Association of ankle-brachial index with cognitive decline in patients with lacunar infarction

Masahiro Nakamori; Hayato Matsushima; Keisuke Tachiyama; Yuki Hayashi; Eiji Imamura; Tatsuya Mizoue; Shinichi Wakabayashi

doi:10.1371/journal.pone.0263525

Peer Review History

Original SubmissionJuly 6, 2021
15 Sep 2021 Decision Letter - Masaki Mogi, Editor PONE-D-21-22076Association of ankle-brachial index with cognitive decline in patients with lacunar infarctionPLOS ONE Dear Dr. Nakamori, 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 Reviewers well assessed this manuscript. However, several major revisions are needed in the present form. See the Reviewers’ comments and respond them appropriately. Please submit your revised manuscript by Oct 29 2021 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, Masaki Mogi 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 financial disclosure: 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. 3. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide. [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: 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: No ****** 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: This manuscript looks at the relationship between arterial health and cognition in a group of patients with lacunar infarct, but no indication of small vessel disease. The authors found an association between cognition ankle-brachial pressure index (ABI), but not brachial-ankle pulse wave velocity (baPWV). This manuscript is interesting and clear, though there are some important issues. The biggest issue with this study is that since there is no control group, it’s difficult to interpret the results in terms of stroke vs other metrics. Stroke and lacune severity were not used in the model and it is possible that these are co-linear with for example ABI. Also, the choices of what to include or not in terms of recruitment criteria seems somewhat arbitrary, further eroding the reader’s understanding of what the authors are trying to achieve. A better justification of the design would be helpful to the reader. Major and minor comments are detailed below: Major: The lack of a control groups makes it difficult to disentangle some of the variables at play. For example, since all participants have a stroke, it may be that stroke severity is related to ABI for example. The addition of a control group or a more thorough list of co-variates would enhance the interpretability of the results. Intro: The authors could do a more convincing job at explaining why it is important to look at the relationship between artery health and cognition in stroke patients with lacunas, but in the absence of WMH, microbleeds and medial temporal atrophy. In the current writing, it basically sounds like this is interesting because that’s what we did. Also, it is not clear in the concluding sentence of the intro that participants are stroke patients with lacunes. Why include lacunes specifically? No correction for multiple comparison was performed so some of the results may be spurious The authors used the median PWV of their cohort to divide the group. This may not be a meaningful cutoff in terms of physiology. It might make more sense to either do a linear regression rather than dichotomize their variable (especially since this has been shown to lead to spurious effects). Alternately, using a value from the literature shown to be associated with cognitive effects may make more sense. These limitations in the interpretation of a lack of correlation for PWV should be acknowledged in the discussion. More information on the multivariate analysis would help evaluate the manuscript. Did the authors mean least squares? How were the factors entered? All at once? Sequentially? The authors have split the MMSE into different scores, but there is no discussion of the significance of different domains being or not decreased with ABI, etc. Discussion of these results should be added. Minor: Table 1. The two last rows are missing units Figure 2. Some indication inside the figure (star perhaps) of which combinations were found to be significantly different would be helpful. Reviewer #2: In the manuscript, Nakamori et al. have shown the “Association of ankle-brachial index with cognitive decline in patients with lacunar infarction". There were several flaws. Major comments Abstract #1: The number of the patients with ABI<1.0 Please provide the number of the patients with ABI<1.0 #2: The IQR of MMSE score It is helpful if the IQR of MMSE score was provided. Methods #2: The power analysis Did the authors perform the power analysis? If not, there was some possibility that the results were derived by chance. #3: Validation data for the device used for measuring ABI Is there any validation paper for the device used for measuring ABI? If there were, please provide those. #4: ASO patients Were there any patients with symptomatic ASO. Were there any patients who needs to be performed PTA? #5: Exclusion of the patients with dementia The each IQR of MMSE was 26 or 29. There might be some patients with dementia in the groups of the lowest quartile of MMSE score. #6: Exclusion of patients with one or more microbleeds, severe WMLs, or severe medial temporal atrophy The authors excluded the patients with one or more microbleeds, severe WMLs, or severe medial temporal atrophy. However, the silent lacunae was not taken into account. Some of the patients with multiple silent lacunaes were associated with cognitive impairment, and might be confounder in this study results. #4: The level of BP It would be helpful if the BP levels were provided. I have missed the data about BP. #5: Reference for MMSE Please provide the reference for MMSE score Results #7: Laterality/ location of stroke Was there any difference in the cognitive function according to lacuna stroke lesion location and laterality? #8: Treatment of cardiovascular risk factors Cardio-cerebro vascular risk factors such as hypertension and T2DM would be associated with cognitive function. Did the antihypertensive treatment or hypoglycemic agents were investigated in the analysis? #9: Antihypertensive medication before and during in-hospital and after discharge. In this study, all the patients underwent the MMSE and ABI/baPWV measurements within three days of admission. This might be similar to the question to #3. Are there any antihypertensive medication before and during in-hospital? Such as intravenous calcium channel blockade might be associated with blood pressure on the acute phase. And this might be associated with the study results. #10: Left and right ABI Were there any difference in the laterality of ABI for the MMSE score? ****** 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:** Michiaki Nagai [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.0263525.r001
