Longitudinal Evaluation of Polyneuropathy in Atypical Parkinsonian Syndromes

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

this is a very interesting resarch topic, but you have very few subjects and compare 2 groups without randomization, in adition you  have baseline difference by age and otehr covariables; I recommend follow a case series design without groups comparison

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The MS addresses an important and understudied topic: the prevalence and progression of polyneuropathy in atypical parkinsonian syndromes (APS). The longitudinal design adds novelty, and the findings suggesting differential peripheral nerve involvement between MSA and PSP are potentially impactful. However, several areas require improvement to enhance clarity, scientific rigor, and overall narrative flow.

Major points:

1. The abstract would benefit from a clearer structure and stronger conclusions. The authors should explicitly state the study's novelty (noting that it is the first longitudinal investigation of this topic). Conclusions should more directly address clinical implications and study limitations, and the sample size constraints should be acknowledged to avoid overinterpretation.
2. The introduction remains with redundancies throughout, particularly repeated references to “few studies”, which need a more systematic summary. The background on PD-related polyneuropathy could be expanded, with stronger emphasis on the specific gap in APS-related data that this study seeks to address. It feels the introduction is too concise, while the discussion is too redundant.
3. Age difference exists between MSA and PSP related to PNP, although the authors state exclusion in a prior study, some discussion should be introduced regarding the possible difference related to age among the two groups.
4. The rationale behind using the lower bilateral amplitude value as the primary electrophysiological measure should be clarified. 
5. The small sample size and attrition rates require a more substantial discussion, although the authors acknowledged this in the discussion. The very limited longitudinal cohorts, such as only six MSA and six PSP patients at T2, significantly reduce statistical power and must be explicitly addressed.
6. Unlike the MSA group, the PSP findings show higher MoCA scores in the PNP subgroup. This unexpected cognitive pattern needs clearer explanation and contextualization.
7. The clarity of the Results section should be improved. The combination of small sample sizes and multiple sub-cohorts (T0–T1, T0–T2, and all three timepoints) makes the narrative difficult to follow. Additionally, Figure 2 panels A and B partially overlap, which limits readability and interpretation.

Minor issues also need attention. Many paragraphs are overly long and would benefit from being divided into shorter units, and some sentences are unnecessarily complex. Figure legends should be expanded to improve clarity. From a statistical perspective, the authors should indicate whether normality testing was conducted before selecting nonparametric tests.

Comments on the Quality of English Language

Minor issues also need attention. Many paragraphs are overly long and would benefit from being divided into shorter units, and some sentences are unnecessarily complex. 

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript entitled “Longitudinal evaluation of polyneuropathy in atypical Parkinsonian syndromes” presents a prospective longitudinal study evaluating the prevalence and progression of polyneuropathy (PNP) in patients with atypical Parkinsonian syndromes (APS), specifically multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). The topic is clinically relevant and insufficiently explored, particularly with regard to longitudinal electrophysiological changes. The study provides novel data suggesting that PNP is highly prevalent in APS and may correlate with disease severity and progression, especially in MSA.

Overall, the manuscript is well written, methodologically sound, and clearly structured. Despite the limitations related to small sample size and attrition during follow-up, the findings are of interest to clinicians and researchers working on movement disorders and peripheral nervous system involvement.

The manuscript comprises:

1. Novelty: This is, to my knowledge, the first longitudinal study systematically evaluating clinical and electrophysiological progression of PNP in both MSA and PSP.
2. Comprehensive assessment: The combination of standardized clinical scales, detailed nerve conduction studies, and laboratory exclusion of common PNP causes strengthens the validity of the results.
3. Clear distinction between synucleinopathies and tauopathies: The differential findings between MSA and PSP are interesting and clinically meaningful.
4. Well-documented methodology: Diagnostic criteria, electrophysiological definitions, and statistical methods are clearly described and appropriate.

Comments:

1. Sample size and attrition: The longitudinal cohort is relatively small, particularly at the two-year follow-up. While this is understandable given disease severity and mortality, the limitation should be more explicitly emphasized in the Discussion, especially regarding subgroup analyses.
2. Interpretation of cognitive findings: The finding that PSP patients with PNP had higher MoCA scores at baseline is counterintuitive and deserves deeper discussion. Possible explanations (selection bias, small numbers, compensatory mechanisms, or statistical fluctuation) should be addressed more explicitly.
3. PNP as a surrogate marker: The suggestion that PNP progression may serve as a surrogate marker for MSA progression is intriguing. However, the conclusion should be slightly tempered, emphasizing that this remains exploratory and hypothesis-generating rather than definitive.

Minor Comments:

1. Some tables are dense and may benefit from slight simplification or clearer highlighting of statistically significant findings.
2. Ensure consistent terminology throughout the manuscript (e.g., “polyneuropathy” vs. “PNP” at first mention in each section).
3. Minor typographical and formatting inconsistencies are present but do not affect comprehension.

The manuscript addresses an important and underexplored topic and provides novel longitudinal data. The suggested revisions mainly concern clarification and contextualization rather than additional analyses. After addressing the comments above, the manuscript will be suitable for publication.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

if sample size is very small, resampling methods are better than rank based methods, in adition, it is recommended to adjust by demographic data with significant differences, if your sample size is n=20, use logistic regression model with group as dependente variable, each outcome plus age (one model by each age), it is very important to control confounder variables in non randomized trials

Author Response

We would like to thank Reviewer 1 for their valuable and insightful comments.
Given the limited sample sizes of 13 and 9 patients, the interpretation of multivariable models such as logoristic regression is constrained. With case numbers less than 20, the risk of unstable estimates and biased odds ratios is high. Consequently, the primary focus was directed towards the utilization of descriptive statistics and non-parametric tests.
Due to the same reason, we also opted out resampling methods, as there is a risk of unstable estimates and biased variance estimates. In the literature, resampling methods are recommended for n ≥ 20 (Kabacoff 2011. R in Action Data analysis and graphics with R) or even n ≥ 50 (Chernick, M.R. (2007). When Bootstrapping Fails Along with Some Remedies for Failures. In Bootstrap Methods, M.R. Chernick (Ed.). https://doi.org/10.1002/9780470192573.ch9).
As the small number of patients is the main limitation of our study and unfortunately allows for only limited statistical analysis, we recommend further studies with larger patient numbers, also to control possible confounder variables.

We hope for the reviewer’s understanding and remain with best regards

Dr. Eun Hae Kwon 

Reviewer 2 Report

Comments and Suggestions for Authors

The authors made considerable efforts to address the concerns, and the current MS is much improved. 

Author Response

We thank Reviewer #3 for the positive and encouraging endorsement of our manuscript.

Round 3

Reviewer 1 Report

Comments and Suggestions for Authors

thnak you for your responses, if you sample size is very small, use bootstrap test, the allow ignorre sample distribution and use robust logistic model controling but at least 2 variables

Author Response

We thank the reviewer for their recommendation. We have added a bootstrap test and logistic regression analysis in the methods and results section as well as in the supplementary materials section.