disease progression in multiple system atrophy. Parkinsonism Relat. Disord. 58, 23–27 (2019).

    PubMed  Google Scholar 

  274. Zhang, L. et al. Neurofilament light chain predicts disease severity and progression in multiple system atrophy. Mov. Disord. 37, 421–426 (2022).

    CAS  PubMed  Google Scholar 

  275. Palma, J. A. et al. Limitations of the unified Multiple System Atrophy Rating Scale as outcome measure for clinical trials and a roadmap for improvement. Clin. Auton. Res. 31, 157–164 (2021).

    PubMed  PubMed Central  Google Scholar 

  276. Foubert-Samier, A. et al. An item response theory analysis of the Unified Multiple System Atrophy Rating Scale. Parkinsonism Relat. Disord. 94, 40–44 (2021).

    PubMed  Google Scholar 

  277. Krismer, F. et al. Sensitivity to change and patient-centricity of the Unified MSA Rating Scale: a data-driven analysis. Mov. Disord. https://doi.org/10.1002/mds.28993 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  278. Warmerdam, E. et al. Long-term unsupervised mobility assessment in movement disorders. Lancet Neurol. 19, 462–470 (2020).

    PubMed  Google Scholar 

  279. Halliday, G. M. Re-evaluating the glio-centric view of multiple system atrophy by highlighting the neuronal involvement. Brain 138, 2116–2119 (2015).

    PubMed  Google Scholar 

  280. Lemos, M., Wenning, G. K. & Stefanova, N. Current experimental disease-modifying therapeutics for multiple system atrophy. J. Neural Transm. 128, 1529–1543 (2021).

    PubMed  Google Scholar 

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Authors and Affiliations

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Contributions

Introduction (W.P.); Epidemiology (I.S.); Mechanisms/pathophysiology (W.G.M. and G.H.); Diagnosis, screening and prevention (W.P., G.K.W., K.S. and M.T.P.); Management (W.P., H.K., J.-A.P. and K.S.); Quality of life (I.S.); Outlook (W.P.); Overview of Primer (W.P.).

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Correspondence to Werner Poewe.

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Competing interests

W.P. reports consultancy and lecture fees from Alterity, AbbVie, Affiris, AstraZeneca, BIAL, Biogen, Britannia, Lilly, Lundbeck, Neuroderm, Neurocrine, Denali Pharmaceuticals, Roche, Takeda, Teva, UCB and Zambon, as well as royalties from Thieme, Wiley Blackwell, Oxford University Press and Cambridge University Press, and grant support from the Michael J. Fox Foundation (MJFF) and the EU FP7 & Horizon 2020 programmes. G.H. reports consultancy for the NHMRC, royalties from Academic Press, Elsevier and Oxford University Press, and research grants from NHMRC, NHMRC-EU Joint Programme on Neurodegenerative Disease, NHMRC-NIHR Collaborative Research, NIH (RO1), Aligning Science Across Parkinson’s (ASAP), MJFF, Shake-it-up Australia, and the University of Sydney. W.G.M. has received fees for editorial activities with Elsevier, has served as adviser for Lundbeck, Biohaven, Roche, Alterity, Servier, Inhibikase and Takeda, and has received teaching honoraria from UCB. G.K.W. reports consultancy and lecture fees from Biogen, Biohaven, Inhibikase, Lundbeck, Ono, Takeda, and Theravance, and research grants from the FWF Austrian Science Fund, the Austrian National Bank, the US MSA Coalition, Parkinson Fonds Austria, and International Parkinson and Movement Disorder Society outside the submitted work. M.T.P. reports consultancy and lecture fees from Zambon, Orion, Teva and Theravance. K.S. reports personal fees from Teva, UCB, Lundbeck, AOP Orphan Pharmaceuticals AG, Roche, Grünenthal, Stada, Licher Pharma, Biogen, BIAL and Abbvie, honoraria from the International Parkinson and Movement Disorders Society, research grants from FWF Austrian Science Fund, MJFF, and AOP Orphan Pharmaceuticals AG. J.-A.P. reports research funding from the National Institutes of Health (NIH, R01, U54, U01), MJFF, MSA Coalition, Familial Dysautonomia Foundation, and the FDA. He has served as advisory board member for Takeda, Astellas and Dr. Reddy’s Laboratories, and as principal investigator in studies funded by Biohaven Pharmaceuticals, Theravance Biopharma and Biogen, and has received salary from Novartis. H.K. reports research funding from the National Institutes of Health (NIH R01, U54, U01), MJFF, MSA Coalition, Familial Dysautonomia Foundation, and the FDA; is an advisory board member for Lundbeck, Biogen, Biohaven, Theravance, PTC Therapeutics, ONO, Takeda, Vaxxinity and Elly Lilly; he is Editor-in-Chief of Clinical Autonomic Research and principal investigator in studies funded by Biogen. I.S. declares no competing interests.

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Poewe, W., Stankovic, I., Halliday, G. et al. Multiple system atrophy. Nat Rev Dis Primers 8, 56 (2022). https://doi.org/10.1038/s41572-022-00382-6

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