Title:Cognitive profile in patients with a first-ever lacunar infarct with and without silent lacunes: a comparative study.

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1 Author's response to reviews Title:Cognitive profile in patients with a first-ever lacunar infarct with and without silent lacunes: a comparative study. Authors: Lorena Blanco-Rojas (l.blanco.rojas@copc.cat) Adria Arboix (aarboix@hscor.com) David Canovas (dcanovas@tauli.cat) Marta Grau-Olivares (martagrau76@hotmail.com) Joan Carles Soliva Morera (jcsoliva@tauli.cat) Olga Parra (oparra@ub.edu) Version:3Date:15 November 2013 Author's response to reviews: see over

2 Mr. Josefino Rodis on behalf of Dr. Anil K. Nair BMC Neurology Web: Ref.: MS: , entitled Cognitive profile in patients with a firstever lacunar infarct with and without silent lacunes: a comparative study, Blanco- Rojas L, et al., revised version (Dr. Adrià Arboix, corresponding author) Dear Mr. Rodis: We have uploaded the revised version of our manuscript using the following link id= Please, note: 1) the manuscript has been edited by a professional medical editor, and her task is now mentioned in the Acknowledgements; 2) we have paid attention to follow the instructions of the Journal regarding the format of the paper; and 3) you will find our point-by-point responses to each comment made by the reviewers with precise indication of new text added in the manuscript. For an easier identification, all new amendments are highlighted with the pen function of Word. We continue to appreciate very much your attention to our paper. Yours sincerely, Adrià Arboix, MD, PhD Head, Cerebrovascular Division, Department of Neurology Capio Hospital Universitari del Sagrat Cor C/ Viladomat 288 E Barcelona, Spain Tel.: , fax: aarboix@hscor.com AUTHORS COMMENTS TO SUGGESTIONS OF DR. MARK SLEVIN (REVIEWER #1) This report communicates compares pathology and degenerative effects of first ever lacunar stroke versus silent lacunes-with LI. It shows findings that neuropsychological abnormalities are mainly associated with LI-in the presence of silent infarcts and this is an important conclusion allowing discrimination between the two entities and may have clinical/prognostic impact. The authors appreciate very much your comments regarding the scientific interest of our study. AUTHORS COMMENTS TO SUGGESTIONS OF DR. CARME JUNQUE (REVIEWER #2) In the paper Cognitive profile in patients with a first-ever lacunar infarct with and without silent lacunes: A comparative study by Blanco-Rojas et al. the authors

3 compared the neuropsychological performance of 34 subjects with a single lacunar infarct (SI) with those with multiple lacunar infarcts (MLI). Groups did not differ in age, sex, education, MMSE, in vascular risk factors or in laterality of lesions. As expected, they found that patients with MLI had significantly poorer performance in some neuropsychological tests such as semantic verbal fluency and short term memory. The strong points of this paper are: 1) The originality in comparing single versus multiple silent lacunar infarcts. 2) Large, matched sample. The authors would like to thank the referee for these encouraging and positive comments of our study. 1. The main problems with the manuscript are in the analysis and interpretation of the data. Since leukoaraiosis (LA) was more frequent in the MLI than in the SI group, neuropsychological differences might be due to its presence rather than to the greater amount of focal lacunae. Lacunae per se may partially impair specific cognitive functions, but LA is indicative of greater diffuse vascular damage which could better explain the cognitive impairment than the sum of dispersed focal lacunae, and could perhaps indicate concurrent Alzheimer s disease The problem with this study is that the effect of LA is neither analyzed nor controlled for. 2. The authors should quantify the LA and analyze its effect on neuropsychological performance. All analyses should therefore be repeated using an analysis of variance, adding LA as a covariate. We have added a multiple liner regression analysis to assess the effect of leukoaraiosis on neuropsychological performance. In the two models (semantic fluency and short term memory), leukoaraiosis was not statistically significant when adjusted by covariates. These results indicate that in the initial stages of small vessel disease, mild neuropsychological abnormalities appear to be related to lacunae rather than to leukoaraiosis or perivascular hyperintensities of vascular cause. This new analysis has undoubtedly improved the quality of our report. New text is added in the Abstract: leukoaraiosis was not statistically significant in multivariate linear regression models adjusted by confounding covariates. Also, in the interpretation of our findings, we have added: According to these findings, in the initial stages of small vessel disease, mild neuropsychological abnormalities appear to be related to lacunae rather than to leukoaraiosis or perivascular hyperintensities of vascular cause. In the Methods section, new text reads: Multiple linear regression analysis was performed to assess the effect of leukoaraiosis on neuropsychological performance adjusted by confounding covariates. In the Results section: In the multiple linear regression analysis to assess independent variables associated with performance of semantic fluency and short delayed verbal memory, the presence of leukoaraiosis was not statistically significant. In both models, multiple silent LIs and education were the only statistically significant variables (Table 3). Table 3 reports the results of the linear regression analysis. The same conclusion included in the Abstract is added at the end of the body of the text. In the Discussion section, we have included as a limitation of the study that leukoaraiosis was assessed qualitatively: A limitation of the study is the fact that leukoaraiosis was assessed qualitatively as presence versus absence and not quantified using a quantitative measure (e.g. Scheltens scale, Wahlund scale, Fazekas scale).

