Determinants of cognitive impairment in multiple system atrophy: Clinical and genetic study

Amina Nasri; Alya Gharbi; Ikram Sghaier; Saloua Mrabet; Amira Souissi; Amina Gargouri; Mouna Ben Djebara; Imen Kacem; Riadh Gouider

doi:10.1371/journal.pone.0277798

Peer Review History

Original SubmissionOctober 8, 2021
30 Mar 2022 Decision Letter - Tuhin Virmani, Editor PONE-D-21-32170Determinants of cognitive impairment in Multiple System Atrophy: Clinical and genetic studyPLOS ONE Dear Dr. Gouider, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by May 14 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Tuhin Virmani Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQ Additional Editor Comments: Dear Dr. Gouider, I apologize for the delay in your manuscript but it has been difficult to secure reviewers. I have therefore decided to proceed with the reviews of the single reviewer. If you decide to resubmit based on those requests for major revision, your manuscript will need to be sent to this reviewer and possibly additional reviewers if they can be obtained. Best regards, Tuhin Virmani [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: No ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: No ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: This manuscript appears to have been submitted in the form of a very early draft. Multiple problematic tables are presented, some of which are larger than a page and difficult to read. There are numerical errors and cells with omitted data. In some places means are provided, in some places medians, in some places both. Means are more appropriate. There are problems with the statistical analysis. The figures lack proper explanation. There are major issues with the study design. What proportion of subjects had possible vs probable MSA by the 2008 criteria? (highly relevant to diagnostic accuracy.) How long were these patients followed? Was the diagnosis made at the first or the last visit? What is the explanation for the high percentage of hallucinations? High percentage of levodopa response in some groups? I would recommend that the authors make major revisions to all sections of the manuscript, and enlist the expertise of a statistician. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0277798.r001
Revision 1
4 Jun 2022 Author Response EDITORS’ COMMENTS EDITOR: Editor: Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Authors: We appreciate the editor’s response to our submission and we believe that the modifications and revisions conducted in the manuscript will enhance the paper quality and we agree with all the comments raised by the reviewer. We hope that our revision will be suitable for publication in PLOS ONE journal. RESPONSE TO REVIEWERS’ COMMENTS REVIEWER #1: Reviewer: This manuscript appears to have been submitted in the form of a very early draft. Multiple problematic tables are presented, some of which are larger than a page and difficult to read. There are numerical errors and cells with omitted data. Authors: Done, we agree with the reviewer comments and we revised the tables. Numerical errors were addressed and the empty cells were filled. We adapted the tables to the page dimensions and we hope that our revision made the data clearer and our modifications will satisfy the reviewer. Reviewer: In some places means are provided, in some places medians, in some places both. Means are more appropriate. There are problems with the statistical analysis. Authors: Indeed, we generally used the means and +/- the standard deviation (SD). However, we purposely used the median in some cases because the data was not normally distributed. Hence, from a statistically point of view the median and the 1st quartile-3rd quartile are more appropriate. We added this explanation in the material and methods part (section statistics) and we discussed the issue with professional statistician who confirmed our methodology. Reviewer: The figures lack proper explanation. Authors: Done, we added further detailed explanation to the figure as suggested by the reviewer Reviewer: There are major issues with the study design. What proportion of subjects had possible vs probable MSA by the 2008 criteria? (highly relevant to diagnostic accuracy.) Authors: Done, we added the proportions of subjects with possible vs probable MSA by the 2008 criteria and specified the dysautonomic features that allowed this probability subtyping in the manuscript in the part of the methods and the results’parts. We are thankful for the reviewer’s careful revision. Reviewer: How long were these patients followed? Was the diagnosis made at the first or the last visit? Authors: Done, we added the mean follow-up of our cohort. It is worthy to note that the follow-up duration was calculated as the difference between the age at the last visit (or the age of death) and the age at the first consultation to our department. Furthermore, diagnostic delay was defined as the difference between the age at first consultation and the age of disease onset. These details were added to the methods ‘part. The diagnosis of MSA was raised mostly at first consultation and finally