Revision 1
20 Oct 2021 Author Response Thank you for reviewing our manuscript. We appreciate your comments and suggestions. We have revised the manuscript accordingly. Our point-by-point responses are presented below. Response to the Editor Comment 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 Response 1: Thank you for the comment. We have ensured that the manuscript meets the style requirements of PLOS ONE. Comment 2: Thank you for stating the following financial disclosure: 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. Response 2: We have added the following sentence in the Funding section and the cover letter: The authors received no specific funding for this work. Comment 3: We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide. Response 3: We do not intend to make any changes in our Data Availability statement. Response to the reviewers Reviewer #1: This manuscript looks at the relationship between arterial health and cognition in a group of patients with lacunar infarct, but no indication of small vessel disease. The authors found an association between cognition ankle-brachial pressure index (ABI), but not brachial-ankle pulse wave velocity (baPWV). This manuscript is interesting and clear, though there are some important issues. The biggest issue with this study is that since there is no control group, it’s difficult to interpret the results in terms of stroke vs other metrics. Stroke and lacune severity were not used in the model and it is possible that these are co-linear with for example ABI. Also, the choices of what to include or not in terms of recruitment criteria seems somewhat arbitrary, further eroding the reader’s understanding of what the authors are trying to achieve. A better justification of the design would be helpful to the reader. Major and minor comments are detailed below: Response: We appreciate your insightful comments and advice. According to your advice, we have provided point-by-point responses to each of your comments below and denoted the corresponding revisions in the manuscript in red text. Comment 1: The lack of a control groups makes it difficult to disentangle some of the variables at play. For example, since all participants have a stroke, it may be that stroke severity is related to ABI for example. The addition of a control group or a more thorough list of co-variates would enhance the interpretability of the results. Response 1: We appreciate your advice. Unfortunately, owing to the study design, obtaining a purely normal control group was difficult. However, we have added the National Institutes of Health Stroke Scale (NIHSS) scores (stroke severity scores) as baseline data, which were statistically analyzed. We found no significant association between the NIHSS and Mini-Mental State Examination (MMSE) scores. In addition, we found no association between NIHSS scores and ankle-brachial pressure index/brachial-ankle pulse wave velocity (ABI/baPWV). In this study, we focused on lacunar infarction (mild stroke). Lacunar stroke itself does not directly affect cognitive function, because it does not damage the cerebral cortex. Therefore, we considered the presence of stroke lesions and analyzed their effect on cognitive function. However, we did not find any association. Since we focused on patients with lacunar infarction, the neurological symptoms were mild. Some patients had almost no symptoms. We considered patients with NIHSS score 0 as almost normal controls and analyzed the effects, which revealed no significant relationship with MMSE score, ABI, and baPWV. Moreover, we have added a list of covariates to enhance the statistical rigorousness. We have revised the tables and added the description in the manuscript as follows: Lines 130-134 We recorded baseline clinical characteristics, including age, sex, body mass index (BMI), duration of education, complications (hypertension, diabetes mellitus, dyslipidemia, and chronic kidney disease), current smoking, habitual drinking, and medication before admission (antihypertensive and antidiabetic drugs). The severity of stroke was evaluated using the National Institutes of Health Stroke Scale (NIHSS) [23]. 23. Lyden P, Brott T, Tilley B, Welch KM, Mascha EJ, Levine S, et al. Improved reliability of the NIH Stroke Scale using video training. NINDS TPA Stroke Study Group. Stroke. 1994;25: 2220-2226. Lines 177-183 We evaluated the influence of stroke severity on cognitive function or ABI/baPWV. Linear regression analyses showed no association between NIHSS and MMSE scores (p=0.108). Further, there was also no association between NIHSS scores and ABI or baPWV (p=0.376, p=0.233, respectively). We considered patients with NIHSS score 0 as almost normal controls and analyzed the effects, which revealed no significant relationship with MMSE score, ABI, or baPWV (p=0.646, p=0.546, p=0.132, respectively). Comment 2: Intro: The authors could do a more convincing job at explaining why it is important to look at the relationship between artery health and cognition in stroke patients with lacunas, but in the absence of WMH, microbleeds and medial temporal atrophy. In the current writing, it basically sounds like this is interesting because that’s what we did. Also, it is not clear in the concluding sentence of the intro that participants are stroke patients with lacunes. Why include lacunes specifically? Response 2: We appreciate the insightful comments. Regarding the recruitment criteria, we had to exclude cases of other pathologies, primarily those of Alzheimer’s pathology. Medial temporal atrophy is strongly associated with Alzheimer’s pathology. Microbleeds, especially cortical microbleeds are associated with amyloid (Alzheimer’s) pathology. In addition, severe white matter lesions are sometimes associated with neurodegenerative diseases such as leukoencepalopathy. We had to evaluate the interaction with covariates statistically; however, other neurodegenerative diseases or pathologies had to be excluded. Therefore, we