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  • Review Article
  • Published:

Multiple system atrophy: insights into a rare and debilitating movement disorder

Nature Reviews Neurology volume 13, pages 232–243 (2017)Cite this article

Subjects

Key Points

  • Multiple system atrophy (MSA) is a sporadic and rare neurodegenerative movement disorder with an estimated annual incidence of 0.6 per 100,000 (ORPHA102)

  • The clinical presentation is highly variable, with parkinsonism, cerebellar ataxia and autonomic failure being the most common — and often debilitating — symptoms

  • α-Synuclein-immunoreactive (oligodendro)glial cytoplasmic inclusions are the neuropathological hallmark of MSA

  • Permissive templating ('prion-like' propagation) of misfolded α-synuclein is currently thought to be the key event in the pathophysiological cascade

  • No disease-modifying therapies are currently available; symptomatic treatment options are limited, and the therapeutic benefits of these therapies is often only transient

  • International collaboration is gaining momentum with the recent formation of international study groups and novel funding opportunities dedicated exclusively to MSA research

Abstract

Multiple system atrophy (MSA) is a devastating and fatal neurodegenerative disorder. The clinical presentation of this disease is highly variable, with parkinsonism, cerebellar ataxia and autonomic failure being the most common — and often debilitating — symptoms. These symptoms progress rapidly, and patients die from MSA-related complications after 9 years of symptom duration on average. Unfortunately, the course of the disease cannot be improved by drug or surgical treatment. In addition, symptomatic treatment options are currently limited, and therapeutic benefits are often only transient. Thus, further interventional studies of candidate disease-modifying and symptomatic therapies are essential to improve patient care. In the past 15 years, the understanding of MSA-specific requirements in trial methodology has improved, resulting in a substantial increase in high-quality interventional studies. In this Review, we discuss MSA risk factors, clinical presentation and neuropathology, and we provide a hypothesis on key pathophysiological events, a summary of recent randomized controlled trials, and an overview of ongoing international collaborations.

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Figure 1: Key events in the pathophysiological cascade of MSA.
Figure 2: Diagnostic scheme for MSA.
Figure 3: Common findings on routine MRI in patients with multiple system atrophy.
Figure 4: Flow chart of the MDS MSA Study Group aims.

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References

  1. 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).

    Article  PubMed  Google Scholar 

  2. Lin, D. J., Hermann, K. L. & Schmahmann, J. D. The diagnosis and natural history of multiple system atrophy, cerebellar type. Cerebellum 15, 663–679 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Wenning, G. K. et al. The natural history of multiple system atrophy: a prospective European cohort study. Lancet Neurol. 12, 264–274 (2013). A large prospective, multicentre cohort study from Europe that describes the natural history of MSA and studies predictors for aggressive disease course.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Low, P. A. et al. Natural history of multiple system atrophy in the USA: a prospective cohort study. Lancet Neurol. 14, 710–719 (2015). A large prospective, multicentre cohort study from the USA that explores the natural history and determining predictors of accelerated decline in MSA.

    Article  PubMed  PubMed Central  Google Scholar 

  5. 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). Current neuropathological criteria to diagnose definite MSA.

    Article  CAS  PubMed  Google Scholar 

  6. Stefanova, N. & Wenning, G. K. Multiple system atrophy: emerging targets for interventional therapies. Neuropathol. Appl. Neurobiol. 42, 20–32 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lee, S. J. & Masliah, E. Neurodegeneration: aggregates feel the strain. Nature 522, 296–297 (2015).

    Article  CAS  PubMed  Google Scholar 

  8. McCann, H., Cartwright, H. & Halliday, G. M. Neuropathology of alpha-synuclein propagation and braak hypothesis. Mov. Disord. 31, 152–160 (2016).

    Article  CAS  PubMed  Google Scholar 

  9. Dehay, B., Vila, M., Bezard, E., Brundin, P. & Kordower, J. H. Alpha-synuclein propagation: new insights from animal models. Mov. Disord. 31, 161–168 (2016).