retained after performing the required work-up in order to discard other differential diagnosis or after a period of follow-up/ levodopa treatment showing subsequent resistance to levodopa or the emergence of additional clinical features favoring MSA diagnosis. The mean delay between first consultation and MSA diagnosis in our cohort was 1.42 years ranging from 0 (diagnosis made at first consultation) to 5 years. Reviewer: What is the explanation for the high percentage of hallucinations? Authors: We thank the reviewer for this interesting point that has been raised. Indeed, hallucinations not induced by drugs are considered as non-supporting features of MSA. However, according to previous reports, the frequency of MSA patients experiencing hallucinations ranged from 5.5% in the European Multiple System Atrophy registry, to 15% in studies where Neuropsychiatric Inventory was used as in our study [Watanabe H, et al, J Mov Disord. 2018]. All these details along with the corresponding reference were added to the discussion section. Reviewer: What is the explanation High percentage of levodopa response in some groups? Authors: Again, we are thankful for the careful review. Indeed, a poor levodopa response is one of the consensus criteria for the diagnosis of MSA and helps to differentiate MSA from Parkinson’s disease (PD). Nonetheless, approximately one third of patients may experience some benefit, especially if they have MSA-P, as in our patients. Indeed, in pathologically-confirmed MSA series, a positive L-dopa response was reported in 28% to 65% of patients, persisting for several years in only 13% of cases (Perez-Lloret et al. Mov Disord Clin Pract, 2015). Hence, the rate of effectiveness of levodopa found in our series is still within this range (Total MSA patients (52.1%), MSA-P (63.5%) and MSA-C (21.1%). Reviewer: I would recommend that the authors make major revisions to all sections of the manuscript, and enlist the expertise of a statistician. Authors: Done, all the sections of the manuscript were revised according to the comments made by the reviewer and the tables were revised by statistician and validated by all co-authors after discussion of the revised version of tables. We hope the changes made would satisfy the reviewer. Attachments Attachment Submitted filename: response to reviewer.docx https://doi.org/10.1371/journal.pone.0277798.r002
31 Aug 2022 Decision Letter - Tuhin Virmani, Editor PONE-D-21-32170R1Determinants of cognitive impairment in Multiple System Atrophy: Clinical and genetic studyPLOS ONE Dear Dr. Gouider, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Oct 15 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Tuhin Virmani, MD, PhD Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: (No Response) ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Partly ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: In the last year new MDS consensus criteria for the diagnosis of MSA were published. Wenning GK et al. The Movement Disorder Society Criteria for the Diagnosis of Multiple System Atrophy. Mov Disord. 2022 Jun;37(6):1131-1148. doi: 10.1002/mds.29005. Epub 2022 Apr 21. PMID: 35445419; PMCID: PMC9321158. What proportion of subjects had clinically established, clinically probable, or possible prodromal MSA? The manuscript should be updated to this new criteria. Table 1: I am confused by several sections: History of Neurodegenerative diseases: what does this mean? If this is a personal history, one would expect 100% of the MSA-P group to have parkinsonism for example. Age and duration of ataxia – Why is there such a high prevalence of ataxia in the MSA-P group? All MSA-C patients had hallucinations? UPDRS score – I assume this means the MDS-UPDRS III score? This should be specified. How was levodopa-response defined? Table 2: consider omitting Table 5: consider omitting Figure 2: this should be omitted or at minimum explained more adequately. It is difficult to know what one is looking at here Regarding levodopa responsivity. The author’s response is poorly researched. Their statement about 28-65% response comes from a review article in Movement Disorders Clinical Practice that references 4 actual studies. Of those studies, by far the best quality is Wenning GK, Tison F, Ben Shlomo Y, Daniel SE, Quinn NP. Multiple system atrophy: a review of 203 pathologically proven cases. Mov Disord 1997;12:133–147 which reports 28% of patients responding to levodopa which is closer to the true number. A better explanation is warranted. In the discussion you cite a study (reference 38, Cao et al) that you say reported 32% cognitive impairment in “autopsy-confirmed MSA patients.” Reference 38 was not an autopsy confirmed study! Those patients were diagnosed clinically and not pathologically-confirmed. This must be revised. In the conclusion you neglect to mention disease duration as a major determinant for cognitive impairment. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0277798.r003
Revision 2
