Corpus callosum anatomical changes in Alzheimer patients and the effect of acetylcholinesterase inhibitors on corpus callosum morphometry

Ramada R. Khasawneh; Ejlal Abu-El-Rub; Ayman Alzu’bi; Gamal T. Abdelhady; Hana S. Al-Soudi

doi:10.1371/journal.pone.0269082

Peer Review History

Original SubmissionFebruary 14, 2022
8 Mar 2022 Decision Letter - Yasmina Abd‐Elhakim, Editor PONE-D-22-04511Corpus Callosum anatomical changes in Alzheimer patients and the effect of acetylcholinesterase inhibitors on Corpus Callosum morphometryPLOS ONE Dear Dr. Khasawneh, 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 Apr 22 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. 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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, Yasmina Abd‐Elhakim 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. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified (1) whether consent was informed and (2) what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information. If you are reporting a retrospective study of medical records or archived samples, please ensure that you have discussed whether all data were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data from their medical records used in research, please include this information. 3. Thank you for stating the following financial disclosure: "NO, The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." At this time, please address the following queries: a) Please clarify the sources of funding (financial or material support) for your study. List the grants or organizations that supported your study, including funding received from your institution. b) State what role the funders took in the study. If the funders had no role in your study, please state: “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.” c) If any authors received a salary from any of your funders, please state which authors and which funders. d) If you did not receive any funding for this study, please state: “The authors received no specific funding for this work.” Please include your amended statements within your cover letter; we will change the online submission form on your behalf. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer #1: S.No. Saction Line no. Remarks 1. Methods Explain how the sample size was calculated. 2. Methods 139, 140 The total study sample size is 439. The study participants written were divided into the groups: 300 healthy control and 130 patients with Alzheimer disease. So total no. of participants were 130+300=430. What about remaining 9 patients. 3. Methods 141-144 Explain briefly about clinical dementia rating (CDR) and mini-mental state examination (MMSE) scores and criteria for differentiation into mild & severe Alzheimer disease. Authors have taken into account only mild & severe cases. What about moderate cases. 4. Methods 145-149 Since the study is retrospective, methodology is written in present tense. Need corrections. 5. Methods 158-159 Authors are requested to explain that how did they differentiate between medications-related dementia & mild Alzheimer disease. 6. Results 225-227 Authors validate the appropriateness to exclude the age and gender themself as a factors that could affect the CC size but the sample size is too small in the present study to validate. Authors are requested to confirm validation with reference to previous studies. 7. Results Discussion 278 – 287, 415-416 Authors should comment upon clinical outcome of the disease after medications and side effects if any due to chronic use of ace inhibitors. 8. Discussion 345 – 349 Irrelevant, can be omitted Reviewer #2: This manuscript presents corpus callosum (CC) measurements for a large number of normal human subjects (150 males; 150 females) in comparison to comparable measurements from 130 Alzheimer’s Disease patients (55 males; 75 females). The authors report no sex differences for the controls, and significant reductions in CC measurements for the patient population. For a large subset of the patient population (n=70), the authors also report improvements in MMSE scores and increases in CC measurements associated with treatment with Donepezil, Rivastigmine, or a combination of both drugs. The authors have a quite substantial body of data, and the findings are clearly worthy of publication. That said, there are (mostly minor) issues that should be addressed. 1) It is always impressive to see authors for whom English is not their primary language develop manuscripts. This manuscript is in desperate need of editorial assistance from someone with greater proficiency in English. 2) The authors generally need to exercise more caution in describing their results. See below. 3) Line 138: the authors need to correct a typographical error – not 439, but 430 4) Line 178: for part A, CC area is in red and whole skull surface is in yellow (rather than the reverse as stated in the legend) 5) Line 204: the authors state that “The CC was larger in females than males…” This is not so, as clearly shown in Table 1 where non-significant differences are reported for all comparisons. So, one does not say, “it was larger but not significant.” One says “there were no differences.” 