    Article  PubMed  Google Scholar 

  10. Fernagut, P. O. et al. Multiple system atrophy: a prototypical synucleinopathy for disease-modifying therapeutic strategies. Neurobiol. Dis. 67, 133–139 (2014).

    Article  PubMed  Google Scholar 

  11. Krismer, F. et al. Multiple system atrophy as emerging template for accelerated drug discovery in alpha-synucleinopathies. Parkinsonism Relat. Disord. 20, 793–799 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Hughes, A. J., Daniel, S. E., Ben-Shlomo, Y. & Lees, A. J. The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain 125, 861–870 (2002).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  14. 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).

    Article  CAS  PubMed  Google Scholar 

  15. 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).

    Article  PubMed  Google Scholar 

  16. Linder, J., Stenlund, H. & Forsgren, L. Incidence of Parkinson's disease and parkinsonism in northern Sweden: a population-based study. Mov. Disord. 25, 341–348 (2010).

    Article  PubMed  Google Scholar 

  17. Winter, Y. et al. Incidence of Parkinson's disease and atypical parkinsonism: Russian population-based study. Mov. Disord. 25, 349–356 (2010).

    Article  PubMed  Google Scholar 

  18. Chio, A., Magnani, C. & Schiffer, D. Prevalence of Parkinson's disease in Northwestern Italy: comparison of tracer methodology and clinical ascertainment of cases. Mov. Disord. 13, 400–405 (1998).

    Article  CAS  PubMed  Google Scholar 

  19. 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).

    Article  CAS  PubMed  Google Scholar 

  20. Tison, F., Yekhlef, F., Chrysostome, V. & Sourgen, C. Prevalence of multiple system atrophy. Lancet 355, 495–496 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Wermuth, L., Joensen, P., Bunger, N. & Jeune, B. High prevalence of Parkinson's disease in the Faroe Islands. Neurology 49, 426–432 (1997).

    Article  CAS  PubMed  Google Scholar 

  22. The Multiple-System Atrophy Research Collaboration. Mutations in COQ2 in familial and sporadic multiple-system atrophy. N. Engl. J. Med. 369, 233–244 (2013). The first study to identify relevant functional mutations in the COQ2 gene that are associated with an increased risk of developing MSA.

  23. Wullner, U. et al. Probable multiple system atrophy in a German family. J. Neurol. Neurosurg. Psychiatry 75, 924–925 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  25. Jeon, B. S., Farrer, M. J., Bortnick, S. F. & Korean Canadian Alliance on Parkinson's Disease and Related Disorders. Mutant COQ2 in multiple-system atrophy. N. Engl. J. Med. 371, 80 (2014).

    Article  CAS  PubMed  Google Scholar 

  26. Chen, Y. P. et al. Mutation scanning of the COQ2 gene in ethnic Chinese patients with multiple-system atrophy. Neurobiol. Aging 36, 1222.e7–1222.e11 (2015).

    Article  CAS  Google Scholar 

  27. 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).

    Article  PubMed  Google Scholar 

  28. Lin, C. H., Tan, E. K., Yang, C. C., Yi, Z. & Wu, R. M. COQ2 gene variants associate with cerebellar subtype of multiple system atrophy in Chinese. Mov. Disord. 30, 436–437 (2015).

    Article  CAS  PubMed  Google Scholar 

  29. Schottlaender, L. V., Houlden, H. & Multiple-System Atrophy Brain Bank Collaboration. Mutant COQ2 in multiple-system atrophy. N. Engl. J. Med. 371, 81 (2014).

    CAS  PubMed  Google Scholar 

  30. 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).

    Article  CAS  PubMed  Google Scholar 

  31. Federoff, M. et al. Genome-wide estimate of the heritability of multiple system atrophy. Parkinsonism Relat. Disord. 22, 35–41 (2016).