4 Other minor issues: 1. In the neuropsychological assessment, only tests not subject to motor aspects should be included. A considerable percentage of patients have motor or sensory deficits which might interfere in the execution of some of the tests used. Previous data of WAIS-III Block Design Test are deleted. 2. The manuscript s composition should be thoroughly revised. The second paragraph in the background session and the second paragraph in the discussion session are very difficult to understand. The manuscript has been extensively rewritten and copyedited by a professional medical editor, and her task is mentioned in the Acknowledgment section. 3. The use of the verbs in the text should be revised. They are not adequate to scientific vocabulary. This point has been addressed by the medical editor. 4. In the tables, besides p values, test statistics should be included. Results of tests statistics are added in all tables in a new column. 5. All paragraphs in the discussion should be linked to some of the study s results. The Discussion now is more focused on the results and has been extensively rewritten. 6. Current literature on leukoaraiosis and cognition from the LADIS Study Group should be reviewed and included in the discussion. Data of the LADIS Study Group is added in the Discussion. See paragraphs with the new references #23 and #25. AUTHORS COMMENTS TO SUGGESTIONS OF DR. JERZY KRUPINSKI (REVIEWER #3) 1. Please add limitations to the study i.e. some of the patients were included in the clinical trial We have added this limitation: The fact that some patients were included in a clinical trial (SPS3 randomized trial) of secondary prevention of cerebral ischemia (aspirin 325 mg/day versus aspirin 325 mg/day plus clopidogrel 75 mg/day) may be view as a limitation of the study. However, participation in the trial did not interfere with radioimaging and neuropsychological studies of the patients because all those included in the present study presented a first-ever lacunar stroke. 2. How the sample was calculated A previous calculation of the sample size was not applicable since all consecutive patients (n = 72) fulfilling the inclusion criteria (first-ever lacunar stroke, brain MRI examination, cognitive performance allowing to complete the battery of neuropsychological tests, and written informed consent) were eligible. 3. Was the performance on neuropsychological tests different between lacunar subtypes. We have added this sentence in the text: There were no differences in the performance of neurological tests between lacunar subtypes. In our

5 opinion, the inclusion of a new table with these extensive results is not of primary interest for the readers. Differences in neuropsichological performance in lacunar symdrome No se evidencian diferencias en el rendimiento neuropsicologico en funcion de los diferentes sindromes lacunares Regresió lineal. (Anova test) Neuropsychological tests Lacunar syndrome IC 95% P Digits Spam Forwards (direct Score) Digits Spam Forwards (scalar Score) PMR Semantic Fluency (animals) CVLT (short-delayed) CVLT (learning trial 1-5) PMH PSS DCH SMS AH PMH PSS DCH SMS AH PMH PSS DCH SMS AH PMH PSS DCH SMS AH PMH PSS DCH SMS AH PMH PSS DCH SMS AH CVLT (long delayed cued recall) PMH ,545

6 PSS DCH SMS AH CVLT (long delayed recognition) CVLT (total learning sum trial 1 to 5) PMH ,988 PSS DCH SMS AH PMH ,892 PSS DCH SMS AH PMH: pure motor hemiparesis; PSS: pure sensory stroke; DCH: dysarthria-clumsy hand; SMS: sensorimotor stroke; AH: ataxic hemiparesis; : atypical lacunar syndrome 4. Which of the patients had post stroke cognitive rehabilitation. None of the patients had post-stroke cognitive rehabilitation as cognitive impairment was not present (MMSE mean score of 27.8 and 28 in the groups of single LI and multiple silent LIs, respectively), 5. Did the authors try to quantify white matter abnormalities with available imaging scales/scores like Wahlund, etc... This was not quantified as is now commented on as a limitation of the study in the Discussion section: A limitation of the study is the fact that leukoaraiosis was assessed qualitatively as presence versus absence and not quantified using a quantitative measure (e.g. Scheltens scale, Wahlund scale, Fazekas scale).