6) Lines 227-228: Similarly, Table 1 does not present “differences” between males and females; rather the absence of differences 7) Lines 251-252: The authors state that “The results show a significant decrease to male patients in total CC size in Alzheimer females compared to male patients.” This is not what the numbers in Table 1 say (5.11 for males; 5.72 for females. 8) Lines 252-253; Similarly, mean body thickness was not significantly smaller in females… 9) Lines 300-301: The authors state they find “no significant differences between Donepezil…and Rivastigmine…in the degree of improvement in CC size and MMSE…” Table 4 does not distinguish the drugs. 10) In examining the data presented in Supplementary Table 1, this reviewer cannot work out what exactly the “Response Percentage” axis signifies in Figure 4. I see only one patient (# 59) who showed no improvement in MMSE score. Indeed, the before and after MMSE scores presenting in the supplementary table are impressive. Why not simply graph % improvement in MMSE score with drug treatment. 11) Moreover, since the authors have MMSE and CDR scores and CC measures for the drug-treated patients, it would be of interest to see scatter plots of CC improvement versus MMSE score improvement, along with some simple correlation coefficients. The authors certainly imply a relationship between these measures, and they have the data to show the extent to which a relationship exists. 12) Lines 345-346: The authors state that “in this study, we found that women had a larger splenium than men.” They report no significant difference in Table 1. 13) Lines 369-371: The authors state that the total CC area of Alzheimer females was higher than males (yes, but Table 3 values would suggest that it is all due to differences in mean body thickness). They go on to state “A similar gender-related difference in …healthy controls.” This is not so (see Table 1). 14) The finding that CC sizes increase with drug treatment is remarkable. The authors might wish to speculate on the cause of this change. Seemingly, it would have to be to either increases in the number of fibers (which would see unlikely) or an increase in the caliber of the fibers. Are there ultrastructural data in the literature? ********** [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/. 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Revision 1
18 Apr 2022 Author Response Point-by-point response: Your valuable comments, suggestions, and remarks are highly valued and appreciated, and they will be taken into consideration. Dear Editor: 1. The manuscript meets PLOS ONE's style requirements. 2. we also attached the ethical approval as requested. 3. The authors received no specific funding for this work. 4. regarding the consent form, King Abdallah Hospital is consider as a training and medical educational facility, so the patients must sign a consent form that there data from their medical records can be used for a research purpose .. this sentence was added to the text Reviewers' comments: Reviewer #1 1. Methods 139, 140 The total study sample size is 439. The study participants written were divided into the groups: 300 healthy control and 130 patients with Alzheimer disease. So total no. of participants was 130+300=430. What about remaining 9 patients? Response: Thank you for your notification. It was a typo mistake, we already corrected the total number of participants to be 430. 2. Methods 141-144 Explain briefly about clinical dementia rating (CDR) and mini-mental state examination (MMSE) scores and criteria for differentiation into mild & severe Alzheimer disease. Authors have taken into account only mild & severe cases. What about moderate cases. Response: Thank you for your valuable comment. We are taking in consideration the cases that are mild and severe where the treatment can either slow disease progression and slow the cognitive impairment as in mild cases or restore some cognitive functions that are hugely deteriorated as in severe cases. It is difficult to find moderate cases since the majority of Alzheimer’s patients are either stays for longer time in early or severe stages while the moderate or middle-stage is so evanescent and usually considered a short term stage. As mentioned in the paper, for mild Alzheimer patients: clinical dementia rating (CDR)was 0.5 and 1 and mini-mental state examination (MMSE) scores were between 13 to 20, while for severe Alzheimer patients the CDR was 2 and 3 and MMSE score was less than 12. 3. Methods 145-149 Since the study is retrospective, methodology is written in present tense. Need corrections Response: Thank you for your insightful observation. We already went through the methodology part and re-wrote it in the past tense. 