    Article  CAS  PubMed  Google Scholar 

  32. Scholz, S. W. et al. SNCA variants are associated with increased risk for multiple system atrophy. Ann. Neurol. 65, 610–614 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Al-Chalabi, A. et al. Genetic variants of the alpha-synuclein gene SNCA are associated with multiple system atrophy. PLoS ONE 4, e7114 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sailer, A. et al. A genome-wide association study in multiple system atrophy. Neurology 87, 1591–1598 (2016). The first MSA genome-wide association study. Despite the fact that none of the single nucleotide polymorphisms reached genome-wide significance, single nucleotide polymorphisms in four genes ( FBXO47, ELOVL7, EDN1 and MAPT ) emerged as potentially interesting for follow-up.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Reuter, J. A., Spacek, D. V. & Snyder, M. P. High-throughput sequencing technologies. Mol. Cell 58, 586–597 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mills, J. D., Ward, M., Kim, W. S., Halliday, G. M. & Janitz, M. Strand-specific RNA-sequencing analysis of multiple system atrophy brain transcriptome. Neuroscience 322, 234–250 (2016).

    Article  CAS  PubMed  Google Scholar 

  37. 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).

    Article  CAS  PubMed  Google Scholar 

  38. Nee, L. E. et al. Environmental-occupational risk factors and familial associations in multiple system atrophy: a preliminary investigation. Clin. Auton. Res. 1, 9–13 (1991).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  40. Cho, J. W. et al. Association between parkinsonism and participation in agriculture in Korea. J. Clin. Neurol. 4, 23–28 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  43. Vanacore, N. et al. Smoking habits in multiple system atrophy and progressive supranuclear palsy. European Study Group on Atypical Parkinsonisms. Neurology 54, 114–119 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Jellinger, K. A. & Lantos, P. L. Papp-Lantos inclusions and the pathogenesis of multiple system atrophy: an update. Acta Neuropathol. 119, 657–667 (2010).

    Article  CAS  PubMed  Google Scholar 

  45. 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).

    Article  CAS  PubMed  Google Scholar 

  46. Yoshida, M. Multiple system atrophy: alpha-synuclein and neuronal degeneration. Neuropathology 27, 484–493 (2007).

    Article  PubMed  Google Scholar 

  47. Daniel, S. in Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System (eds Mathias, C. J. & Bannister, R.) 321–328 (Oxford Univ. Press, 1999).

    Google Scholar 

  48. Wenning, G. K., Ben-Shlomo, Y., Magalhaes, M., Daniel, S. E. & Quinn, N. P. Clinicopathological study of 35 cases of multiple system atrophy. J. Neurol. Neurosurg. Psychiatry 58, 160–166 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 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).

    Article  PubMed  Google Scholar 

  50. Benarroch, E. E., Schmeichel, A. M., Sandroni, P., Low, P. A. & Parisi, J. E. Involvement of vagal autonomic nuclei in multiple system atrophy and Lewy body disease. Neurology 66, 378–383 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Ozawa, T. Morphological substrate of autonomic failure and neurohormonal dysfunction in multiple system atrophy: impact on determining phenotype spectrum. Acta Neuropathol. 114, 201–211 (2007).

    Article  PubMed  Google Scholar 

  52. Hlavanda, E. et al. Brain-specific p25 protein binds to tubulin and microtubules and induces aberrant microtubule assemblies at substoichiometric concentrations. Biochemistry 41, 8657–8664 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Lindersson, E. et al. p25alpha stimulates alpha-synuclein aggregation and is co-localized with aggregated alpha-synuclein in alpha-synucleinopathies. J. Biol. Chem. 280, 5703–5715 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Song, Y. J. et al. p25alpha relocalizes in oligodendroglia from myelin to cytoplasmic inclusions in multiple system atrophy. Am. J. Pathol. 171, 1291–1303 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kovacs, G. G. et al. The brain-specific protein TPPP/p25 in pathological protein deposits of neurodegenerative diseases. Acta Neuropathol. 113, 153–161 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Braak, H. et al. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. Aging 24, 197–211 (2003).