decided the inclusion/exclusion criteria. We have explained the reason in detail in the revised manuscript. Moreover, we evaluated stroke patients focusing on lacunar infarction, because the basic mechanism of stroke differs among stroke subtypes. This difference in the mechanism could affect the results of this study. Additionally, in other stroke types, i.e., other than lacunar infarction, the stroke lesions usually involve the cerebral cortex, which itself can affect the cognitive function. Therefore, we focused on patients with lacunar infarction. We have revised the Introduction section as follows: Lines 66-80 We aimed to investigate the relationship of ABI and baPWV with cognitive function. In this study, we focused on the first-ever acute stroke and a diagnosis of lacunar infarction because the basic mechanism of stroke differs among stroke subtypes. Additionally, in other stroke types, i.e., other than lacunar infarction, the stroke lesions usually involve the cerebral cortex, which itself can affect the cognitive function. In addition, we had to exclude cases of neurodegenerative diseases, primarily those of Alzheimer’s pathology. Therefore, we tried to exclud cases with cerebral microbleeds (CMBs), white matter lesions (WMLs), and medial temporal atrophy. CMBs, especially lobar type CMBs, are associated with amyloid pathology. Severe WMLs are sometimes associated with neurodegenerative diseases such as leukoencepalopathy. Medial temporal atrophy is strongly associated with Alzheimer’s pathology. Few reports have assessed the association between atherosclerosis and cognitive decline by excluding such factors. In this study, we investigated the relationship of ABI and baPWV with cognitive function in patients with first-ever lacunar infarction and without CMBs, WMLs, and medial temporal atrophy. Comment 3: No correction for multiple comparison was performed so some of the results may be spurious Response 3: We appreciate your comment. Accordingly, for multiple comparisons, we have analyzed the data using one-way analysis of variance and Tukey’s honestly significant difference test. We have revised the manuscript (Methods and Results section) and Figure 2. Lines 143-149 Univariate analysis was used to investigate the association of MMSE scores with several factors, and a value of p = 0.10 was used to indicate statistical significance. Subsequently, multivariate analysis was performed with selected factors determined from univariate analysis. In multivariate analysis, the least squares test was performed with the selected factors, which were entered simultaneously. For multiple comparisons, the data were analyzed using one-way analysis of variance (ANOVA) and Tukey’s honestly significant difference (HSD) test. Lines 194-202 The median baPWV was 2019 cm/s. The patients were categorized into the following four groups: patients with ABI ≥ 1.0 and baPWV ≤ 2019 cm/s; ABI ≥ 1.0 and baPWV > 2019 cm/s; ABI < 1.0 and baPWV ≤ 2019 cm/s; or ABI < 1.0 and baPWV > 2019 cm/s. S2 Table presents the characteristics of each group. Fig 2 shows the MMSE scores for each group. ANOVA showed that the MMSE scores were directly and inversely correlated with ABI and baPWV, respectively (p < 0.05). Tukey’s HSD tests revealed that the MMSE scores for the group with ABI < 1.0 and baPWV > 2019 cm/s were significantly lower than those for the group with ABI ≥ 1.0 and baPWV ≤ 2019 cm/s. Comment 4: The authors used the median PWV of their cohort to divide the group. This may not be a meaningful cutoff in terms of physiology. It might make more sense to either do a linear regression rather than dichotomize their variable (especially since this has been shown to lead to spurious effects). Alternately, using a value from the literature shown to be associated with cognitive effects may make more sense. These limitations in the interpretation of a lack of correlation for PWV should be acknowledged in the discussion. Response 4: We appreciate the insightful comments and advice. Regarding baPWV, we performed linear regression as well as dichotomized analysis. The meaningful cutoff values of baPWV have varied among studies. Thus, we used the median value in this study. Lines 127-129 For baPWV, we used the higher ankle side and the cases were categorized into two groups based on the median value of the participants. In addition, we performed linear analysis for baPWV. Lines 218-222 We also performed linear analysis for baPWV. Univariate analysis showed that baPWV was associated with MMSE scores (p=0.011). However, multivariate analysis using age, BMI, education, and chronic kidney disease as covariates showed that baPWV was not significantly associated with MMSE scores (p=0.117). Comment 5: More information on the multivariate analysis would help evaluate the manuscript. Did the authors mean least squares? How were the factors entered? All at once? Sequentially? Response 5: We appreciate your valuable questions and comments. For multivariate analysis, we selected factors using univariate analysis, in which a value of p = 0.10 was used to indicate statistical significance. Then, the least squares test was performed and all factors were entered simultaneously. We have explained the process of multivariate analysis in detail as follows: Lines 143-147 Univariate analysis was used to investigate the association of MMSE scores with several factors, and a value of p = 0.10 was used to indicate statistical significance. Subsequently, multivariate analysis was performed with selected factors determined from univariate analysis. In multivariate analysis, the least squares test was performed with the selected factors, which were entered simultaneously. Comment 6: The authors have split the MMSE into different scores, but there is no discussion of the significance of different domains being or not decreased with ABI, etc. Discussion of these results should be added. Response 6: We appreciate your advice. We have added the information about the domains of MMSE in the Discussion section as follows: Lines 282-293 In our study, the sub-scores for orientation and immediate recall, but not delayed recall, were lower in the ABI < 1.0 group than in the ABI ≥ 1.0 group. In addition, the sub-scores for attention and calculation were relatively low in all patients. Patients with mild cognitive impairment and vascular features tend to exhibit decreased frontal lobar function including self-motivation and executive function [35]. In this study, sub-score analyses did not strongly suggest memory function, but attention, self-motivation, and executive function, which was not consistent with cognitive decline and vascular features. These results suggest that cerebral microangiopathy might contribute to impaired cognitive function. The mechanisms underlying the association between the pathological and physiological mechanisms remain unclear. There is a need for further studies on the correlations between lower ABI and pathology to validate the specificity of the relationship with cognitive decline. 