4. Methods 158-159 Authors are requested to explain that how did they differentiate between medications-related dementia & mild Alzheimer disease. Response: Dementia and Alzheimer’s disease aren’t the same. Dementia is the term applied to a group of symptoms that negatively impact memory, but Alzheimer’s is a specific progressive disease of the brain that slowly causes impairment in memory and cognitive function. Currently, many studies suggested a stronger correlation between certain drug groups and the rise in the risk of dementia in elderly patients. For example, there were several reports that linked benadryl (diphenhydramine), antipsychotics and Parkinson's medications with dementia onset. Further, Anticholinergic drugs which help in relaxing muscles by blocking acetylcholine, an important chemical that transmits messages in the nervous system, can also induce cognitive impairment. We already excluded patients who are taking medications for psychiatric and neuro- diseases or chronically used prescribed medications. 5. Results 225-227 Authors validate the appropriateness to exclude the age and gender themself as a factors that could affect the CC size but the sample size is too small in the present study to validate. Authors are requested to confirm validation with reference to previous studies Response: We thank the reviewer for their careful evaluation of our manuscript, three references were added to confirm the exclusion of age and gender as a factors that could affect the CC size. These references are numbered in the revised manuscript as 27, 28, and 29. 6. Discussion 278 – 287, 415-416 Authors should comment upon clinical outcome of the disease after medications and side effects if any due to chronic use of ace inhibitors Response: We thank you for this comment. We already mentioned in the manuscript that the improvement in CC has been associated with improvement in the clinical dementia rating (CDR) and mini-mental state examination (MMSE) scores. Since our focus to investigate the correlation between acetylcholinesterase inhibitors and CC size, we didn’t mention the side effects, further, some of the patients selected to be included in the current study are still taking these medications and no reported side effects have been found in the patients’ files. 7. Discussion 345 – 349 Irrelevant, can be omitted Response: We thank the reviewer for their careful evaluation of our manuscript. The sentence has been omitted Reviewer #2 1. It is always impressive to see authors for whom English is not their primary language develop manuscripts. This manuscript is in desperate need of editorial assistance from someone with greater proficiency in English. Response: We highly appreciated your comment. We already assigned an expert to edit and proofread the manuscript in order to correct any grammatical and spelling errors. 2. The authors generally need to exercise more caution in describing their results. See below from number 3 to number 9: Response: We thank the reviewer for his careful evaluation of our manuscript. All these mistakes were corrected as requested in the revised manuscript. 3. In examining the data presented in Supplementary Table 1, this reviewer cannot work out what exactly the “Response Percentage” axis signifies in Figure 4. I see only one patient (# 59) who showed no improvement in MMSE score. Indeed, the before and after MMSE scores presenting in the supplementary table are impressive. Why not simply graph % improvement in MMSE score with drug treatment? Response: Thank you for this suggestion. We already added a graph % labeled as fig 5 to the main text, which shows the improvement in MMSE score with drug treatment 4. Moreover, since the authors have MMSE and CDR scores and CC measures for the drug-treated patients, it would be of interest to see scatter plots of CC improvement versus MMSE score improvement, along with some simple correlation coefficients. The authors certainly imply a relationship between these measures, and they have the data to show the extent to which a relationship exists. Response: Thank you for this suggestion. We already added a scatter plots of CC improvement versus MMSE improvement to the main text, it is labeled as fig 6. 5. Lines 345-346: The authors state that “in this study, we found that women had a larger splenium than men.” They report no significant difference in Table 1 Response: We thank the reviewer this comment. It was an unintentional oversight, and we rephrased the sentence and corrected the mistake presented. 6. Lines 369-371: The authors state that the total CC area of Alzheimer females was higher than males (yes, but Table 3 values would suggest that it is all due to differences in mean body thickness). They go on to state “A similar gender-related difference in …healthy controls.” This is not so (see Table 1). Response: Thank you for this comment. The mean internal skull surface is almost constant between males and females with Alzheimer’s disease, which means that the significant difference in the body thickness lead to significant decrease in CC size in comparing to the constant internal skull surface as shown by the statistical results. 