The absence of orthostatic heart rate increase is associated with cognitive impairment in Parkinson’s disease

Ryota Tanaka; Kazuo Yamashiro; Takashi Ogawa; Genko Oyama; Kenya Nishioka; Atsushi Umemura; Yasushi Shimo; Nobutaka Hattori

doi:10.1371/journal.pone.0240491

Peer Review History

Original SubmissionJuly 18, 2020
17 Aug 2020 Decision Letter - Pasquale Abete, Editor PONE-D-20-22293 The absence of orthostatic heart rate increase is associated with cognitive impairment in Parkinson’s disease PLOS ONE Dear Dr. TANAKA, 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 01 2020 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols We look forward to receiving your revised manuscript. Kind regards, Pasquale Abete 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.Thank you for stating the following in the Financial Disclosure section: [R.T. reports personal fees from honoraria: not related to the current work: Takeda Pharmaceutical Co.,Ltd., Nippon Boehringer Ingelheim,Co.,Ltd, Dai-Nippon Sumitomo Pharma Co.,Ltd., Bayer Yakuhin, Ltd, Otsuka Pharmaceutical, Co.,Ltd, Pfizer Japan Inc., , DAIICHI SANKYO Co.,Ltd., Eisai Co.,Ltd., Bristol-Myers Squibb Co., Stryker Japan K.K., CSL Behring K.K. and Kowa Co.,Ltd. K.Y. reports grants from Grants from Grant-in-Aid for Scientific Research, and personal fees from honoraria for work unrelated to the current study: Pfizer Inc,, Takeda Pharmaceutical Co.,Ltd., Dai-Nippon Sumitomo Pharma Co.,Ltd., Bayer Yakuhin, Ltd, Otsuka Pharmaceutical, Co.,Ltd., DAIICHI SANKYO Co.,Ltd., and Novartis Pharma K.K. T.O. reports the following disclosures: None K.N. reports the following disclosures: Grant from Japan Society for the Promotion of Science (JSPS) KAKENHI Grant and a research grant from Biogen Japan Ltd. not granted for the current study. G.O. reports grants from Grants from Japan Society for the Promotion of Science; Grant-in-Aid for Young Scientists (B), honoraria from work unrelated to the current study: Medtronic, Boston Scientific, Otsuka Pharmaceutical, Sumitomo Dainippon Pharma, Novartis Pharma, MSD, Nihon Medi-Physics, FP Pharmaceutical Corporation, Kyowa Hakko Kirin, and Abbvie. A.U. reports grants from Grants from Japan Society for the Promotion of Science; Grant-in-Aid for Scientific Research (C), Research Grant from Novartis Pharma K.K, consultancy: Boston Scientific Japan, and honoraria: Medtronic Japan Inc., Novartis Pharma K.K, Kyowa Hakko-Kirin Co.,Ltd., Takeda Pharmaceutical Co.,Ltd. And Abbvie, for work unrelated to the current study. Y.S. reports grants from the Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research and speaker honoraria from Medtronic, Boston Scientific, Otsuka Pharmaceutical, Takeda Pharmaceutical CO, Sumitomo Dainippon Pharma, Novartis Pharma, MSD, FP Pharmaceutical Corporation, Kyowa Hakko Kirin, and AbbVie, Inc N.H. reports grants from the Japan Society for the Promotion of Science (JSPS); grants from Ministry of Education Culture,Sports,Science and Technology Japan, grants from Health Labour Sciences Research Grant, grants from Japan Agency for Medical Research and Development (AMED), AbbVie GK, FP Pharma. Co, Dai-Nippon Sumitomo Pharma Co.,Ltd, Eisai Co.,Ltd., and received honoraria of as a speaker and advisory boards from Kyowa Kirin Co., Ltd., Dai-Nippon Sumitomo Pharma Co., Ltd, Takeda Pharmaceutical Co., Ltd., Otsuka Pharmaceutical, Co., Ltd, AbbVie GK, Eisai Co., Ltd., FP Pharma. Co, Mitsubishi Tanabe Pharma Co., Otsuka Pharmaceutical, Novartis Pharma, MSD, Nihon Medi-Physics, Bristol-Myers Squibb Company, Ono Pharmaceutical Co., Ltd., EA Pharma Co., Ltd, Asahi Kasei Medical Co., Ltd., and Chugai Pharma Manufacturing Co., Ltd. Also he received honoraria from Biogen Japan Ltd for Subcontracting (Trial cases) and he has the Equity stock (8%) of PARKINSON Laboratories Co. Ltd.]. We note that you received funding from multiple commercial sources. Please provide an amended Competing Interests Statement that explicitly states this commercial funder, along with any other relevant declarations relating to employment, consultancy, patents, products in development, marketed products, etc. Within this Competing Interests Statement, please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. Please include your amended Competing Interests Statement within your cover letter. We will change the online submission form on your behalf. Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests Additional Editor Comments (if provided): The authors retrospectively analyzed 147 cases of clinically diagnosed PD to determine the association between the absence of a heart rate response and cognitive impairment in PD with OH. Among the patients with OH, neurogenic OH was diagnosed in cases without a heart rate increase, while all other patients were diagnosed with nonneurogenicOH. Dementia was found in 25 of 147 PD cases (17%) in this cohort. The presence of OH was an independent risk factor for dementia in PD in addition to the disease severity and years of education. Neurogenic OH was significantly associated with dementia compared to the no OH group (harzard ratio [HR] 8.2, 95% confidence interval [CI] 2.5-26.9, P<0.001), an association that was preserved after adjusting for age, gender and other covariant factors. However, no such association was observed for non-neurogenic OH (HR 2.7, 95%CI 0.7-10.5, P=0.13). While the cognitive impairment was significantly worse in the neurogenic OH group than the no-OH group, the groups were otherwise similar. The blood pressure