35. Frisoni GB, Galluzzi S, Bresciani L, Zanetti O, Geroldi C Mild cognitive impairment with subcortical vascular features: clinical characteristics and outcome. J Neurol. 2002;249: 1423-1432. Comment 7: Table 1. The two last rows are missing units Response 7: We apologize for the error. We have revised the Table. Comment 8: Figure 2. Some indication inside the figure (star perhaps) of which combinations were found to be significantly different would be helpful. Response 8: We appreciate your advice. We have revised the figure and provided an indication (star) inside the figure for ease of understanding. Reviewer #2: In the manuscript, Nakamori et al. have shown the “Association of ankle-brachial index with cognitive decline in patients with lacunar infarction". There were several flaws. Response: We appreciate your insightful comments and advice. We have provided point-by-point responses to each of your comments below and denoted the corresponding revisions in the manuscript in red text. Abstract: Comment 1: The number of the patients with ABI<1.0 Please provide the number of the patients with ABI<1.0 Response 1: We provided the number of the patients with ABI<1.0 in Abstract. Line 30 We analyzed 176 patients with stroke (age 72.5 ± 11.4 years, 67 females). The median score of the Mini-Mental State Examination (MMSE) was 27. The number of the patients with ABI<1.0 was 19 (10.8%). Comment 2: The IQR of MMSE score It is helpful if the IQR of MMSE score was provided. Response 2: We have mentioned the IQR of MMSE scores in the manuscript and Table 1. Methods Comment 3: The power analysis Did the authors perform the power analysis? If not, there was some possibility that the results were derived by chance. Response 3: We appreciate your valuable comments. We have performed power analysis in advance. We have added the relevant information in the manuscript as follows: Lines 140-143 We calculated the required sample size for this study according to previous studies that compared MMSE scores with ABI/baPWV or CMBs [11, 25]. Based on an alpha level of 0.05 and power of 0.80, we estimated that we would require at least 128 participants. 11. Sugawara N, Yasui-Furukori N, Umeda T, Kaneda A, Sato Y, Takahashi I, et al. Comparison of ankle-brachial pressure index and pulse wave velocity as markers of cognitive function in a community-dwelling population. BMC Psychiatry. 2010;10: 46. 25. Nakamori M, Hosomi N, Tachiyama K, Kamimura T, Matsushima H, Hayashi Y, et al. Lobar microbleeds are associated with cognitive impairment in patients with lacunar infarction. Sci Rep 2020;10: 16410. Comment 4: Validation data for the device used for measuring ABI Is there any validation paper for the device used for measuring ABI? If there were, please provide those. Response 4: We have added the study that has validated the method of ABI/baPWV measurement as a reference. Lines 121-125 MMSE scores were recorded and ABI/baPWV measurements were performed within three days of admission for all patients [21]. The accuracy of the method of ABI/baPWV measurement has been validated previously [22]. ABI/baPWV measurements were performed using BP-203RPE III (OMRON HEALTHCARE Co., Ltd., Kyoto, Japan). 21. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12: 189-198. 22. Yamashina A, Tomiyama H, Takeda K, Tsuda H, Arai T, Hirose K, et al. Validity, Reproducibility, and clinical significance of noninvasive brachial-ankle pulse wave velocity measurement. Hypertens Res. 2002;25: 359-364. Comment 5: ASO patients Were there any patients with symptomatic ASO. Were there any patients who needs to be performed PTA? Response 5: In this study, there were no patients who had symptomatic ASO and in whom PTA had to be performed. Lines 174-183 Data pertaining to systolic and diastolic blood pressure in the four limbs and bilateral ABI and baPWV are shown in S1 Table. We investigated the association between the laterality of ABI and the MMSE score but found no association. We evaluated the influence of stroke severity on cognitive function or ABI/baPWV. Linear regression analyses showed no association between NIHSS and MMSE scores (p=0.108). Further, there was also no association between NIHSS scores and ABI or baPWV (p=0.376, p=0.233, respectively). We considered patients with NIHSS score 0 as almost normal controls and analyzed the effects, which revealed no significant relationship with MMSE score, ABI, or baPWV (p=0.646, p=0.546, p=0.132, respectively). Comment 6: Exclusion of the patients with dementia The each IQR of MMSE was 26 or 29. There might be some patients with dementia in the groups of the lowest quartile of MMSE score. Response 6: The minimum MMSE score of patients in this study was 21. However, we did not diagnose dementia on the bases of lower scores on cognitive tests. We diagnosed dementia according to the clinical history (education, occupation), data (blood, imaging, neurological, and cognitive tests), and interview with patients and their families. In this study, despite lower MMSE scores, we did not diagnose these patients with dementia. Comment 7: Exclusion of patients with one or more microbleeds, severe WMLs, or severe medial temporal atrophy. The authors excluded the patients with one or more microbleeds, severe WMLs, or severe medial temporal atrophy. However, the silent lacunae was not taken into account. Some of the patients with multiple silent lacunaes were associated with cognitive impairment, and might be confounder in this study results. Response 7: We appreciate your insightful comments. In this study, we included patients with first-ever stroke. As you mentioned, it is important to consider the presence of silent lacunar lesions. However, it is difficult to definitely differentiate lacunar lesions from other lesions such as dilation of