1 Oct 2022 Author Response RESPONSE TO THE EDITORS’ COMMENTS EDITOR: Editor: Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Authors: We appreciate the editor’s response to our submission and we believe that the modifications and revision conducted in the manuscript will enhance the paper quality and we agree with all the comments given by the reviewer. We hope that our revision will be suitable for publication in PLOS ONE journal. RESPONSE TO REVIEWERS’ COMMENTS REVIEWER #1: Reviewer: In the last year new MDS consensus criteria for the diagnosis of MSA were published. Wenning GK et al. The Movement Disorder Society Criteria for the Diagnosis of Multiple System Atrophy. Mov Disord. 2022 Jun;37(6):1131-1148. doi: 10.1002/mds.29005. Epub 2022 Apr 21. PMID: 35445419; PMCID: PMC9321158. What proportion of subjects had clinically established, clinically probable, or possible prodromal MSA? The manuscript should be updated to this new criteria. Authors: We appreciate the reviewer suggestion. Indeed, the new MDS consensus criteria for the diagnosis of MSA were published in 2022, while our study was conducted between 2003 and 2020. Therefore, we applied the Gilman criteria of 2008 (doi: 10.1212/01.wnl.0000324625.00404.15). Accordingly, our patients were stratified into 1- probable (for autonomic dysfunction: inability to control the release of urine from the bladder, with erectile dysfunction in males) or an orthostatic decrease of blood pressure within 3 min of standing by at least 30 mmHg systolic or15 mmHg diastolic) and 2- possible MSA (for autonomic dysfunction: otherwise unexplained urinary urgency, frequency or incomplete bladder emptying, erectile dysfunction in males, or significant orthostatic blood pressure decline that does not meet the level required in probable MSA). However, according to the New Criteria (2022), the stratification of MSA (clinically established /clinically probable) cannot be verified in our cohort, since the cases included in the study may not be rechecked for the requirements of the new criteria, mainly for those of orthostatic hypotension and urinary dysfunction. 1-clinically established: for instance, Neurogenic OH (≥20/10 mmHg blood pressure drop) within3 minutes of standing or head-up tilt test), Unexplained voiding difficulties with post-void urinary residual volume ≥100 mL) 2- clinically probable: Neurogenic OH (≥20/10 mmHg blood pressure drop) within 10 minutes of standing or head-up tilt test). Nonetheless, we mentioned this point in the limitation part of our manuscript. Reviewer: Table 1: I am confused by several sections: - History of Neurodegenerative diseases: what does this mean? If this is a personal history, one would expect 100% of the MSA-P group to have parkinsonism for example. Authors: We thank the reviewer for the careful revision. We meant by history of neurodegenerative diseases, the family history of neurodegenerative diseases. We added this information in the table 1. Reviewer: Table 1: - Age and duration of ataxia – Why is there such a high prevalence of ataxia in the MSA-P group? Authors: In the study of Roncevic et al (doi:10.1007/s00702-013-1133-7.), where included 100 MSA patients were included and stratified into 60 MSA-P and 40 MSA-C (Four patients eventually had post mortem neuropathological confirmation), the authors reported 32% out of the 60 MSA-P patients had Gait Ataxia and 25% of MSA-P exhibit a limb ataxia. These frequencies are higher than our findings (15% (8 out of 52) of our MSA-P patients). Reviewer: Table 1: - All MSA-C patients had hallucinations? Authors: We appreciate the reviewer’s careful revision. Indeed, the totality of MSA-C cases did not have hallucinations, and it was a typos mistake as the frequencies are correct for the total population of MSA ((6 out of 71) 8.45%). We corrected the typos in the table, which has been added in the supplementary materials according to the reviewer’s instructions. Reviewer: Table 1: -UPDRS score – I assume this means the MDS-UPDRS III score? This should be specified. Authors: Done, we are grateful for the detailed revision of the reviewer. We added this specification in the methods’ part as well as in the table footnote. Reviewer: Table 1: -How was levodopa-response defined? Authors: Done. We defined the levodopa-response in the methods section. Reviewer: Table 2: consider omitting Table 5: consider omitting Authors: Done the tables were omitted from the manuscript and submitted as supplementary data. Reviewer: Figure 2: this should be omitted or at minimum explained more adequately. It is difficult to know what one is looking at here Authors: Done, we omitted the figure. Reviewer: Regarding levodopa responsivity. The author’s response is poorly researched. Their statement about 28-65% response comes from a review article in Movement Disorders Clinical Practice that references 4 actual studies. Of those studies, by far the best quality is Wenning GK, Tison F, Ben Shlomo Y, Daniel SE, Quinn NP. Multiple system atrophy: a review of 203 pathologically proven cases. Mov Disord 1997;12:133–147 which reports 28% of patients responding to levodopa which is closer to the true number. A better explanation is warranted. Authors: We totally agree with the reviewer. However, we would like to mention that the degree of