decrease was significantly lower in both OH groups than in the no-OH group, despite no significant differences between the OH groups. The manuscript is interesting. However, I have a concern regarding the presence of syncope and/or unexplained falls in this sample. Please see and discuss Ungar A: Etiology of Syncope and Unexplained Falls in Elderly Adults with Dementia: Syncope and Dementia (SYD) Study. J Am Geriatr Soc. 2016 Aug;64(8):1567-73. [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 Reviewer #2: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 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: Yes Reviewer #2: Yes ****** 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 Reviewer #2: 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: The paper is of interest and the association between orthostatic hypotension (OH) , cognitive impairment and Parkinson’s disease (PD) is clinically relevant. The association between the heart rate response and cognitive impairment was retrospectively analyzed in 147 cases of clinically diagnosed PD to determine the association between the absence of a heart rate response and cognitive impairment in PD with OH. Among the patients with OH, neurogenic OH was diagnosed in caseswithout a heart rate increase, while all other patients were diagnosed with non-neurogenic OH. Dementia was found in 25 of 147 PD cases (17%). Neurogenic OH was significantly associatedwith dementia compared to the no OH group (harzard ratio [HR] 8.2, 95% confidenceinterval [CI] 2.5-26.9, P<0.001), an association that was preserved after adjusting forage, gender and other covariate. No association was observedfor non-neurogenic OH (HR 2.7, 95%CI 0.7-10.5, P=0.13). The manuscript is well written, data support conclusions. Reviewer #2: The paper is interesting, resulting in a great impact on management of PD patients. The correlation of dementia in PD patients with neurogenic OH is a relevant finding to better understand evolution and prognosis of PD. However, some aspects should be more extensively argued to avoid confounding data. Major revision Materials and methods: In this study, drugs were not considered with exception of anti-hypotensive medications and levodopa. The influence of some classes of medications on postural response of arterial pressure is well known. In particular, there is no mention about beta-blockers. Patients with congestive heart failure were excluded from the study, but use of beta-blockers is also and often requested in hypertensive patients or in coronary artery disease (enrolled in this study). This class of medications could fade postural heart rate response leading to a wrong diagnosis of neurogenic OH. The study should be improved by adding data on medications to avoid that the association of neurogenic OH with dementia in PD patients is considered only a winsome suggestion. ****** 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 Reviewer #2: 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.0240491.r001
Revision 1
14 Sep 2020 Author Response Response to reviewers, Additional Editor Comments (if provided): The authors retrospectively analyzed 147 cases of clinically diagnosed PD to determine the association between the absence of a heart rate response and cognitive impairment in PD with OH. Among the patients with OH, neurogenic OH was diagnosed in cases without a heart rate increase, while all other patients were diagnosed with nonneurogenicOH. Dementia was found in 25 of 147 PD cases (17%) in this cohort. The presence of OH was an independent risk factor for dementia in PD in addition to the disease severity and years of education. Neurogenic OH was significantly associated with dementia compared to the no OH group (harzard ratio [HR] 8.2, 95% confidence interval [CI] 2.5-26.9, P<0.001), an association that was preserved after adjusting for age, gender and other covariant factors. However, no such association was observed for non-neurogenic OH (HR 2.7, 95%CI 0.7-10.5, P=0.13). While the cognitive impairment was significantly worse in the neurogenic OH group than the no-OH group, the groups were otherwise similar. The blood pressure decrease was significantly lower in both OH groups than in the no-OH group, despite no significant differences between the OH groups. The manuscript is interesting. However, I have a concern regarding the presence of syncope and/or unexplained falls in this sample. Please see and discuss Ungar A: Etiology of Syncope and Unexplained Falls in Elderly Adults with Dementia: Syncope and Dementia (SYD) Study. J Am Geriatr Soc. 2016 Aug;64(8):1567-73. Response: We thank the editor for the important suggestion concerning the presence of syncope and unexplained fall in this study. Unfortunately, we did not collect information on syncope or unexplained fall in this study, so we could not analyze these issues. However, as the editor indicated, whether or not syncope and unexplained fall are risks for dementia and the relationship between orthostatic hypotension and syncope or unexplained fall in PD are clinically important issues. We have now mentioned this in the Discussion of the revised manuscript (page 18, line 267-271, page 198, line 272). Reviewer #1: The paper is of interest and the association between orthostatic hypotension (OH) , cognitive impairment and Parkinson’s disease (PD) is clinically relevant. The association between the heart rate response and cognitive impairment was retrospectively analyzed in 147 cases of clinically diagnosed PD to