Disease Progression in Multiple System Atrophy—Novel Modeling Framework and Predictive Factors

Abstract

Background Multiple system atrophy (MSA) is a rare and aggressive neurodegenerative disease that typically leads to death 6 to 10 years after symptom onset. The rapid evolution renders it crucial to understand the general disease progression and factors affecting the disease course. Objectives The aims of this study were to develop a novel disease‐progression model to estimate a population‐level MSA progression trajectory and predict patient‐specific continuous disease stages describing the degree of progress into the disease. Methods The disease‐progression model estimated a population‐level progression trajectory of subscales of the Unified MSA Rating Scale and the Unified Parkinson's Disease Rating Scale using patients in the European MSA natural history study. The predicted disease continuum was validated via multiple analyses based on reported anchor points, and the effect of MSA subtype on the rate of disease progression was evaluated. Results The predicted disease continuum spanned approximately 6 years, with an estimated average duration of 51 months for a patient with global disability score 0 to reach the highest level of 4. The predicted continuous disease stages were shown to be correlated with time of symptom onset and predictive of survival time. MSA motor subtype was found to significantly affect disease progression, with MSA‐parkinsonian (MSA‐P) type patients having an accelerated rate of progression. Conclusions The proposed modeling framework introduces a new method of analyzing and interpreting the progression of MSA. It can provide new insights and opportunities for investigating covariate effects on the rate of progression and provide well‐founded predictions of patient‐level future progressions. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Disease Progression in Multiple System Atrophy: The Value of Clinical Cohorts with Long Follow‐Up

“…Kühnel's study relied on 121 patients with rather advanced stage, outdated diagnosis criteria, and short follow-up of 2 years. 1,3 We replicated Kühnel's analysis on repeated Unified MSA Rating Scale sum scores I (activities of daily living) and II (motor examination) from the French MSA cohort 4 (663 patients) with maximum follow-up of 11 years, consensus diagnosis criteria, 5 and early stages at entry (see Supplementary Material Data S1 for details). MSA progression spanned a larger period than in the original paper (Fig.…”

“…In their recent publication, Kühnel et al 1 described the progression of multiple system atrophy (MSA) in the European MSA study group (EMSA-SG) cohort via an innovative disease progression model (DPM). DPMs are valuable longitudinal methods to describe MSA natural history while accounting for data uncertainty (delayed diagnosis, uncertain timing, heterogeneous staging).…”

“…Research data are not shared. Tiphaine Saulnier, MS, 1 Margherita Fabbri, MD, PhD, 2,3 Anne Pavy-Le Traon, MD, PhD, 2,3 Mélanie Le Goff, MS, 1 Catherine Helmer, PhD, 1,4 Patrice Péran, PhD, 5 Wassilios G. Meissner, MD, PhD, 6,7,8 Olivier Rascol, MD, PhD, 2,3 Alexandra Foubert-Samier, MD, PhD, 1,4,6,7…”

Reply to Letter to the Editor: “Disease Progression in Multiple System Atrophy: The Value of Clinical Cohorts with Long Follow‐Up”

“…Significant heterogeneity in a meta-analysis results in pooled estimates that are difficult to interpret, and this is very much the case here. The pooled prevalence and incidence estimates reported by Medina et al 1 do not in any meaningful sense represent the prevalence or incidence in a defined population. However, this is exactly how the pooled estimates reported in a previous meta-analysis study 5 have been used.…”

“…We read with interest the updated review of the epidemiology of Huntington's disease (HD) by Medina et al 1 In their article, the authors present results from a series of metaanalyses of prevalence and incidence studies conducted in populations in Africa, Asia, Europe, and the Americas between 2011 and 2022. Worldwide pooled estimates are reported for prevalence and incidence, along with separate pooled incidence estimates for each continent where there was more than a single study.…”