Prodromal MSA Criteria, Validated: What the New Data Mean for Research and Clinical Practice

A study published in Movement Disorders in July offered the first prospective validation of the Movement Disorder Society's research diagnostic criteria for possible prodromal multiple system atrophy, a category designed to capture patients at the earliest recognizable stage of the disease. The study followed 76 patients with pure autonomic failure across eight centers for at least six years, finding that the criteria identified patients who subsequently developed MSA with a sensitivity of 92%. However, specificity ranged from 56% to 67%, and positive predictive value was limited, as a number of patients meeting the criteria ultimately developed Parkinson's disease or dementia with Lewy bodies rather than MSA.

The research emerged from more than a decade of work by Horacio Kaufmann, MD, Director of the Dysautonomia Center at NYU Langone, whose longstanding interest in blood pressure regulation led him to begin following patients with isolated autonomic failure years before the neurodegenerative synucleinopathy field had fully characterized the prodromal stage. His laboratory's longitudinal observations helped lay the groundwork for the MDS prodromal MSA category and now for its first prospective validation.

In this Q&A, Kaufmann discussed the principal gaps the validation study was designed to address, how a refined olfactory testing threshold meaningfully improved specificity without sacrificing sensitivity, and where the field stands in developing biomarkers robust enough to move prodromal MSA detection from a research category into routine clinical use.

NeurologyLive: What were the biggest gaps in the existing prodromal MSA criteria that this update was trying to close?

Horacio Kaufmann, MD: Because of my interest in BP regulation, 15 years ago, we began following patients whose only complaint was a fall in blood pressure upon standing with a blunted heart-rate response, indicating abnormal autonomic function. Within a few years, many of these patients developed Parkinson’s disease, dementia with Lewy bodies, or multiple system atrophy. This evolution suggested that isolated autonomic failure could represent a prodromal, nonmotor stage of a neurodegenerative synucleinopathy.

Based in part on these findings, the Movement Disorder Society proposed a new research diagnostic category called possible prodromal MSA.² This category was specifically designed to capture patients at the earliest recognizable stage of the disease, but the criteria had not yet been prospectively validated.

We therefore studied 76 patients with pure autonomic failure from eight centers and followed them for at least six years or until they developed a defined neurological syndrome. Using these longitudinal data, we examined whether the criteria could identify patients who subsequently developed MSA, a particular focus of our laboratory.

The criteria identified these patients with a sensitivity of 92% at six years. However, specificity was only 56% to 67%, and the positive predictive value was relatively low because several patients who met the criteria ultimately developed Parkinson’s disease or dementia with Lewy bodies, while others remained with pure autonomic failure.³ The principal gap was therefore not sensitivity, but specificity, particularly the ability to distinguish prodromal MSA from the earliest stages of other synucleinopathies.

The current study provides the first prospective evidence defining both the strengths and limitations of this research category. It also shows that a small change in the olfactory testing threshold can markedly improve specificity.³

RBD and isolated autonomic failure anchor the prodromal category, but both have significant overlap with other synucleinopathies. How does this update improve specificity without sacrificing sensitivity too early in the disease course?

It is important to clarify that this was not an update of the criteria, but a prospective validation of them. The key finding was that their diagnostic performance could be improved by refining how olfactory function is used.

Preserved smell has long been recognized as more characteristic of MSA, whereas substantial loss of smell is more common in Parkinson’s disease and dementia with Lewy bodies. The original MDS criteria exclude patients with anosmia, but this is an extreme threshold and therefore allows many patients with significant hyposmia to remain in the possible prodromal MSA category.²

In our cohort, using a stricter olfactory threshold, a University of Pennsylvania Smell Identification Test score of 28 or lower as an exclusion criterion, increased specificity to 97% and the positive predictive value to 83%. Importantly, sensitivity remained 83%. We therefore achieved a substantial improvement in specificity with only a modest reduction in sensitivity.³

This is particularly attractive because smell testing is inexpensive, noninvasive, and widely available. It does not solve the diagnostic problem by itself, but it provides a practical way to enrich research cohorts and future clinical trials with patients who are substantially more likely to develop MSA.

