Recent Advances in Clinical Trials in Multiple System Atrophy

Poewe W, Stankovic I, Halliday G, Meissner WG, Wenning GK, Pellecchia MT, Seppi K, Palma J-A, Kaufmann H. Multiple system atrophy. Nat Rev Dis Primers. 2022;8:1–21.

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• Shahnawaz M, Mukherjee A, Pritzkow S, et al. Discriminating α-synuclein strains in Parkinson’s disease and multiple system atrophy. Nature. 2020;578:273–7. This article explores the accuracy of a seed amplification assay to detect different patterns of alpha-synuclein aggregation between MSA and PD patients. They combined different methods to compare these patterns and observed distinct conformational strains of alpha-synuclein between MSA and PD

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• Schweighauser M, Shi Y, Tarutani A, et al. Structures of α-synuclein filaments from multiple system atrophy. Nature. 2020;585:464–9. Using cryo-electron microscopy, the authors observed different structures of alpha-synuclein filaments in MSA and between MSA and DLB patients. This suggests that different alpha-synuclein strains could be related to distinct synucleinopathies

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•• Wenning GK, Stankovic I, Vignatelli L, et al. The movement disorder society criteria for the diagnosis of multiple system atrophy. Movement Disorders. 2022;37:1131–48. This revision of diagnostic criteria of MSA aims to improve diagnosis accuracy at earlier stages of the disease and describes a new category of clinically established MSA that requires the presence of brain imaging features

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Miki Y, Foti SC, Asi YT, Tsushima E, Quinn N, Ling H, Holton JL. Improving diagnostic accuracy of multiple system atrophy: a clinicopathological study. Brain. 2019;142:2813–27.

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Osaki Y, Ben-Shlomo Y, Lees AJ, Wenning GK, Quinn NP. A validation exercise on the new consensus criteria for multiple system atrophy. Mov Disord. 2009;24:2272–6.

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• Virameteekul S, Revesz T, Jaunmuktane Z, Warner TT, De Pablo-Fernández E. Pathological validation of the MDS criteria for the diagnosis of multiple system atrophy. Movement Disorders. 2023;38:444–52. This article provides evidence of enhanced diagnostic performances of the new diagnostic criteria of MSA and excellent accuracy of the new category of clinically established MSA, even at the early stages of the disease

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Wenning GK, Tison F, Seppi K, et al. Development and validation of the Unified Multiple System Atrophy Rating Scale (UMSARS). Mov Disord. 2004;19:1391–402.

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•• Krismer F, Palma J-A, Calandra-Buonaura G, et al. The unified multiple system atrophy rating scale: status, critique, and recommendations. Movement Disorders. 2022;37:2336–41. This review article describes the main limitation of the UMSARS and provides a roadmap to a revised version of the scale. The authors announced the creation of a task force of experts and the preparatory steps for an exhaustive documentation to provide a more comprehensive and patient-centered scale

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Krismer F, Seppi K, Jönsson L, et al. Sensitivity to change and patient-centricity of the unified multiple system atrophy rating scale items: a data-driven analysis. Movement Disorders. 2022;37:1425–31.

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Potashman M, Brady L, Durham S, et al (2023) Psychometric validation of a modified united multiple system atrophy rating scale (S43.002). In: Wednesday, April 26. Lippincott Williams & Wilkins, p 1958

Potashman M, Huang I, Durham S, et al. Patient concept elicitation interviews: insights into multiple system atrophy (MSA) patient experiences and relevance of a modified united multiple system atrophy rating scale (P8-9.003). In: Tuesday, April 25. Lippincott Williams & Wilkins; 2023. p. 2057.

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Palma J-A, Vernetti PM, Perez MA, 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. 2021;31:157–64.

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Foubert-Samier A, Pavy-Le Traon A, Saulnier T, Le-Goff M, Fabbri M, Helmer C, Rascol O, Proust-Lima C, Meissner WG. An item response theory analysis of the unified multiple system atrophy rating scale. Parkinsonism & Related Disorders. 2022;94:40–4.

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Foubert-Samier A, Pavy-Le Traon A, Guillet F, Le-Goff M, Helmer C, Tison F, Rascol O, Proust-Lima C, Meissner WG. Disease progression and prognostic factors in multiple system atrophy: a prospective cohort study. Neurobiol Dis. 2020;139:104813.

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Saulnier T, Philipps V, Meissner WG, Rascol O, Pavy-Le Traon A, Foubert-Samier A, Proust-Lima C. Joint models for the longitudinal analysis of measurement scales in the presence of informative dropout. Methods. 2022;203:142–51.

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Péran P, Barbagallo G, Nemmi F, Sierra M, Galitzky M, Traon AP-L, Payoux P, Meissner WG, Rascol O. MRI supervised and unsupervised classification of Parkinson’s disease and multiple system atrophy. Mov Disord. 2018;33:600–8.

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Chougar L, Faouzi J, Pyatigorskaya N, et al. Automated categorization of Parkinsonian syndromes using magnetic resonance imaging in a clinical setting. Movement Disorders. 2021;36:460–70.

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• Smith R, Capotosti F, Schain M, et al. The α-synuclein PET tracer [18F] ACI-12589 distinguishes multiple system atrophy from other neurodegenerative diseases. Nat Commun. 2023;14:6750. This article shows a promising perspective for the use of an alpha-synuclein PET tracer to enhance diagnostic performances. The authors presented a specific biding to strategic brain regions related to MSA pathology and the ability of the tracer to distinguish between MSA patients and healthy controls or other synucleinopathies

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• Poggiolini I, Gupta V, Lawton M, et al. Diagnostic value of cerebrospinal fluid alpha-synuclein seed quantification in synucleinopathies. Brain. 2022;145:584–95. In this article, the authors explored the ability of seed amplification assay to distinguish between synucleinopathies and predict disease conversion of REM-sleep behavior disorder. This highlights the potential use of this method to detect synucleinopathy at prodromal stages

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Rossi M, Candelise N, Baiardi S, et al. Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies. Acta Neuropathol. 2020;140:49–62.

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Chelban V, Nikram E, Perez-Soriano A, et al. Neurofilament light levels predict clinical progression and death in multiple system atrophy. Brain. 2022;145:4398–408.

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Singer W, Schmeichel AM, Shahnawaz M, et al. Alpha-synuclein oligomers and neurofilament light chain in spinal fluid differentiate multiple system atrophy from Lewy body synucleinopathies. Ann Neurol. 2020;88:503–12.

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Tabrizi SJ, Leavitt BR, Landwehrmeyer GB, et al. Targeting huntingtin expression in patients with Huntington’s disease. New England Journal of Medicine. 2019;380:2307–16.

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Wave Life Sciences Provides Update on Phase 1b/2a PRECISION-HD Trials - Wave Life Sciences. https://ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-provides-update-phase-1b2a-precision-hd. Accessed 17 May 2023

Alarcón-Arís D, Recasens A, Galofré M, et al. Selective α-synuclein knockdown in monoamine neurons by intranasal oligonucleotide delivery: potential therapy for Parkinson’s disease. Mol Ther. 2018;26:550–67.

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Uehara T, Choong C-J, Nakamori M, et al. Amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides targeting α-synuclein as a novel therapy for Parkinson’s disease. Sci Rep. 2019;9:7567.

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Miquel-Rio L, Alarcón-Arís D, Torres-López M, et al. Human α-synuclein overexpression in mouse serotonin neurons triggers a depressive-like phenotype. Rescue by oligonucleotide therapy. Transl Psychiatry. 2022;12:79.

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