the perivascular space and white matter lesions. In fact, inter-rater match was poor. Thus, it was impossible to perform quantitative analysis. In addition, there is no gold standard grading for lacunar burden. However, according to a previous report, the number of lacunae was graded as follows: grade 0, absent; grade 1, 1 to 2 lacunae; grade 2, 3 to 5 lacunae; and grade 3, 6 lacunae. In this study, two stroke neurologists analyzed the patients, and all patients were determined as grade 3 or less. This was because we excluded patients with severe white matter lesions. We believe that we excluded the confounder using this method. We have revised the text as follows: Lines 107-119 The severity of WMLs (deep and subcortical white matter hyperintensity [DSWMH] and periventricular hyperintensity [PVH]) was rated visually on fluid-attenuated inversion recovery images using the Fazekas scale (DSWMH: grade 1, punctuate; grade 2, early confluence; and grade 3, confluent; and PVH: grade 1, caps or lining; grade 2, bands; and grade 3, irregular extension into the deep white matter) [18]. Patients with WMLs (DSWMH or PVH) of grades 3 were assigned to the severe WML groups. The degree of medial temporal atrophy was semi quantitatively evaluated as described in previous reports [19], using a 5-point score scale ranging from 0 (no atrophy) to 4 (severe atrophy). In addition, according to a previous report, we evaluated the presence of silent lacunar lesions and graded the number of lacunae as follows: grade 0, absent; grade 1, 1 to 2 lacunae; grade 2, 3 to 5 lacunae; and grade 3, 6 or more lacunae [20]. Two stroke neurologists (MN and KT) graded the patients after consensus. 20. Yamamoto Y, Akiguchi I, Oiwa K, Hayashi M, Kasai T, Ozasa K. Twenty-four- hour blood pressure and MRI as predictive factors for different outcomes in patients with lacunar infarct. Stroke. 2002;33: 297-305. Lines 160-166 A total of 826 patients were diagnosed with lacunar infarction; of these, 468 patients were admitted for their first-ever stroke. We excluded 43 patients without MRI data, 25 patients without MMSE scores, and 127 patients diagnosed with dementia, including strategic single-infarct dementia (n = 3), before or after stroke onset. Moreover, we excluded 97 patients with CMBs, severe WMLs, or severe medial temporal atrophy. Ultimately, we analyzed 176 patients with stroke (age: 72.5 ± 11.4 years, 67 females; Fig 1). Regarding to the silent lacunar lesion, all patients were judged as grade 3 or less. Comment 8: The level of BP It would be helpful if the BP levels were provided. I have missed the data about BP. Response 8: We have added the information about blood pressure in S1 Table. Lines 173-176 Table 1 shows the patient background characteristics. Data pertaining to systolic and diastolic blood pressure in the four limbs and bilateral ABI and baPWV are shown in S1 Table. Comment 9: Reference for MMSE Please provide the reference for MMSE score. Response 9: We have added the reference as follows: Lines 121-125 MMSE scores were recorded and ABI/baPWV measurements were performed within three days of admission for all patients [21]. The accuracy of the method of ABI/baPWV measurement has been validated previously [22]. ABI/baPWV measurements were performed using BP-203RPE III (OMRON HEALTHCARE Co., Ltd., Kyoto, Japan). 21. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12: 189-198. 22. Yamashina A, Tomiyama H, Takeda K, Tsuda H, Arai T, Hirose K, et al. Validity, reproducibility, and clinical significance of noninvasive brachial-ankle pulse wave velocity measurement. Hypertens Res. 2002;25: 359-364. Results Comment 10: Laterality/ location of stroke Was there any difference in the cognitive function according to lacuna stroke lesion location and laterality? Response 10: We have added the laterality and location of stroke lesions in baseline data and performed statistical analysis. We did not find any significant association. We have revised the Tables. Comment 11: Treatment of cardiovascular risk factors Cardio-cerebro vascular risk factors such as hypertension and T2DM would be associated with cognitive function. Did the antihypertensive treatment or hypoglycemic agents were investigated in the analysis? Response 11: We have added the number of patients with previous antihypertensive or antidiabetic treatment in the Tables and performed the statistical analysis. We did not find any significant association. Lines 130-133 We recorded baseline clinical characteristics, including age, sex, body mass index (BMI), duration of education, complications (hypertension, diabetes mellitus, dyslipidemia, and chronic kidney disease), current smoking, habitual drinking, and medication before admission (antihypertensive and antidiabetic drugs). Comment 12: Antihypertensive medication before and during in-hospital and after discharge. In this study, all the patients underwent the MMSE and ABI/baPWV measurements within three days of admission. This might be similar to the question to ＃11. Are there any antihypertensive medication before and during in-hospital? Such as intravenous calcium channel blockade might be associated with blood pressure on the acute phase. And this might be associated with the study results. Response 12: In this study, we focused on patients with acute ischemic stroke in whom the systolic blood pressure was maintained under 220 mmHg. In the hospital, no patient required antihypertensive medications such as intravenous calcium channel blockers at the time of parameter measurement within three days of admission. Because some patients moved to other clinics or rehabilitation hospitals, we could not get the information about the use of antihypertensive medication after discharge. We have added the following information in the manuscript: Lines 166-171 In this study, no patient had symptomatic peripheral artery disease and required percutaneous transluminal angioplasty. The systolic blood pressure in all patients was maintained under 220 mmHg. No patient required antihypertensive medications such as intravenous calcium channel blockers at the time of parameter measurement within three days of admission. Comment 13: Left and right ABI Were there any difference in the laterality of ABI for the MMSE score? Response 13: We investigated the association between the laterality of ABI and the MMSE scores but did not find any association. We have added this information in the manuscript. Lines 174-177 Data pertaining to systolic and diastolic blood pressure in the four limbs and bilateral ABI and baPWV are shown in S1 Table. We investigated the association between the laterality of ABI and the MMSE scores, but found no association. Attachments Attachment Submitted filename: response_to_reviewers_R1_submission.docx https://doi.org/10.1371/journal.pone.0263525.r002
17 Nov 2021 Decision Letter - Masaki Mogi, Editor PONE-D-21-22076R1Association of ankle-brachial index with cognitive decline in patients with lacunar infarctionPLOS ONE Dear Dr. Nakamori, 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. Major revisions are needed in the present form. See the Reviewers' comments carefully and respond them appropriately. Please submit your revised manuscript by Jan 01 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, Masaki Mogi Academic Editor PLOS ONE [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: (No Response) 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: Partly 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: This manuscript explores the relationship between ABI and baPWV and cognition, as assessed by MMSE, in patients suffering from lacunar stroke. Patients with significant microbleeds and SVD were excluded from the analysis. Data show that ABI, but not baPWV is associated with lower overall cognition, orientation and immediate recall. This is an interesting and well-written study investigating these relationships in a unique population. My main concern is that the numerous exclusion criteria resulted in a more limited sample size, especially for the low ABI groups, which were of most interest in this study. Major and minor concerns about this study are detailed below: Major: The authors used numerous exclusion criteria to define their group, resulting in a limited sample of low ABI patients. This is unfortunate as their main results are in this group, but could also be driven by a number of other variable of interest which differs in this group. The authors should therefore better justify their choice of population, since this population is also not representative of the general population (since they all have a stroke). Field strength/MRI model was not taken into account in the analyses as a covariate of no interest. This should be done, especially if the distribution of patients scanned on each model is not equal amongst the different groups. Was multiple comparison correction used for the analyses presented? Several comparisons are made and should therefore be corrected for. Since other aspects of health could explain some of the results shown for the four sub-groups, the demographic table should be expanded to include characteristics of the overall sample as shown currently, as well as for the four subgroups, rather than including this information in the supplemental materials. Was Fazekas score, or better, WMH volume used in any of the analyses. Since WMH is likely to be related to cognition, it would be pertinent to use this in analyses as it could independently explain some of the variance in MMSE score. The sample size in two of the groups is very small, potentially biasing some of the results. This should be acknowledged in the discussion. Minor: Fezekas score for each group should be reported in the demographics table. In the discussion, the authors mention that baPWV is preferable, but cfPWV has been established as a more robust measure and is the gold standard in the literature. It is also non-invasive. These caveats of baPWV should be acknowledged in the discussion. Reviewer #2: The manuscript was substantially revised. Minor comments #1: “exclud”→”exclude” In line 72, “…Alzheimer’s pathology. Therefore, we tried to exclud cases with cerebral microbleeds…” should be changed as “…Alzheimer’s pathology. Therefore, we tried to exclude cases with cerebral microbleeds…”? #2: p=0.10 In the methods, the authors described that “a value of p = 0.10 was used to indicate statistical significance.” Is there any literature that could refer to defend the choice of p=0.10? ****** 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:** Michiaki Nagai [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.0263525.r003
Revision 2
14 Dec 2021 Author Response Thank you for reviewing our manuscript. We appreciate your comments and suggestions. We have revised the manuscript in accordance with your comments. Our point-by-point responses to the comments are presented below. Response to the reviewers Reviewer #1: This manuscript explores the relationship between ABI and baPWV and cognition, as assessed by MMSE, in patients suffering from lacunar stroke. Patients with significant microbleeds and SVD were excluded from the analysis. Data show that ABI, but not baPWV is associated with lower overall cognition, orientation and immediate recall. This is an interesting and well-written study investigating these relationships in a unique population. My main concern is that the numerous exclusion criteria resulted in a more limited sample size, especially for the low ABI groups, which were of most interest in this study. Major and minor concerns about this study are detailed below: Response: We appreciate your insightful comments and advice. To address the main concern raised by you, we reanalyzed after adding the patients who were excluded based on MRI findings. We have responded to each of your comments below and denoted the corresponding revisions in the manuscript in red color. Comment 1: The authors used numerous exclusion criteria to define their group, resulting in a limited sample of low ABI patients. This is unfortunate as their main results are in this group, but could also be driven by a number of other variable of interest which differs in this group. The authors should therefore better justify their choice of population, since this population is also not representative of the general population (since they all have a stroke). Response 1: We appreciate your insightful comment. We tried to include patients with lacunar infarction and exclude patients with other etiologies. In fact, some cerebral microbleeds are associated with amyloid pathology, and some white matter lesions are associated with neurodegenerative diseases. However, cerebral microbleeds and white matter lesions are associated with small vessel diseases such as lacunar infarction. I also understand the critical point that you mentioned. To justify patient selection and perform comprehensive analyses, we added and analyzed the patients with CMBs and severe white matter lesions (who were excluded based on MRI findings) as well. The analyses revealed that low ABI was independently associated with the MMSE score. We have revised the manuscript and added the new results in the Supplemental Tables. Lines 243-251 Finally, we added the patients with CMBs and severe white matter lesions (who were excluded based on MRI findings) and reanalyzed again (n=268). S3 shows the background characteristics of these patients. The median baPWV was 2086.5 cm/s and we divided the patients based on the median baPWV. We investigated the association of the MMSE score with the factors listed in S3. Univariate analysis revealed that the MMSE score was associated with age, BMI, education, chronic kidney disease, cerebral microbleeds, PVH, and ABI < 1.0 (p < 0.10), but not with baPWV > 2086.5 cm/s. Multivariate analysis revealed an independent association of BMI (p = 0.009) and ABI < 1.0 (p = 0.019) with the MMSE score (S4). Comment 2: Field strength/MRI model was not taken into account in the analyses as a covariate of no interest. This should be done, especially if the distribution of patients scanned on each model is not equal amongst the different groups. Response 2: Owing to the appointments in our institution, we used 1.5T MRI from July 1, 2011, and 3.0T MRI from April 2015 to December 31, 2018. This was incidental, not intentional. The imaging protocols were the same for the two groups. We investigated the differences in background characteristics between the two groups and found no significant differences. We have added the following text: Lines 101-103 The imaging protocols were the same for the two MRI groups. We investigated the differences in background characteristics between the two groups and found no significant differences. Comment 3: Was multiple comparison correction used for the analyses presented? Several comparisons are made and should therefore be corrected for. Response 3: For multiple comparisons, we performed Bonferroni correction and Tukey’s honestly significant difference (HSD) test. We have revised the manuscript (Methods and Results section). Lines 146-148 For multiple comparisons, the data were analyzed using one-way analysis of variance (ANOVA), and Bonferroni correction and Tukey’s honestly significant difference (HSD) test were performed. Lines 201-203 Bonferroni correction and the HSD test revealed that the MMSE scores for the group with ABI < 1.0 and baPWV > 2019 cm/s were significantly lower than those for the group with ABI ≥ 1.0 and baPWV ≤ 2019 cm/s. Comment 4: Since other aspects of health could explain some of the results shown for the four sub-groups, the demographic table should be expanded to include characteristics of the overall sample as shown currently, as well as for the four subgroups, rather than including this information in the supplemental materials. Response 4: We have added the clinical information in Table 1. Comment 5: Was Fazekas score, or better, WMH volume used in any of the analyses. Since WMH is likely to be related to cognition, it would be pertinent to use this in analyses as it could independently explain some of the variance in MMSE score. Response 5: We added the data pertaining to CMBs and the Fazakas score and analyzed. We have revised the manuscript and tables accordingly. Comment 6: The sample size in two of the groups is very small, potentially biasing some of the results. This should be acknowledged in the discussion. Response 6: Thank you for this pointing this out. Per your suggestion, we have mentioned it as a limitation in the Discussion. Lines 308-311 This study has several limitations. First, this study was a retrospective single-center study. The sample size and selection bias were limitations. We divided the patients into four groups according to the ABI and baPWV; however, the sample size of these two groups was very small, potentially biasing some of the results. Comment 7: Fazekas score for each group should be reported in the demographics table. Response 7: Per your suggestion, we have added the Fazekas score in the Tables. Comment 8: In the discussion, the authors mention that baPWV is preferable, but cfPWV has been established as a more robust measure and is the gold standard in the literature. It is also non-invasive. These caveats of baPWV should be acknowledged in the discussion. Response 8: Thank you for the suggestion. We have added the following text: Lines 280-282 The baPWV is measured between two sites along the arterial system and is preferred as it is easy to perform; however, cfPWV has been established as a more robust measure and is the gold standard. Reviewer #2: The manuscript was substantially revised. Comment 1: “exclud”→”exclude” In line 72, “…Alzheimer’s pathology. Therefore, we tried to exclud cases with cerebral microbleeds…” should be changed as “…Alzheimer’s pathology. Therefore, we tried to exclude cases with cerebral microbleeds…”? Response 1: We apologize for the typographical error. We have fixed the error. Comment 2: p=0.10 In the methods, the authors described that “a value of p = 0.10 was used to indicate statistical significance.” Is there any literature that could refer to defend the choice of p=0.10? Response 2: For performing the multivariate analyses, we selected the significant factors from the univariate analyses using the cut-off value of p=0.10. In order to select the optimal number of co-variates, we used the cut-off value of p=0.10. There is no fixed rule, but p=0.10 is sometimes used. Lines 141-143 Univariate analysis was used to investigate the association of MMSE scores with several factors, and a value of p = 0.10 was used to indicate statistical significance for multivariate analysis. Attachments Attachment Submitted filename: response_to_reviewrs_R2_submission.docx https://doi.org/10.1371/journal.pone.0263525.r004
