Mild-moderate CKD is not associated with cognitive impairment in older adults in the Alzheimer’s Disease Neuroimaging Initiative cohort

Aditi Gupta; Kevin Kennedy; Jaime Perales-Puchalt; David Drew; Srinivasan Beddhu; Mark Sarnak; Jeffrey Burns; the Alzheimer’s Disease Neuroimaging Initiative

doi:10.1371/journal.pone.0239871

Peer Review History

Original SubmissionJuly 2, 2020
13 Aug 2020 Decision Letter - Tatsuo Shimosawa, Editor PONE-D-20-20489 Mild to moderate CKD is not associated with cognitive impairment in the elderly PLOS ONE Dear Dr. Gupta, 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. Two experts raised important issues. Normal vs declined eGFR should be analyzed. Also you claimed this article is focus on aged cohort but the cohort selection is not clearly described in regards of age. Please submit your revised manuscript by Sep 27 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. 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Please amend either the title on the online submission form (via Edit Submission) or the title in the manuscript so that they are identical. 3. One of the noted authors is a group or consortium Alzheimer’s Disease Neuroimaging Initiative. In addition to naming the author group, please list the individual authors and affiliations within this group in the acknowledgments section of your manuscript. Please also indicate clearly a lead author for this group along with a contact email address. 4. Thank you for including the following funding information within the acknowledgements section of your manuscript; " Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. " We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. 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Please include the updated Competing Interests Statement and Funding Statement in 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'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: Partly Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No 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: No 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: To examine whether the relationship between CKD and dementia hold true in the elderly, the authors conducted a cross-sectional secondary analysis of an established observational cohort of data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) including a non-probability sample of all ADNI participants with serum creatinine measurements at baseline. The authors showed that modestly low eGFR was not associated with lower memory or executive function in the elderly population of the ADNI cohort using multivariable linear regression analysis. The theme of this study is intriguing and the manuscript is well-written; however, there are some concerns to be addressed. 1. It is considered that eGFR correlates with the measured GFR in patients with renal dysfunction, while it is doubtful that the same correlation is shown in patients with normal renal function. How would you describe that point? 2. BMI should be entered into all multivariable models. 3. I wonder whether the decorrelation between eGFR and cognition in the multivariable linear regression analysis would be maintained when stratified by eGFR (eGFR<60 or eGFR ≥60). The authors should show the results stratified by eGFR. 4. The authors describe “Unadjusted correlation analysis showed weak negative associations of ADNI-Mem scores and ADNI-EF scores with eGFR with correlation coefficients of -0.105 (p=0.001) and -0.02, p=0.43) respectively (Figure 1)” in Page 8 and “Weak correlation between eGFR and ADNI-Mem and ADNI-EF scores were again seen (Supplementary Figure 2)” in Page 10 in the Results section. These descriptions are incorrect because some of these associations are not significant. The authors should revise these descriptions. Reviewer #2: This is a well done study examining the association of eGFR with cognitive impairment from the Alzheimers Disease Neuroimaging initiative. I have only a few minor suggestions for improvement. Could the authors include more details on entry criteria for the parent study, I don't see age criteria mentioned, perhaps include age range to clarify whether the cohort was restricted to older adults or not? Much of the rationale for why the authors chose to conduct this study in this particular cohort does not come out until the discussion. I believe the argument is that this is an older cohort without much underlying comorbidity other than dementia or mild cognitive impairment for some? Presenting this in the introduction could provide a stronger rationale for why the authors chose to conduct this study in this particular cohort. In the introduction, it would be good to present more detail on the demographic characteristics of study populations in which the association between eGFR and cognitive function has been measured. The introduction makes it sound like there have been no prior studies of cognitive impairment and eGFR in older populations? My sense is that some prior studies have been conducted in older adults, so summarizing those studies and their results would be helpful then highlighting original contribution of this study (it sounds like the contribution of this study is that it included mostly healthy older adults?) Consider less sweeping title, the authors found no association of eGFR in this particular cohort, but I am not sure this justifies the statement that there is no association in "the elderly." Maybe no association in older adults enrolled in the Alzheimers Disease Neuroimaging initiative? ****** 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: Yes:** ann ohare [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. 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Revision 1