    Article  PubMed  Google Scholar 

  57. Kordower, J. H., Chu, Y., Hauser, R. A., Freeman, T. B. & Olanow, C. W. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nat. Med. 14, 504–506 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Kordower, J. H., Chu, Y., Hauser, R. A., Olanow, C. W. & Freeman, T. B. Transplanted dopaminergic neurons develop PD pathologic changes: a second case report. Mov. Disord. 23, 2303–2306 (2008).

    Article  PubMed  Google Scholar 

  59. Desplats, P. et al. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc. Natl Acad. Sci. USA 106, 13010–13015 (2009).

    Article  CAS  PubMed  Google Scholar 

  60. Kordower, J. H. et al. Transfer of host-derived alpha synuclein to grafted dopaminergic neurons in rat. Neurobiol. Dis. 43, 552–557 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Luk, K. C. et al. Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338, 949–953 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Luk, K. C. et al. Intracerebral inoculation of pathological alpha-synuclein initiates a rapidly progressive neurodegenerative alpha-synucleinopathy in mice. J. Exp. Med. 209, 975–986 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Watts, J. C. et al. Transmission of multiple system atrophy prions to transgenic mice. Proc. Natl Acad. Sci. USA 110, 19555–19560 (2013).

    Article  CAS  PubMed  Google Scholar 

  64. Prusiner, S. B. et al. Evidence for alpha-synuclein prions causing multiple system atrophy in humans with parkinsonism. Proc. Natl Acad. Sci. USA 112, E5308–E5317 (2015). Preclinical evidence that α -synuclein assemblies derived from MSA brains induce an aggregation pathology that is consistent with MSA.

    Article  CAS  PubMed  Google Scholar 

  65. Bernis, M. E. et al. Prion-like propagation of human brain-derived alpha-synuclein in transgenic mice expressing human wild-type alpha-synuclein. Acta Neuropathol. Commun. 3, 75 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Danzer, K. M. et al. Different species of alpha-synuclein oligomers induce calcium influx and seeding. J. Neurosci. 27, 9220–9232 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Danzer, K. M., Krebs, S. K., Wolff, M., Birk, G. & Hengerer, B. Seeding induced by alpha-synuclein oligomers provides evidence for spreading of alpha-synuclein pathology. J. Neurochem. 111, 192–203 (2009).

    Article  CAS  PubMed  Google Scholar 

  68. Luk, K. C. et al. Exogenous alpha-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc. Natl Acad. Sci. USA 106, 20051–20056 (2009).

    Article  CAS  PubMed  Google Scholar 

  69. Peelaerts, W. et al. Alpha-synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 522, 340–344 (2015). The first study to describe how different α -synuclein strains can cause different pathologies.

    Article  CAS  PubMed  Google Scholar 

  70. Melki, R. Role of different alpha-synuclein strains in synucleinopathies, similarities with other neurodegenerative diseases. J. Parkinsons Dis. 5, 217–227 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Binolfi, A. et al. Intracellular repair of oxidation-damaged alpha-synuclein fails to target C-terminal modification sites. Nat. Commun. 7, 10251 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Theillet, F. X. et al. Structural disorder of monomeric alpha-synuclein persists in mammalian cells. Nature 530, 45–50 (2016).

    Article  CAS  PubMed  Google Scholar 

  73. Gilman, S. et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71, 670–676 (2008). Report on the current consensus diagnostic criteria for MSA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 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).

    Article  PubMed  Google Scholar 

  75. Saito, Y., Matsuoka, Y., Takahashi, A. & Ohno, Y. Survival of patients with multiple system atrophy. Intern. Med. 33, 321–325 (1994).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  77. 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).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  79. Kollensperger, M. et al. Red flags for multiple system atrophy. Mov. Disord. 23, 1093–1099 (2008).

    Article  PubMed  Google Scholar 

  80. Beck, R. O., Betts, C. D. & Fowler, C. J. Genitourinary dysfunction in multiple system atrophy: clinical features and treatment in 62 cases. J. Urol. 151, 1336–1341 (1994).