determine the association between the absence of a heart rate response and cognitive impairment in PD with OH. Among the patients with OH, neurogenic OH was diagnosed in caseswithout a heart rate increase, while all other patients were diagnosed with non-neurogenic OH. Dementia was found in 25 of 147 PD cases (17%). Neurogenic OH was significantly associatedwith dementia compared to the no OH group (harzard ratio [HR] 8.2, 95% confidenceinterval [CI] 2.5-26.9, P<0.001), an association that was preserved after adjusting forage, gender and other covariate. No association was observedfor non-neurogenic OH (HR 2.7, 95%CI 0.7-10.5, P=0.13). The manuscript is well written, data support conclusions. Rensponse: We thank the reviewer for this positive evaluation. In accordance with the comment from the academic editor and Reviewer 2, we modified the manuscript accordingly. Reviewer #2: The paper is interesting, resulting in a great impact on management of PD patients. The correlation of dementia in PD patients with neurogenic OH is a relevant finding to better understand evolution and prognosis of PD. However, some aspects should be more extensively argued to avoid confounding data. Major revision Materials and methods: In this study, drugs were not considered with exception of anti-hypotensive medications and levodopa. The influence of some classes of medications on postural response of arterial pressure is well known. In particular, there is no mention about beta-blockers. Patients with congestive heart failure were excluded from the study, but use of beta-blockers is also and often requested in hypertensive patients or in coronary artery disease (enrolled in this study). This class of medications could fade postural heart rate response leading to a wrong diagnosis of neurogenic OH. The study should be improved by adding data on medications to avoid that the association of neurogenic OH with dementia in PD patients is considered only a winsome suggestion. Response: First, we reviewed the data and found four patients had been treated with midodrine during the investigation. We apologize for our mistake, and those four patients have been excluded from this study. As the reviewer suggested, we reviewed the data again and added the information on anti-hypertensive medications such as angiotensin-converting-enzyme inhibitors (ACE-Is), angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), beta blockers, and diuretics. There were no patients who were treated with ACE-Is. There were no significant differences in the prevalence of the use of any anti-hypertensive medications, except for beta-blockers, between PD and PDD (Table 1). Beta-blocker use was found in only four patients, including two patients who used these agents for hypertension and another two patients who used them for tremor. The basal results showed a similar trend to the original data; however, beta-blocker use was significantly associated with PDD (Table 2), and the ORs for dementia of non-neurogenic OH were significant after adjusting for beta-blocker use (Table 3). Because the number of patients prescribed beta-blockers in this study was very small, we were unable to draw any conclusion regarding whether or not beta-blocker use is a risk factors significantly associated with dementia in PD. Further, large-scale clinical studies will be needed to clarify this issue. We have now revised these results in the Abstract (page 3), Methods (page 7, line 87, line 90-93), and Results (page 10, line 140, line 146-147, page 11, line 151, line 154-157, page 12, line 167-174, page 13, line 185-187) sections and all tables. We also discussed this in the Discussion section (page 14, line 198, page 15, line 201, page 18, line 257-263, line 267-271, page 19, line 272). Attachments Attachment Submitted filename: Response to Reviewers PLOS ONE [PONE-D-20-22293].docx https://doi.org/10.1371/journal.pone.0240491.r002
28 Sep 2020 Decision Letter - Pasquale Abete, Editor The absence of orthostatic heart rate increase is associated with cognitive impairment in Parkinson’s disease PONE-D-20-22293R1 Dear Dr. TANAKA, 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, Pasquale Abete Academic Editor PLOS ONE Additional Editor Comments (optional): No further comments. 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: All comments have been addressed Reviewer #2: All comments have been addressed ******** 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 Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: 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 Reviewer #2: 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 Reviewer #2: 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: (No Response) Reviewer #2: The authors have fully addressed my comments. The correlation between the absence of heart rate response to postural change and dementia in patients affected by Parkinson disease should be an interesting subject to be more extensively treated in the future. ****** 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 Reviewer #2: No https://doi.org/10.1371/journal.pone.0240491.r003
Formally Accepted
2 Oct 2020 Acceptance Letter - Pasquale Abete, Editor PONE-D-20-22293R1 The absence of orthostatic heart rate increase is associated with cognitive impairment in Parkinson’s disease Dear Dr. Tanaka: 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 Prof. Pasquale Abete Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0240491.r004

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .