Can Phonemic Verbal Fluency Be Used to Predict Alzheimer’s Disease?

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This essay examines two verbal fluency markers in patients with mild cognitive impairment over a period of two years. It concludes that phonetic verbal fluency rather than semantic verbal fluency deteriorates earlier than semantic verbal fluency and is regarded as a possible indicator towards the development of Alzheimer‘s disease. This essay is of great interest to anyone involved in the management of the elderly. The essay follows a clear pathway although clarification is wanted in some areas.

 The first sentence in the Abstract is unfortunate as it makes no sense. It should rather read: Among the cognitive maskers deterioration of semantic and phonemic verbal fluency seem to be an early indicator of Alzheimer‘s disease (AD).

The Abstract however follows an acceptable format. 
The last sentence of Method belongs to Results. In the Results we miss further explanation in order to understand the conclusion. E.g. what of the tests in Method was the determining factor for the conclusion.

The Introduction is well written and informative. It clearly states why the study was done and its aim.

The Method is written well and easy to understand.

In the Results we find what was missing in the Abstract that formed the basis of the conclusion at the end of the essay.

The  legend of Table 4 requires clarification of the abbreviations MMSE and MoCA.

In the Discussion more information is needed regarding the choice of the Z-score and the Mann-Whitney U test. What are the reasons why they were employed. what are their limitations.

The limitations of the essay are well addressed.

The conclusion becomes evident when an explanation for employing the above mentioned tests is given.

Overall a good essay that deserves publication.

 

 

Author Response

1. The first sentence in the Abstract is unfortunate as it makes no sense. It should rather read: Among the cognitive maskers deterioration of semantic and phonemic verbal fluency seem to be an early indicator of Alzheimer‘s disease (AD). Thank you for pointing this out. I have changed it.
2. The last sentence of Method belongs to Results. I agree with the reviewer, so I integrated that section into the Results.
3. In the Results we miss further explanation in order to understand the conclusion. E.g. what of the tests in Method was the determining factor for the conclusion. I thank the reviewer for his suggestion of further explaining the results to facilitate understanding of the conclusions.
4. The legend of Table 4 requires clarification of the abbreviations MMSE and MoCA. According to the proper observation of the reviewer, the abbreviations were clarified.
5. In the Discussion more information is needed regarding the choice of the Z-score and the Mann-Whitney U test. What are the reasons why they were employed. what are their limitations. Thank you for pointing this out. I added extra explanation in the Discussion.

Reviewer 2 Report

Comments and Suggestions for Authors

For AD diagnosis, the earlier, the better. So it's meaningful for the current research to find some test to evaluate and predict the progression of AD. I have some question mainly about the Result and Conclusion parts.

1. For Table 2, I think you repeated the PVF data. And the font sizes of the numbers are inconsistent. Because the differences in Table 2 are not significant, so the descriptions in line 126-128 are inaccurate.

2. For Table 3, the difference of ZSVF (mean) is much more obvious, but the statistical analysis showed no significant difference. I'm afraid this is because of the huge variation. The sample size is too small, which will have effect on your conclusion. Please add more sample.

3. For Table 5, there's no significant difference in MCI-nonAD and MCI-AD in both tests. Have you ever tried to analyze the difference in the change (pre- and post) between these two group in both tests?

4. For Table 6, I'm confused with "AD" group. Please explain it much more clearer.

5. There are some minor question, like keep the consistant reference numbering in format. Show the full name when the abbreviation appears at the first time.

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Author Response

1. For Table 2, I think you repeated the PVF data. And the font sizes of the numbers are inconsistent. Because the differences in Table 2 are not significant, so the descriptions in line 126-128 are inaccurate. I thank the reviewer for his observations. I corrected formatting errors and rephrased the data description in table 2.
2. For Table 3, the difference of ZSVF (mean) is much more obvious, but the statistical analysis showed no significant difference. I'm afraid this is because of the huge variation. The sample size is too small, which will have effect on your conclusion. Please add more sample. I agree that it would be very interesting to add more sample. In the future I would like to be able to recruit more participants for the study who meet the required criteria.
3. For Table 5, there's no significant difference in MCI-nonAD and MCI-AD in both tests. Have you ever tried to analyze the difference in the change (pre- and post) between these two group in both tests? I thank the reviewer for his suggestion. Statistically significant differences were found between the pre- and post-test for the group formed by the eight patients who converted to AD, as expected. Nevertheless, the proposed analysis was not included in the article because it was considered not to fit the objectives of the manuscript.
4. For Table 6, I'm confused with "AD" group. Please explain it much more clearer. On the one hand, table 5 compares the results obtained by the patients after the first evaluation (MCI-non AD vs MCI-AD). On the other hand, Table 6 compares the results obtained by the patients after the second evaluation, that is to say, after two years (MCI vs AD). Information about who composed the AD group has also been added to the text.
5. There are some minor question, like keep the consistant reference numbering in format. Show the full name when the abbreviation appears at the first time. Thank you for pointing this out. The text has been reviewed.

Reviewer 3 Report

Comments and Suggestions for Authors

The topic is timely and important.  It needs more discussion on where episodic and semantic memory fit into the verbal fluency schema  and why they haven't been incorporated into the testing procedures.  Given the complexity of cognition, more and varied tests ought to be considered, especially since the current ones haven't proved to be effective.

Comments on the Quality of English Language

(1)  English seems adequate except for line 222 where "worse" doesn't work.  Maybe substitute the word "less" in its place.

(2) It seems that the authors could separate the scores of men vs women; what about other health variables, such as diabetes, BMI, and hearing status?  

(3) A discussion of what the different fluency values signify would be helpful.   

(4)  Line 3 in Table 2 is a repeat of line 1.

(5)  Why are the U values in Table 5 so different? What does the difference mean?

(6) The study needs a larger number of participants.  This is a difficult request, but the low "n" seems to be a problem.  Maybe there should be more tests as well, given the complexity of the subject matter.

Author Response

1. The topic is timely and important. It needs more discussion on where episodic and semantic memory fit into the verbal fluency schema and why they haven't been incorporated into the testing procedures. Given the complexity of cognition, more and varied tests ought to be considered, especially since the current ones haven't proved to be effective. I added more neurobiological information in the introduction. But rather than talking about the relationship between memory and fluency, the article defends the relationship between verbal fluency, executive functions and semantic knowledge. 
2. English seems adequate except for line 222 where "worse" doesn't work. Maybe substitute the word "less" in its place. Thank you for pointing this out. The word has been changed.
3. It seems that the authors could separate the scores of men vs women; what about other health variables, such as diabetes, BMI, and hearing status? The exclusion criteria included not having any psychiatric, neurological (except MCI in the case of the experimental group) or medical illness that could interfere with the performance of the tests in this study.
4. A discussion of what the different fluency values signify would be helpful. According to the proper observation of the reviewer, we added more information in the discussion.
5. Line 3 in Table 2 is a repeat of line 1. Thank you for pointing this out. I corrected formatting errors.
6. Why are the U values in Table 5 so different? What does the difference mean? Phonemic verbal fluency seems to be less preserved than semantic verbal fluency. Anyway, it would be very interesting to add more sample and analyzed these results again.
7. The study needs a larger number of participants. This is a difficult request, but the low "n" seems to be a problem.  Maybe there should be more tests as well, given the complexity of the subject matter. In the future I would like to recruit more participants who meet the required criteria. Meanwhile, two more neuropsychological tests have been added in table 1.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The author gives a reasonable explanation for each question. But they still need to pay attention to the punctuation, such as Line 44, "[}" is incorrect.

Author Response

Comments 1: The author gives a reasonable explanation for each question. But they still need to pay attention to the punctuation, such as Line 44, "[}" is incorrect.

Response: Thank you for pointed this out. I have reviewed and corrected punctuation mistakes. 

Reviewer 3 Report

Comments and Suggestions for Authors

(1) I wasn't certain about how the author reacted to my comments--and I didn't know if the text that was highlighted in yellow was an indicator of what was new.

(2) It seems that MMSE scores for the experimental group indicated that the members had MCI.  The control group apparently did not, so the experimental group was already ahead of the control group with respect to cognitive decline.  That they should show more decline in 2 years is probably not a surprise.

(3) It was not stated but I am assuming that the 2 original groups remained separate throughout the study.

(4) I disagree with one of the concluding statements: I think that a treatment for AD is more important than finding a sensitive test for predicting AD.

 

Author Response

Comments 1: I wasn't certain about how the author reacted to my comments--and I didn't know if the text that was highlighted in yellow was an indicator of what was new.

Response 1: When I reviewed the manuscript the first time I highlighted in yellow the modifications made to the original text and attached a document explaining point by point the reviewer’s comments.

Comments 2: It seems that MMSE scores for the experimental group indicated that the members had MCI. The control group apparently did not, so the experimental group was already ahead of the control group with respect to cognitive decline.  That they should show more decline in 2 years is probably not a surprise.

Response 2: What I intended to evaluate after two years was whether or not the experimental group, diagnosed with mild cognitive impairment, progressed to AD.

Comments 3: It was not stated but I am assuming that the 2 original groups remained separate throughout the study.

Response 3: I thank the reviewer for his observations. Indeed, they remained separate.

Comments 4: I disagree with one of the concluding statements: I think that a treatment for AD is more important than finding a sensitive test for predicting AD.

Response 4: Although the ideal would be to find a treatment for Alzheimer's disease, the reality is that currently there is still no cure. In this context, early detection continues to have great relevance in daily clinical practice. Therefore, it is expected that these types of studies will be useful for doctors.

I have introduced some lines to clarify the argument defended in the article in the conclusions section.