    Article  CAS  PubMed  Google Scholar 

  81. Freeman, R. et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin. Auton. Res. 21, 69–72 (2011).

    Article  PubMed  Google Scholar 

  82. Benarroch, E. E. et al. Involvement of medullary regions controlling sympathetic output in Lewy body disease. Brain 128, 338–344 (2005).

    Article  PubMed  Google Scholar 

  83. Benarroch, E. E., Schmeichel, A. M. & Parisi, J. E. Involvement of the ventrolateral medulla in parkinsonism with autonomic failure. Neurology 54, 963–968 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Forno, L. S. Neuropathology of Parkinson's disease. J. Neuropathol. Exp. Neurol. 55, 259–272 (1996).

    Article  CAS  PubMed  Google Scholar 

  85. Mathias, C. J. & Kimber, J. R. Postural hypotension: causes, clinical features, investigation, and management. Annu. Rev. Med. 50, 317–336 (1999).

    Article  CAS  PubMed  Google Scholar 

  86. Low, P. A. & Singer, W. Management of neurogenic orthostatic hypotension: an update. Lancet Neurol. 7, 451–458 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Donadio, V. et al. Anhidrosis in multiple system atrophy: a preganglionic sudomotor dysfunction? Mov. Disord. 23, 885–888 (2008).

    Article  PubMed  Google Scholar 

  88. Lipp, A. et al. Prospective differentiation of multiple system atrophy from Parkinson disease, with and without autonomic failure. Arch. Neurol. 66, 742–750 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Wenning, G. K., Colosimo, C., Geser, F. & Poewe, W. Multiple system atrophy. Lancet Neurol. 3, 93–103 (2004).

    Article  PubMed  Google Scholar 

  90. Higo, R., Nito, T. & Tayama, N. Swallowing function in patients with multiple-system atrophy with a clinical predominance of cerebellar symptoms (MSA-C). Eur. Arch. Otorhinolaryngol. 262, 646–650 (2005).

    Article  PubMed  Google Scholar 

  91. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Quinn, N. Disproportionate antecollis in multiple system atrophy. Lancet 1, 844 (1989).

    Article  CAS  PubMed  Google Scholar 

  94. Ghorayeb, I. et al. Toward a primate model of l-dopa-unresponsive parkinsonism mimicking striatonigral degeneration. Mov. Disord. 15, 531–536 (2000).

    Article  CAS  PubMed  Google Scholar 

  95. Kaindlstorfer, C., Granata, R. & Wenning, G. K. Tremor in multiple system atrophy — a review. Tremor Other Hyperkinet. Mov. http://dx.doi.org/10.7916/D8NV9GZ9 (2013).

  96. Silber, M. H. & Levine, S. Stridor and death in multiple system atrophy. Mov. Disord. 15, 699–704 (2000).

    Article  CAS  PubMed  Google Scholar 

  97. 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).

    Article  PubMed  Google Scholar 

  98. Iranzo, A. et al. Characteristics of idiopathic REM sleep behavior disorder and that associated with MSA and PD. Neurology 65, 247–252 (2005).

    Article  CAS  PubMed  Google Scholar 

  99. Rascol, O. & Schelosky, L. 123I-metaiodobenzylguanidine scintigraphy in Parkinson's disease and related disorders. Mov. Disord. 24, S732–S741 (2009).

    Article  PubMed  Google Scholar 

  100. Paviour, D. C., Williams, D., Fowler, C. J., Quinn, N. P. & Lees, A. J. Is sphincter electromyography a helpful investigation in the diagnosis of multiple system atrophy? A retrospective study with pathological diagnosis. Mov. Disord. 20, 1425–1430 (2005).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  102. Abele, M., Riet, A., Hummel, T., Klockgether, T. & Wullner, U. Olfactory dysfunction in cerebellar ataxia and multiple system atrophy. J. Neurol. 250, 1453–1455 (2003).