7. The finding that CC sizes increase with drug treatment is remarkable. The authors might wish to speculate on the cause of this change. Seemingly, it would have to be to either increases in the number of fibers (which would see unlikely) or an increase in the caliber of the fibers. Are there ultrastructural data in the literature? Response: We highly appreciate this suggestion. Actually the improvement in CC size with medications is an intriguing outcome to be investigated in future studies. We can anticipate possible mechanisms for this improvement. CC is responsible of interhemispheric correlations that can modulate and control many higher brain functions such as the cognition. Since these acetylcholinesterase inhibitors reduce the breakdown of Acetylcholine and boost its level in the neuronal cells, this can enhance the synaptic transmission and restore the integrity of neuronal network in the CC. It has been shown that the loss of Acetylcholine can disturb the integrity of CC and initiate its degeneration. Further, studies revealed that the presence of Acetylcholine in plentiful amount can act on the M2 muscarinic receptors of neural stem cells, thus increasing their proliferation, differentiation and recruitment which may help in restoring the nerve fibers network in the CC. The findings of the current study can be used to design future studies to rule out the possible mechanisms that lead to the improvement in CC size, and also these findings can be used to study the possible correlation between these medications and the morphometry of other structures that control the memory and cognition mainly hippocampus. https://doi.org/10.1371/journal.pone.0269082.r002
1 May 2022 Decision Letter - Yasmina Abd‐Elhakim, Editor PONE-D-22-04511R1Corpus Callosum anatomical changes in Alzheimer patients and the effect of acetylcholinesterase inhibitors on Corpus Callosum morphometryPLOS ONE Dear Dr. Khasawneh, 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 Jun 13 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, Yasmina Abd‐Elhakim 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: 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: (No Response) 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: Authors have written that This retrospective study was approved by the institutional research board. Authors didn't mention about institutional ethical committee approval. Reviewer #2: The authors have adequately addressed all of the issues raised in the initial review. They have added figures to flesh out the presentation of their results. ****** 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: Yes:** Preston E Garraghty [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.0269082.r003
Revision 2
13 May 2022 Author Response Point-by-point response: Your valuable comments, suggestions, and remarks are highly valued and appreciated, and they will be taken into consideration Journal Requirements: 1. 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 Response: Dear Editor, we have checked all the references, I would like to assure you that all references are complete and correct, and we do not have any retracted references. Reviewer #1 1. Authors have written that This retrospective study was approved by the institutional research board. Authors didn't mention about institutional ethical committee approval Response: We thank the reviewer for his careful evaluation of our manuscript, the ethical approval was claimed from the human ethical committee in the Jordan University of Science and Technology, the ethical approval number was IRB #5/134/2020, this already mentioned and highlighted in the manuscript, we also attached the ethical approval document which is in Arabic and a translated copy in English. Reviewer #2 We would like to thank Prof. Preston E Garraghty for his participation in reviewing and evaluating this paper, which help improving the manuscript, thank you. Attachments Attachment Submitted filename: Response to Reviewers 2.docx https://doi.org/10.1371/journal.pone.0269082.r004
16 May 2022 Decision Letter - Yasmina Abd‐Elhakim, Editor Corpus Callosum anatomical changes in Alzheimer patients and the effect of acetylcholinesterase inhibitors on Corpus Callosum morphometry PONE-D-22-04511R2 Dear Dr. Khasawneh, 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, Yasmina Abd‐Elhakim Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0269082.r005
Formally Accepted
26 May 2022 Acceptance Letter - Yasmina Abd‐Elhakim, Editor PONE-D-22-04511R2 Corpus Callosum anatomical changes in Alzheimer patients and the effect of acetylcholinesterase inhibitors on Corpus Callosum morphometry Dear Dr. Khasawneh: 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. Yasmina Abd‐Elhakim Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0269082.r006

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