Association between Toxoplasma gondii seropositivity and serointensity and brain volume in adults: A cross-sectional study

Lance D. Erickson; Bruce L. Brown; Shawn D. Gale; Dawson W. Hedges

doi:10.1371/journal.pone.0245994

Peer Review History

Original SubmissionSeptember 23, 2020
18 Nov 2020 Decision Letter - Niels Bergsland, Editor PONE-D-20-30012 Association between Toxoplasma gondii Seropositivity and Serointensity and Brain Volume in Adults: A Cross-Sectional Study PLOS ONE Dear Dr. Gale, 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. In addition to the comments from the Reviewers, I see that “gender” is used throughout the manuscript, although "sex" is also used. Usually, “sex” (the biological designation) is meant. “Gender” is the social construct and is rarely relevant in the context of the current manuscript. Please revise the text to use “sex” rather than “gender” throughout. Please submit your revised manuscript by Jan 02 2021 11:59PM. 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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: Associating Toxoplasma gondii to regional brain volume is an interesting research question. The authors used data available from UKBioBank to assess the relationship between serological data for exposure to Toxoplasma gondii and five prefrontal brain regions, the hippocampus and the thalamus. This is a very well written manuscript. The authors discuss "changes" due to Toxoplasma gondii however this is a cross-sectional study and the authors are only able to estimate "associations". Brain volume is not directly associated with cognitive ability so this is unlikely to explain reductions in those that are seropositive. Minor points: Table 1 Income should be in £ not lb. Reviewer #2: -Add the uniqueness of this study compared to other studies to discuss the same issue. -Add more on the basis of this disease in the introduction -Add shortly about routine MR imaging of brain in this disorder -Add images of brain volume for patients and controls Discus role of imaging using these refs -Discuss the merits and limitations of the technique applied ****** 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: Gordon D. Waiter Reviewer #2: Yes:** Ahmed Abdel Khalek Abdel Razek MD [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.0245994.r001
Revision 1
5 Jan 2021 Author Response Reviewer #1: Associating Toxoplasma gondii to regional brain volume is an interesting research question. The authors used data available from UK BioBank to assess the relationship between serological data for exposure to Toxoplasma gondii and five prefrontal brain regions, the hippocampus and the thalamus. This is a very well written manuscript. The authors discuss "changes" due to Toxoplasma gondii however this is a cross-sectional study and the authors are only able to estimate "associations". We fully agree that we can only estimate associations in this study. We have now either eliminated references to “changes” and have used “associations” instead or have made it clear that we mean association. Brain volume is not directly associated with cognitive ability so this is unlikely to explain reductions in those that are seropositive. This is a really good point. There is evidence, though, that in healthy individuals, total brain volume does correlate with intelligence (see meta-analysis by Pietschnig et al., 2015), although the mechanism is unclear and the overall correlations while significant are small. In addition, there is evidence that brain volume in late life is associated with concurrent cognitive function (Royle NA, et al., 2013). We have added these references and clarified that we were looking for a potential mechanism by which Toxoplasma gondii could be associated with changes in brain function including cognition. As such, we now make an argument in the revised version of the manuscript that brain volume requires consideration in understanding how Toxoplasma gondii might affect brain and cognitive function. Table 1 Income should be in £ not lb. We have made this change. Reviewer #2: Add the uniqueness of this study compared to other studies to discuss the same issue. We indicate in the introduction section that there are very few studies that have investigated the association between volumetric brain measurements and Toxoplasma gondii. The paper by Horacek et al. (2012) used a slightly different neuroimaging technique (VBM) than did the UK Biobank to compare controls with and without Toxoplasma gondii as well as those with schizophrenia who were either seropositive or seronegative. The sample size of the controls was only 56, of whom only 13 were seropositive for Toxoplasma gondii. Our use of a much larger sample size makes our study unique and less prone to error. Add more on the basis of this disease in the introduction We have added additional information about the biology and epidemiology of Toxoplasma gondii in the introduction section. Add shortly about routine MR imaging of brain in this disorder Routine MR imaging is not used clinically in latent toxoplasmosis. Further, few studies have investigated MR imaging in toxoplasmosis, and we have included in our paper the available studies that have used MR imaging in studying brain volume associated with Toxoplasma gondii. Add images of brain volume for patients and controls In our analyses, we used preprocessed MRI data made available by the UK Biobank and did not analyze the original MRI images ourselves. Although we recognize the intellectual value of presenting characteristic Toxoplasma gondii positive and negative brain images, the simple response to this request is that cannot because we do not have access to the images themselves. Furthermore, because we did not use the MRI images at any stage of our analyses, we feel that it could misrepresent the MRI data we did use as the product of our own analysis of the MRI images if we included images in our report. Please note that Table 1 contains data about brain volumes in the study sample. Discus role of imaging using these refs MRI imaging is not used clinically in latent toxoplasmosis, and few findings from studies investigating MR imaging in latent toxoplasmosis are available. Our study is one of the few available studies reporting abnormalities in brain imaging of latent toxoplasmosis. As such, there is not enough information about the role of imaging in latent toxoplasmosis. Based on the findings currently available, we believe that the best we can do is to write as we have that additional research is required to better understand the associations between Toxoplasma gondii and brain volume. Discuss the merits and limitations of the technique applied As discussed in the discussion section and other sections of the manuscript, we acknowledge the following merits: utilization of a large dataset, standardized automated neuroimaging methods, statistical adjustment for variables known to be associated with brain volume (age, sex, education etc.), and validated cognitive measures were all strengths of this study. We described the limitations including decreased power in some analyses, the inability to know when a given participant initially acquired the infection, focusing on gray-matter volume in prefrontal regions when white-matter pathways could have been affected in prefrontal regions, the potential difference that different strains of Toxoplasma gondii may be related to, and the fact that our subjects were in the middle age to late age range. These were all limitations. In the revised manuscript, we have added material about the potential for residual confounding and also mention that the cross-sectional design precludes determination of causal relationships. While presentation of potential weaknesses of our study is not necessarily exhaustive, we fell that it identifies what we think are critical issues that readers should be aware of as they read the results of the paper. https://doi.org/10.1371/journal.pone.0245994.r002
12 Jan 2021 Decision Letter - Niels Bergsland, Editor Association between Toxoplasma gondii Seropositivity and Serointensity and Brain Volume in Adults: A Cross-Sectional Study PONE-D-20-30012R1 Dear Dr. Gale, 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, Niels Bergsland Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0245994.r003
Formally Accepted
14 Jan 2021 Acceptance Letter - Niels Bergsland, Editor PONE-D-20-30012R1 Association between Toxoplasma gondii Seropositivity and Serointensity and Brain Volume in Adults: A Cross-Sectional Study Dear Dr. Gale: 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. Niels Bergsland Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0245994.r004

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