    Article  PubMed  Google Scholar 

  103. Garland, E. M., Raj, S. R., Peltier, A. C., Robertson, D. & Biaggioni, I. A cross-sectional study contrasting olfactory function in autonomic disorders. Neurology 76, 456–460 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Wenning, G. K. et al. Olfactory function in atypical parkinsonian syndromes. Acta Neurol. Scand. 91, 247–250 (1995).

    Article  CAS  PubMed  Google Scholar 

  105. Brooks, D. J. & Seppi, K. Proposed neuroimaging criteria for the diagnosis of multiple system atrophy. Mov. Disord. 24, 949–964 (2009).

    Article  PubMed  Google Scholar 

  106. Tang, C. C. et al. Differential diagnosis of parkinsonism: a metabolic imaging study using pattern analysis. Lancet Neurol. 9, 149–158 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Poston, K. L. et al. Network correlates of disease severity in multiple system atrophy. Neurology 78, 1237–1244 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Poston, K. L. & Eidelberg, D. Functional brain networks and abnormal connectivity in the movement disorders. Neuroimage 62, 2261–2270 (2012).

    Article  PubMed  Google Scholar 

  109. 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).

    Article  PubMed  Google Scholar 

  110. Koga, S. et al. When DLB, PD, and PSP masquerade as MSA: an autopsy study of 134 patients. Neurology 85, 404–412 (2015). Clinicopathological study showing that misdiagnosis of MSA is common, particularly when diagnostic criteria are not applied.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Stankovic, I. et al. Cognitive impairment in multiple system atrophy: a position statement by the Neuropsychology Task Force of the MDS Multiple System Atrophy (MODIMSA) study group. Mov. Disord. 29, 857–867 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Asi, Y. T. et al. Neuropathological features of multiple system atrophy with cognitive impairment. Mov. Disord. 29, 884–888 (2014).

    Article  CAS  PubMed  Google Scholar 

  113. Abele, M., Minnerop, M., Urbach, H., Specht, K. & Klockgether, T. Sporadic adult onset ataxia of unknown etiology: a clinical, electrophysiological and imaging study. J. Neurol. 254, 1384–1389 (2007).

    Article  CAS  PubMed  Google Scholar 

  114. Wenning, G. K. & Working Group on Atypical Parkinsonism of the Austrian Parkinson's Society. Placebo-controlled trial of amantadine in multiple-system atrophy. Clin. Neuropharmacol. 28, 225–227 (2005).

    Article  CAS  PubMed  Google Scholar 

  115. Colosimo, C., Merello, M. & Pontieri, F. E. Amantadine in parkinsonian patients unresponsive to levodopa: a pilot study. J. Neurol. 243, 422–425 (1996).

    Article  CAS  PubMed  Google Scholar 

  116. 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).

    Article  PubMed  Google Scholar 

  117. Muller, J., Wenning, G. K., Wissel, J., Seppi, K. & Poewe, W. Botulinum toxin treatment in atypical parkinsonian disorders associated with disabling focal dystonia. J. Neurol. 249, 300–304 (2002).

    Article  CAS  PubMed  Google Scholar 

  118. 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).

    Article  CAS  PubMed  Google Scholar 

  119. Halaska, M. et al. Controlled, double-blind, multicentre clinical trial to investigate long-term tolerability and efficacy of trospium chloride in patients with detrusor instability. World J. Urol. 20, 392–399 (2003).

    CAS  PubMed  Google Scholar 

  120. Fowler, C. J. & O'Malley, K. J. Investigation and management of neurogenic bladder dysfunction. J. Neurol. Neurosurg. Psychiatry 74 (Suppl. 4), iv27–iv31 (2003).

    PubMed  PubMed Central  Google Scholar 

  121. Shannon, J. R. et al. Water drinking as a treatment for orthostatic syndromes. Am. J. Med. 112, 355–360 (2002).

    Article  PubMed  Google Scholar 

  122. Young, T. M. & Mathias, C. J. The effects of water ingestion on orthostatic hypotension in two groups of chronic autonomic failure: multiple system atrophy and pure autonomic failure. J. Neurol. Neurosurg. Psychiatry 75, 1737–1741 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Deguchi, K. et al. Effects of daily water drinking on orthostatic and postprandial hypotension in patients with multiple system atrophy. J. Neurol. 254, 735–740 (2007).