responsiveness is difficult to standardize between the existing studies. In fact, for the study of Wenning et al., 1997 which is a review and a collection of other reports of MSA cases pathologically proven, the responsiveness was considered “where available” as the best and latest response to levodopa without mentioning the details of such classification. Moreover, in the same study 28% of treated patients showed a good or excellent response to levodopa at some stage of their treatment, but for our current study, we assessed the initial levodopa response of MSA cases. Hence the discrepancy would be expected between our study and Wenning et al review. Furthermore, several methods and scales were used in the literature, going from acute levodopa challenge (ALC) (doi:10.1097/00002826-199304000-00006 and doi:10.1136/jnnp.55.11.1009) to prolonged levodopa intake at different doses and durations (doi:10.1001/archneur.1995.00540270090024, doi:10.1093/brain/113.6.1823, doi:10.1097/00002826-199012000-00007, doi:10.1002/mds.870120203, and doi:10.1093/brain/117.4.835). For the current study, we used the ALC at the dose of 250mg of levodopa to assess levodopa responsiveness. Indeed, it has been established that acute levodopa challenge may be performed to predict levodopa chronic responsiveness (doi:10.1371/journal.pone.0172145). We discussed further our finding in the discussion part and we hope that our revision will satisfy the reviewer. Reviewer: In the discussion you cite a study (reference 38, Cao et al) that you say reported 32% cognitive impairment in “autopsy-confirmed MSA patients.” Reference 38 was not an autopsy confirmed study! Those patients were diagnosed clinically and not pathologically-confirmed. This must be revised. Authors: We thank the reviewer for the comment. Indeed, the references did not correspond to the sentence. We changed the manuscript accordingly. Reviewer: In the conclusion, you neglect to mention disease duration as a major determinant for cognitive impairment. Authors: Done, we modified the sentence accordingly. We kindly thank the reviewer and the editor for their comments, which we believe have greatly contributed to enriching the content of our paper and clarifying some confusing statements. Attachments Attachment Submitted filename: response to reviewer.docx https://doi.org/10.1371/journal.pone.0277798.r004
2 Nov 2022 Decision Letter - Tuhin Virmani, Editor PONE-D-21-32170R2Determinants of cognitive impairment in Multiple System Atrophy: Clinical and genetic studyPLOS ONE Dear Dr. Gouider, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. As per the reviewer, the authors had reported that revisions had been made to Table 1, however the submitted version did not reflect those changes. Please make the changes as reported. Please submit your revised manuscript by Dec 17 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Tuhin Virmani Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: (No Response) ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: All comments were addressed with one exception: Table 1: The authors responded to a question about the "History of Neurodegenerative Diseases" section by saying that they meant "Family History of Neurodegenerative Diseases." In their response the authors said they had made the revision to Table 1, but it does not appear that this revision was made. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0277798.r005
Revision 3
3 Nov 2022 Author Response RESPONSE TO THE EDITORS’ COMMENTS EDITOR: Editor: Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. As per the reviewer, the authors had reported that revisions had been made to Table 1, however the submitted version did not reflect those changes. Please make the changes as reported. Authors: We appreciate the editor’s response to our submission. The changes requested by the reviewer have been made. We hope that our revision will be suitable for publication in PLOS ONE journal. RESPONSE TO REVIEWERS’ COMMENTS REVIEWER #1: Reviewer: All comments were addressed with one exception: Table 1: The authors responded to a question about the "History of Neurodegenerative Diseases" section by saying that they meant "Family History of Neurodegenerative Diseases." In their response the authors said they had made the revision to Table 1, but it does not appear that this revision was made. Authors: We thank the reviewer for the careful revision. We made the requested changes and added this information in Table 1. . We kindly thank the reviewer and the editor for their comments throughout the whole revision process, which we believe have greatly contributed to enriching the content of our paper. Attachments Attachment Submitted filename: response to reviewer.docx https://doi.org/10.1371/journal.pone.0277798.r006
4 Nov 2022 Decision Letter - Tuhin Virmani, Editor Determinants of cognitive impairment in Multiple System Atrophy: Clinical and genetic study PONE-D-21-32170R3 Dear Dr. Gouider, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Tuhin Virmani Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0277798.r007

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