Decreased cerebrospinal fluid orexin levels not associated with clinical sleep disturbance in Parkinson’s disease: A retrospective study

Takuya Ogawa; Yuta Kajiyama; Hideaki Ishido; Shigeru Chiba; Gajanan S. Revankar; Tomohito Nakano; Seira Taniguchi; Takashi Kanbayashi; Kensuke Ikenaka; Hideki Mochizuki

doi:10.1371/journal.pone.0279747

Peer Review History

Original SubmissionAugust 1, 2022
21 Nov 2022 Decision Letter - Claudio Liguori, Editor PONE-D-22-21585Decreased cerebrospinal fluid orexin levels not associated with clinical sleep disturbance in Parkinson’s disease: A retrospective studyPLOS ONE Dear Dr. Ogawa, 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 review the manusript giving more informations about novelty and clinical significance of the results proposed. Please submit your revised manuscript by Jan 05 2023 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. 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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. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide. Additional Editor Comments (if provided): The Authors proposed an interesting study about CSF orexin levels in patients with PD. Several studies already proposed the same topic and Authors should better delineate the novelty of their research. The main criticism is the lack of pathological reduction of CSF orexin levels in patients than controls, although CSF orexin levels at the mere statistical analysis resulted lower. Authors should better discuss their results. [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: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? 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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: Understanding the role of orexin in Parkinson’s disease (PD) is an intriguing challenge, with both physiopathological and therapeutic implications. In this retrospective study Authors tried to investigate a possible alteration of orexin levels in PD. Authors also looked for possible correlations between altered orexin levels and sleep disorders / clinical characteristics of the pathology. I appreciated Authors’ purpose and study design. The introduction of the study rightly takes into account several controversial findings. Clear rationale, appropriate methods and analysis, well-argued introduction and discussion. The major finding of this study, according to several previous reports, is that PD patients showed decreased CSF orexin levels. However, orexin levels showed no correlation with any clinical characteristic, that is, neither with sleep disorders nor with disease gravity/progression. I greatly appreciate the large number of CSF samples of PD patients, that in my opinion is a great strength of this study. The same authors well explained the limitations of the study, which do not interfere with the scientific validity of the study. Moreover, it is a well written article. ****** 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: Yes: Rocco Cerroni ******** [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.0279747.r001
Revision 1
12 Dec 2022 Author Response Response to Reviewer and Editor #1 Journal Requirements We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide. Answer to #1 Thank you for the notion. Our data is now available in the Dryad repository (https://datadryad.org/stash/share/IFCMVjwCZFzhhIQncweMKlKNH0pP4Fs1h3khfr0VAD0), as we described in the online submission system. The dataset will be available in the citation below after publication. (Ogawa, Takuya et al. (2022), dataset_of_CSF_orexin_level_in_PD_with_clinical_assessment, Dryad, Dataset, https://doi.org/10.5061/dryad.905qfttq0) #2 Additional Editor Comments The Authors proposed an interesting study about CSF orexin levels in patients with PD. Several studies already proposed the same topic and Authors should better delineate the novelty of their research. The main criticism is the lack of pathological reduction of CSF orexin levels in patients than controls, although CSF orexin levels at the mere statistical analysis resulted lower. Authors should better discuss their results. Answer to #2 We agree with your point regarding the lack of pathological reduction of CSF orexin levels in patients compared to controls, although CSF orexin levels were statistically lower. We already mentioned the novelty in terms of the large sample and various sufficient clinical evaluations. We also added a new sentence to the introduction section (p. 6 Lines 105-107) to clarify our motivation for this study. We also reconstructed the discussion section to describe the minimal pathological meaning of a decreased CSF orexin level in PD compared to controls (p. 18, Lines 350-351; p. 18, Lines 355-357; p. 20 Lines 398-400). (Section 1. Introduction) Page 6, lines 105-107: “Since previous studies had insufficient samples or used inconsistent methods of clinical assessment [10,11,13,14,16,18,19,21], the diagnostic or prognostic value of the CSF orexin level in PD lacks evidence. In this study, we measured orexin levels in the CSF samples obtained from patients with PD to clarify the role of orexin as a biomarker of PD, in the following particulars:...” (Section 2. Discussion > Orexin in PD compared to controls) Page 18, lines 348 “Our study showed that CSF orexin levels in patients with PD were lower than those in the controls. However, the pathological relevance of CSF orexin levels needs to be considered. The normal range for CSF orexin level defined for the diagnosis of narcolepsy is as follows: over 200 pg/mL is normal, between 110 and 200 pg/mL is intermediate, and under 110 pg/mL is abnormal [34].” Page 18, lines 354-356 “Although one study showed that CSF orexin levels in patients with PD decreased to an intermediate range [13], other studies demonstrated normal CSF orexin levels in these patients [11,12].” (Section 3. Discussion > Correlation of orexin with clinical characteristics) Page 20, lines 395-397 “Our study showed no significant differences in CSF orexin levels between patients with PD with and those without DAs. Since our study was retrospective, it is possible that DA had already been discontinued owing to adverse effects. A previous study showed an improvement in EDS and an increase in CSF orexin levels after switching from PPX to pergolide [14]. In clinical situations, the effect of DA use on orexin levels seems to be small, but further studies are needed to focus on cases with adverse sleep events. Taking all the results together, we believe that the decreased orexin level in patients with PD does not exert a substantial effect on the PD pathologies, at least at the relatively early stage that we have examined.“ Attachments Attachment Submitted filename: 20221211rebuttalletter.docx https://doi.org/10.1371/journal.pone.0279747.r002
15 Dec 2022 Decision Letter - Claudio Liguori, Editor Decreased cerebrospinal fluid orexin levels not associated with clinical sleep disturbance in Parkinson’s disease: A retrospective study PONE-D-22-21585R1 Dear Dr. Ogawa, 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, Claudio Liguori Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0279747.r003
Formally Accepted
21 Dec 2022 Acceptance Letter - Claudio Liguori, Editor PONE-D-22-21585R1 Decreased cerebrospinal fluid orexin levels not associated with clinical sleep disturbance in Parkinson’s disease: A retrospective study Dear Dr. Ikenaka: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Claudio Liguori Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0279747.r004

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