27 Aug 2020 Author Response We thank the editors and the reviewers for their thoughtful feedback. We are also thankful for their suggestions which we believe have improved the manuscript. Our response to each concern is outlined below. Editors: 1) Normal vs declined eGFR should be analyzed. Response: We have added another multivariable linear regression analysis with this stratification of eGFR (Supplementary Table 1). 2) You claimed this article is focus on aged cohort but the cohort selection is not clearly described in regards of age. Response: We agree. We have clarified the age under methods and described the cohort in more detail under introduction in the revised manuscript. Reviewer #1 1) It is considered that eGFR correlates with the measured GFR in patients with renal dysfunction, while it is doubtful that the same correlation is shown in patients with normal renal function. How would you describe that point? Response: We agree and have clarified this further in our limitations. Obtaining measured GFR is cumbersome and impractical, eGFR is often used in both research and clinical practice. Since our study is essentially a null study and there is no association between any level of eGFR and cognition (Figure 1, Table 2), this does not alter our results or conclusion. 2) BMI should be entered into all multivariable models. Response: We have added BMI in the multivariate models. 3) I wonder whether the decorrelation between eGFR and cognition in the multivariable linear regression analysis would be maintained when stratified by eGFR (eGFR<60 or eGFR ≥60). The authors should show the results stratified by eGFR. Response: We have added this stratification of eGFR (Supplementary Table 1). 4) The authors describe “Unadjusted correlation analysis showed weak negative associations of ADNI-Mem scores and ADNI-EF scores with eGFR with correlation coefficients of -0.105 (p=0.001) and -0.02, p=0.43) respectively (Figure 1)” in Page 8 and “Weak correlation between eGFR and ADNI-Mem and ADNI-EF scores were again seen (Supplementary Figure 2)” in Page 10 in the Results section. These descriptions are incorrect because some of these associations are not significant. The authors should revise these descriptions. Response: Thank you for pointing this out. We have revised the descriptions as suggested. Reviewer #2: 1) Could the authors include more details on entry criteria for the parent study, I don't see age criteria mentioned, perhaps include age range to clarify whether the cohort was restricted to older adults or not? Response: We have added the mean age (74) in ADNI in the introduction and the age range (55-90) in the methods section where we describe the ADNI cohort. For ADNI 2 the minimum age for the normal control group and the significant memory concern group was 65 years. 2) Much of the rationale for why the authors chose to conduct this study in this particular cohort does not come out until the discussion. I believe the argument is that this is an older cohort without much underlying comorbidity other than dementia or mild cognitive impairment for some? Presenting this in the introduction could provide a stronger rationale for why the authors chose to conduct this study in this particular cohort. Response: We agree. We have added this detail in the last paragraph of the introduction in the revised manuscript. 3) In the introduction, it would be good to present more detail on the demographic characteristics of study populations in which the association between eGFR and cognitive function has been measured. The introduction makes it sound like there have been no prior studies of cognitive impairment and eGFR in older populations? My sense is that some prior studies have been conducted in older adults, so summarizing those studies and their results would be helpful then highlighting original contribution of this study (it sounds like the contribution of this study is that it included mostly healthy older adults?) Response: We agree and have added more detail about other published studies as suggested. 4) Consider less sweeping title, the authors found no association of eGFR in this particular cohort, but I am not sure this justifies the statement that there is no association in "the elderly." Maybe no association in older adults enrolled in the Alzheimer’s Disease Neuroimaging initiative? Response: Thank you for this suggestion. We have changed the title to ‘Mild-moderate CKD is not associated with cognitive impairment in older adults in the Alzheimer’s Disease Neuroimaging Initiative cohort’ to more accurately describe this study. Attachments Attachment Submitted filename: Response to Reviewers (PONE-D-20-20489).docx https://doi.org/10.1371/journal.pone.0239871.r002
15 Sep 2020 Decision Letter - Tatsuo Shimosawa, Editor Mild-moderate CKD is not associated with cognitive impairment in older adults in the Alzheimer’s Disease Neuroimaging Initiative cohort PONE-D-20-20489R1 Dear Dr. Gupta, 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, Tatsuo Shimosawa, M.D., Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): 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: The authors' responses to my comments were appropriate and to the point. I have no further comments. Reviewer #2: The authors have addressed my comments, this should be a nice contribution to the literature. I do not have additional comments on the current draft. ****** 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:** ann o'hare https://doi.org/10.1371/journal.pone.0239871.r003
Formally Accepted
29 Sep 2020 Acceptance Letter - Tatsuo Shimosawa, Editor PONE-D-20-20489R1 Mild-moderate CKD is not associated with cognitive impairment in older adults in the Alzheimer’s Disease Neuroimaging Initiative cohort Dear Dr. Gupta: 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. Tatsuo Shimosawa Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0239871.r004

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