17 Jan 2022 Decision Letter - Masaki Mogi, Editor PONE-D-21-22076R2Association of ankle-brachial index with cognitive decline in patients with lacunar infarctionPLOS ONE Dear Dr. Nakamori, 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. ============================== Minor revisions are necessary before acceptance.See the Reviewer's comments and respond them appropriately. ============================== Please submit your revised manuscript by Mar 03 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, Masaki Mogi 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: 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 manuscript was substantially revised, however several questions have been raised. Comment 1: p=0.10 In the methods, the authors described that “Univariate analysis was used to investigate the association of MMSE scores with several factors, and a value of p = 0.10 was used to indicate statistical significance for multivariate analysis. Subsequently, multivariate analysis was performed with selected factors determined from univariate analysis. " This sentence should be changed something like to "Univariate analysis was used to investigate the association of MMSE scores with several factors. Subsequently, multivariate analysis was performed to estimate and test the independent effects of selected factors on MMSE score. Each of those factors was determined from univariate analysis if the p value was 0.1 or less." Comment 2: Power analysis The authors have already declared that "Based on an alpha level of 0.05 and power of 0.80, we estimated that we would require at least 128 participants." However, in the discussion, the sentence "the sample size and selection bias were limitations." was presented. I could not understand this discrepancy. Comment 3: Bonferroni correction and Tukey’s honestly significant difference (HSD) test It is hard to understand the sentence "For multiple comparisons, the data were analyzed using one-way analysis of variance (ANOVA), and Bonferroni correction and Tukey’s honestly significant difference (HSD) test were performed." This should be changed to "For multiple comparisons, the data were analyzed using one-way analysis of variance (ANOVA), followed by post-hoc Tukey HSD test, with Bonferroni correction." ****** 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:** Michiaki Nagai [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.0263525.r005
Revision 3
17 Jan 2022 Author Response Thank you for reviewing our manuscript. We appreciate your comments and suggestions. We have revised the manuscript in accordance with your comments. Our point-by-point responses to the comments are presented below. Response to the reviewers Reviewer #2: The manuscript was substantially revised, however several questions have been raised. Response: We appreciate your comments and advice. We have responded to each of your comments below and denoted the corresponding revisions in the manuscript in red color. Comment 1: p=0.10 In the methods, the authors described that “Univariate analysis was used to investigate the association of MMSE　scores with several factors, and a value of p = 0.10 was used to indicate statistical significance for multivariate analysis. Subsequently, multivariate analysis was performed with selected factors determined from univariate analysis. " This sentence should be changed something like to "Univariate analysis was used to investigate the association of MMSE scores with several factors. Subsequently, multivariate analysis was performed to estimate and test the independent effects of selected factors on MMSE score. Each of those factors was determined from univariate analysis if the p value was 0.1 or less." Response 1: We appreciate your helpful comment. According to your suggestion, we have revised the manuscript as follows. Lines 141-144 Univariate analysis was used to investigate the association of MMSE scores with several factors. Subsequently, multivariate analysis was performed to estimate and test the independent effects of selected factors on MMSE score. Each of those factors was determined from univariate analysis if the p value was 0.10 or less. Comment 2: Power analysis The authors have already declared that "Based on an alpha level of 0.05 and power of 0.80, we estimated that we would require at least 128 participants." However, in the discussion, the sentence "the sample size and selection bias were limitations." was presented. I could not understand this discrepancy. Response 2: We apologize for the confusing expression. We revised as follows. Line 309 The selection bias was limitation. Comment 3: Bonferroni correction and Tukey’s honestly significant difference (HSD) test It is hard to understand the sentence "For multiple comparisons, the data were analyzed using one-way analysis of variance (ANOVA), and Bonferroni correction and Tukey’s honestly significant difference (HSD) test were performed." This should be changed to "For multiple comparisons, the data were analyzed using one-way analysis of variance (ANOVA), followed by post-hoc Tukey HSD test, with Bonferroni correction." Response 3: We appreciate your helpful comment. According to your suggestion, we have revised the manuscript as follows. Lines 146-148 For multiple comparisons, the data were analyzed using one-way analysis of variance (ANOVA), followed by post-hoc Tukey’s honestly significant difference (HSD) test, with Bonferroni correction. Attachments Attachment Submitted filename: response_to_reviewrs_R3_submission.docx https://doi.org/10.1371/journal.pone.0263525.r006
21 Jan 2022 Decision Letter - Masaki Mogi, Editor Association of ankle-brachial index with cognitive decline in patients with lacunar infarction PONE-D-21-22076R3 Dear Dr. Nakamori, 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, Masaki Mogi Academic Editor PLOS ONE No further comment. 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 #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 #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? 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 #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 #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 #2: The manuscript was well revised. I have checked that the authors responded very well to our questions. ****** 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 #2: Yes:** Michiaki Nagai https://doi.org/10.1371/journal.pone.0263525.r007
Formally Accepted
25 Jan 2022 Acceptance Letter - Masaki Mogi, Editor PONE-D-21-22076R3 Association of ankle-brachial index with cognitive decline in patients with lacunar infarction Dear Dr. Nakamori: 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. Masaki Mogi Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0263525.r008

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 .