    Article  PubMed  Google Scholar 

  124. Freeman, R. Clinical practice. Neurogenic orthostatic hypotension. N. Engl. J. Med. 358, 615–624 (2008).

    Article  CAS  PubMed  Google Scholar 

  125. Fanciulli, A. et al. Elastic abdominal binders attenuate orthostatic hypotension in Parkinson's disease. Mov. Disord. Clin. Pract. 3, 156–160 (2016).

    Article  PubMed  Google Scholar 

  126. Jankovic, J. et al. Neurogenic orthostatic hypotension: a double-blind, placebo-controlled study with midodrine. Am. J. Med. 95, 38–48 (1993).

    Article  CAS  PubMed  Google Scholar 

  127. Low, P. A., Gilden, J. L., Freeman, R., Sheng, K. N. & McElligott, M. A. Efficacy of midodrine versus placebo in neurogenic orthostatic hypotension. A randomized, double-blind multicenter study. Midodrine Study Group. JAMA 277, 1046–1051 (1997).

    Article  CAS  PubMed  Google Scholar 

  128. Biaggioni, I. et al. Randomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa. Hypertension 65, 101–107 (2015).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Singer, W. et al. Pyridostigmine treatment trial in neurogenic orthostatic hypotension. Arch. Neurol. 63, 513–518 (2006).

    Article  PubMed  Google Scholar 

  131. Mathias, C. J., Fosbraey, P., da Costa, D. F., Thornley, A. & Bannister, R. The effect of desmopressin on nocturnal polyuria, overnight weight loss, and morning postural hypotension in patients with autonomic failure. Br. Med. J. (Clin. Res. Ed.) 293, 353–354 (1986).

    Article  CAS  Google Scholar 

  132. Fanciulli, A. et al. Supine hypertension in Parkinson's disease and multiple system atrophy. Clin. Auton. Res. 26, 97–105 (2016).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  134. Sakakibara, R. et al. Calcium polycarbophil improves constipation in primary autonomic failure and multiple system atrophy subjects. Mov. Disord. 22, 1672–1673 (2007).

    Article  PubMed  Google Scholar 

  135. Liu, Z. et al. Mosapride citrate, a novel 5-HT4 agonist and partial 5-HT3 antagonist, ameliorates constipation in parkinsonian patients. Mov. Disord. 20, 680–686 (2005).

    Article  PubMed  Google Scholar 

  136. Eichhorn, T. E. & Oertel, W. H. Macrogol 3350/electrolyte improves constipation in Parkinson's disease and multiple system atrophy. Mov. Disord. 16, 1176–1177 (2001).

    Article  CAS  PubMed  Google Scholar 

  137. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Poewe, W., Mahlknecht, P. & Krismer, F. Therapeutic advances in multiple system atrophy and progressive supranuclear palsy. Mov. Disord. 30, 1528–1538 (2015).

    Article  PubMed  Google Scholar 

  139. Holmberg, B. et al. Safety and tolerability of growth hormone therapy in multiple system atrophy: a double-blind, placebo-controlled study. Mov. Disord. 22, 1138–1144 (2007).

    Article  PubMed  Google Scholar 

  140. Bensimon, G. et al. Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders: the NNIPPS study. Brain 132, 156–171 (2009). The largest clinical trial in atypical parkinsonian disorders to date.

    Article  PubMed  Google Scholar 

  141. Dodel, R. et al. Minocycline 1-year therapy in multiple-system-atrophy: effect on clinical symptoms and [11C] (R)-PK11195 PET (MEMSA-trial). Mov. Disord. 25, 97–107 (2010).

