Is Non-Alcoholic Fatty Liver Disease Connected with Cognition? The Complex Interplay between Liver and Brain
, Nathan M. D’Cunha 1,3, Amanda Bulman 1,3, Demosthenes B. Panagiotakos 1,2,3 and Nenad Naumovski 1,2,3,*
Round 1
Reviewer 1 Report
Matina Kouvari et al. wrote an interesting review on the link between NAFLD and neurocognitive disorders. The work is structured in order to describe the mechanistic aspects of this link. However, it seems to lack clearer and more detailed comments on the specific neurological diseases that are described in the cited works, considering that some mechanistic pathway could be tied to specific neurocognitive disease. It would therefore be appropriate
1- to specify which neurological pathologies are specifically taken into consideration and describe in more detail any links with metabolic liver pathologies, to integrate in the various section on suggested mechanisms and “conclusion”
2- If it is a systematic review, it is necessary to implement the section on methods in a proper way (see comment on Page 2, Line 64)
Page 2
Line 64 Searching for the string you provided on pubmed found more than 2000 references. Explain if there is a study protocol, how the works were analyzed, how many investigators collaborated, if there was a cross-check, how any biases were corrected. Possibly provide a flowchart. If it is not possible to trace this information, specify that it is a narrative review.
Page 9
Lines 110-112 Be carefull on the association with hyperammonemia. It is present only in cirrhosis, rarely in NASH and never in NAFLD (stheatosis only). Cognitive impairements secondary to hyperammoniemia and hepatic encelopathy shoud be argumented in a different section.
117-122 Non necessary to specify
131-133 It would be interesting to mention some aspects related to the interruption of the integrity of the BBB by cytokines and ROS in inflammation [REF https://www.frontiersin.org/articles/10.3389/fncel.2021.661838/full]
Page 10
Line 172 Add “markers” after “subclinical ahterosclerosis”
178 Delete “In the present review,”
Comments for author File: 
Comments.pdf
Author Response
Dear Reviewer 1.
We would like to thank you for time taken to provide the comments and suggestions for our manuscript. Please see our responses (attached and listed below) to your comments and suggestions.
Matina Kouvari et al. wrote an interesting review on the link between NAFLD and neurocognitive disorders. The work is structured in order to describe the mechanistic aspects of this link. However, it seems to lack clearer and more detailed comments on the specific neurological diseases that are described in the cited works, considering that some mechanistic pathway could be tied to specific neurocognitive disease.
Reply: We would like to thank the Reviewer for the time spent on our work, the positive feedback as well as the valuable comments.
It would therefore be appropriate
1- to specify which neurological pathologies are specifically taken into consideration and describe in more detail any links with metabolic liver pathologies, to integrate in the various section on suggested mechanisms and “conclusion”
Reply: We have added more information on the mechanisms that may connect liver with brain. Please see the revised version of the manuscript and specifically the subunit entitled “Pathogenetic mechanisms underpinning the development of NAFLD”. Additionally, we have enriched the mechanisms already presented in the original version of our manuscript. Please see the highlighted document in the revised manuscript.
2- If it is a systematic review, it is necessary to implement the section on methods in a proper way (see comment on Page 2, Line 64)
Reply: This is a narrative review – not a systematic review.
Page 2; Line 64 Searching for the string you provided on pubmed found more than 2000 references. Explain if there is a study protocol, how the works were analyzed, how many investigators collaborated, if there was a cross-check, how any biases were corrected. Possibly provide a flowchart. If it is not possible to trace this information, specify that it is a narrative review.
Reply: Please see our previous response. This is a narrative review where we selected some core epidemiological studies that associated NAFLD with cognition.
Page 9; Lines 110-112 Be carefull on the association with hyperammonemia. It is present only in cirrhosis, rarely in NASH and never in NAFLD (stheatosis only). Cognitive impairements secondary to hyperammoniemia and hepatic encelopathy shoud be argumented in a different section.
Reply: We would like to thank the Reviewer for his comment. This has now been rephrased in the revised manuscript. Please see page 8.
117-122 Non necessary to specify
Reply: Thank you for the comment. We have adjusted this.
131-133 It would be interesting to mention some aspects related to the interruption of the integrity of the BBB by cytokines and ROS in inflammation [REF https://www.frontiersin.org/articles/10.3389/fncel.2021.661838/full]
Reply: We would like to thank the Reviewer for his suggestion. This has now been included in the revised manuscript. Please see page 9.
Page 10; Line 172 Add “markers” after “subclinical ahterosclerosis”
Reply: This has now been included.
178 Delete “In the present review,”
Reply: This has now been deleted.
Author Response File: 
Author Response.docx
Reviewer 2 Report
Good reviews explain difficult topics and make use of examples to illustrate how phenomena or theories are connected, or provide synthetic overviews of a large body of literature (empirical or theoretical). In this manuscript, the authors claimed that they summarized the findings of hitherto studies that have linked NAFLD with cognitive function or disorders and discussed the potential liver-brain paths. The review topic is meaningful, but I think that the content of this review does not clarify the relationship between NAFLD and cognitive impairment. In addition, the related molecular mechanisms described in this review are also very simple. In my opinion, a more critical and mechanistic appraisal of this field is required.
Author Response
Dear Reviewer 2.
We would like to thank you for time taken to provide the comments and suggestions for our manuscript. Please see our responses (attached and listed below) to your comments and suggestions.
Reviewer 2
Good reviews explain difficult topics and make use of examples to illustrate how phenomena or theories are connected, or provide synthetic overviews of a large body of literature (empirical or theoretical). In this manuscript, the authors claimed that they summarized the findings of hitherto studies that have linked NAFLD with cognitive function or disorders and discussed the potential liver-brain paths. The review topic is meaningful, but I think that the content of this review does not clarify the relationship between NAFLD and cognitive impairment. In addition, the related molecular mechanisms described in this review are also very simple. In my opinion, a more critical and mechanistic appraisal of this field is required.
Reply: We would like to thank the Reviewer for the time spent on our work, the positive feedback as well as the valuable comments. In the revised manuscript we have now included more details on the mechanisms that may explain the interplay between liver and brain. Please see the updated manuscript version.
Author Response File: Author Response.docx
Round 2
Reviewer 1 Report
Authors modified the document appropriately
Author Response
Dear Reviewer 1.
Thank you for your valuable comments.
Kind Regards
Nenad
Reviewer 2 Report
No further questions.
Author Response
Dear Reviewer 2.
Thank you for your valuable comments.
Kind Regards
Nenad