How close are we to having biomarkers robust enough to move prodromal MSA from a research category into routine clinical use?

We are getting closer, but we are not there yet. The most promising biomarkers are the alpha-synuclein seed amplification assay and neurofilament light chain, particularly when measured in cerebrospinal fluid.

Newer seed amplification assays can detect an MSA-associated alpha-synuclein seeding pattern and distinguish it from the pattern seen in Parkinson’s disease and dementia with Lewy bodies. In a multicenter cohort study, a novel assay detected MSA-associated seeds with an overall sensitivity of 87%, including a sensitivity of 84% in research cohorts.⁴ A subsequent comparison involving 114 patients with MSA detected MSA-type seeds in approximately 89% of cases.⁵

However, these assays still require standardization, independent replication, and prospective validation specifically in prodromal populations. Results may vary according to the assay platform, laboratory methods, sample handling, and patient population. Recent inter-assay studies illustrate that different assay conditions can have substantially different diagnostic performance in MSA.⁶

Neurofilament light chain is also promising. CSF and blood levels are generally higher in MSA than in Parkinson’s disease, and CSF measurements may provide particularly strong diagnostic separation. However, neurofilament light chain is a marker of neuroaxonal injury rather than a pathology-specific marker of MSA.^7,8 MRI, cardiac sympathetic imaging, and clinical markers such as a high post-void residual volume may provide additional information, but none is sufficiently specific to diagnose prodromal MSA on its own.

The likely solution will not be a single biomarker. It will be a combination of clinical features, quantitative autonomic and olfactory testing, and a pathology-based biomarker such as an alpha-synuclein seed amplification assay. I believe these tools are already useful for selecting patients for clinical trials. Moving into routine clinical use will require evidence that they perform reliably across laboratories and accurately predict MSA in patients who have not yet developed the full motor syndrome.

References
1. Kaufmann H, Norcliffe-Kaufmann L, Palma JA, et al. Natural history of pure autonomic failure: a United States prospective cohort. Ann Neurol. 2017;81:287-297. doi:10.1002/ana.24877.
2. Wenning GK, Stankovic I, Vignatelli L, et al. The Movement Disorder Society criteria for the diagnosis of multiple system atrophy. Mov Disord. 2022;37:1131-1148. doi:10.1002/mds.29005.
3. Millar Vernetti P, Palma JA, Biaggioni I, et al. Prospective validation of the Movement Disorder Society prodromal multiple system atrophy criteria in pure autonomic failure. Mov Disord. Published online July 13, 2026. doi:10.1002/mds.70417.
4. Concha-Marambio L, Farris CM, Holguin B, et al. Sensitivity and specificity of a seed amplification assay for diagnosis of multiple system atrophy: a multicentre cohort study. Lancet Neurol. 2025;24:122-132. doi:10.1016/S1474-4422(24)00411-X.
5. Rossi M, Baiardi S, Mammana A, et al. Comparison of two α-synuclein seed amplification assays for discrimination of Parkinson disease and atypical parkinsonism. Mov Disord. Published online 2025. doi:10.1002/mds.70017.
6. Plaza-Clar R, Weber M, Kadam V, et al. Inter-assay and inter-site performance of alpha-synuclein seed amplification assays in synucleinopathies: a multicenter 2 × 2 protocol comparison. Neurol Ther. Published online May 27, 2026. doi:10.1007/s40120-026-00965-5.
7. Singer W, Low PA, Zange L, et al. Neurofilament light chain in spinal fluid and plasma in multiple system atrophy: a prospective, longitudinal biomarker study. Clin Auton Res. 2023. PMID: 37577499.
8. Demiri S, Veltsista D, Siokas V, et al. Neurofilament light chain in cerebrospinal fluid and blood in multiple system atrophy: a systematic review and meta-analysis. Brain Sci. 2025;15:241. doi:10.3390/brainsci15030241.