    Article  PubMed  Google Scholar 

  142. Sacca, F. et al. A randomized clinical trial of lithium in multiple system atrophy. J. Neurol. 260, 458–461 (2013).

    Article  CAS  PubMed  Google Scholar 

  143. Low, P. A. et al. Efficacy and safety of rifampicin for multiple system atrophy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 13, 268–275 (2014). A large randomized controlled trial confirming that rifampicin does not mediate neuroprotective effects in patients with MSA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. 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). A large RCT assessing the disease-modifying efficacy of rasagiline in patients with MSA.

    Article  CAS  PubMed  Google Scholar 

  145. Dehay, B. et al. Targeting alpha-synuclein: therapeutic options. Mov. Disord. 31, 882–888 (2016).

    Article  CAS  PubMed  Google Scholar 

  146. Groft, S. C. & Rubinstein, Y. R. New and evolving rare diseases research programs at the National Institutes of Health. Public Health Genomics 16, 259–267 (2013).

    Article  CAS  PubMed  Google Scholar 

  147. Norcliffe-Kaufmann, L., Palma, J. A. & Krismer, F. Multiple system atrophy: the case for an international collaborative effort. Clin. Auton. Res. 25, 81–83 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Wenning, G. K. et al. Development and validation of the Unified Multiple System Atrophy Rating Scale (UMSARS). Mov. Disord. 19, 1391–1402 (2004). Report on the development and validation of the unified Multiple System Atrophy Rating Scale, a disease-specific and commonly used rating scale to determine the severity of motor and nonmotor symptoms in MSA.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  151. Rockenstein, E. et al. Neuronal to oligodendroglial alpha-synuclein redistribution in a double transgenic model of multiple system atrophy. Neuroreport 23, 259–264 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Miller, D. W. et al. Absence of alpha-synuclein mRNA expression in normal and multiple system atrophy oligodendroglia. J. Neural Transm. (Vienna) 112, 1613–1624 (2005).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Neurology, Medical University Innsbruck, Anichstrasse 35, Innsbruck, A-6020, Austria

    Florian Krismer & Gregor K. Wenning

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  1. Florian Krismer
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Contributions

G.K.W and F.K. contributed equally to writing the article. G.K.W researched the data for the article, and provided a substantial contribution to discussions of the content and to review and editing of the manuscript before submission.

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Correspondence to Gregor K. Wenning.

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The authors declare no competing financial interests.

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Glossary

Permissive templating

Also known as seeding, permissive templating is a phenomenon whereby some protein assemblies can induce folding of the same (or similar) protein into a disease-causing confirmation.

Orphan disease

A disease that affects fewer than 5 in 10,000 people (European Union) or fewer than 7.5 in 10,000 people (USA).

Argyrophilic

A histological term used to describe an affinity to silver, making the protein amenable to silver-staining techniques.

Dysarthria

Slurred or slow speech that can be difficult to understand.

Nystagmus

Involuntary, rapid and repetitive movement of the eyes.

Hypometric saccades

Saccades refer to conjugate and voluntary eye movements that shift the eyes from one target to another. A hypometric saccade is a undershoot movement of the eyes.

Neurogenic orthostatic hypotension

A sign of cardiovascular autonomic dysfunction with substantial blood pressure drops on postural challenge.

Anhidrosis

Inability to sweat.

Camptocormia

Abnormal forward flexion of the trunk that disappears when the patient is lying down.

Pisa syndrome

Lateral flexion of the trunk when sitting or standing.

Antecollis

Also known as dropped head sign: a marked forward flexion of the head and neck.

Polyminimyoclonus

Small-amplitude myoclonic movements of the hands and/or fingers.

Supranuclear gaze palsy

Inability to look in a particular direction, although reflex eye movements remain intact.

Focal dystonia

Involuntary muscular contractions affecting a muscle or a group of muscles in a circumscribed part of the body.

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Krismer, F., Wenning, G. Multiple system atrophy: insights into a rare and debilitating movement disorder. Nat Rev Neurol 13, 232–243 (2017). https://doi.org/10.1038/nrneurol.2017.26

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