Biomarkers for Assessing Diet-Related Neurocognitive Deficits in Children—A Systematic Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Authors,

Thank you for the opportunity to review your manuscript” Biomarkers for Assessing Diet-Related Neurocognitive Deficits in Children- A Systematic Review”.

Overall, this is a well-presented review, however, there is a need to quantify the requirements, why the tests were chosen and the overall outcome to evaluate the hypothesis.

Within the introduction it would be very helpful if you place the reference to the statements made at the end of every sentence and not at the end of the paragraph.

References are required in line, 39, 42, 44,60,63…………..

Line 50 you refer to the Blood based biomarkers yet you have not set the scene on why these particular test, and as such it need a sentence prior to this statement and justification for the tests.

Line 55 you state” These biomarkers serve as objective indicators, allowing for the identification of potential deficiencies or imbalances that can be associated with diet-related neurocognitive deficits” please enhance this statement with a reference and also why you make this statement and it is currently not supported within the text.

Literature review; Understand the PRISMA format, however, please include your PICO.

Line 94: You state infants to 15 years, please explain why this age group as it is not clear at this point in the criteria.  Who set the level and why is it important??

Line 122” you state” The study population had a lot in common” please explain this statement and elaborate on the commonalities.

Line 132 You state” assessing cognition in the studies was intelligent quotient as reported by most studies” please explain this and how the IQ was measured to ensure commonalities within the review.

Line 138 you state” It was specifically associated…” what is it?

Line 144: you state” It was evident from the review that exposure to chronic systemic inflammation in infancy is associated with adverse neurodevelopmental outcomes” please highlight the respective papers that this statement is associated with and why is inflammation of critical importance.

Line 145 you state” In summary, the relationship between biomarkers and cognition has been established with remarkably positive results and indications.” Please explain that this statement relates to the papers reviewed and what is remarkable referring to and what are the positives you refer to??

Line 153 you state” diet-related biomarkers and cognition in Sub-Saharan Africa.” Why is this mentioned out of context and what is the significance of mentioning Sub-SA as it does not seem inclusive in the study??

In the above situation, why not consider placing here a chart of the global concerns, explain your considerations and potentially why this is the case??

Line 178 You state” The role of inflammation and cognition has been elucidated in this review” please explain this further as you have not reference the respective papers to justify the statement.

Line 181: You state” Consequently, it will be important to elucidate the  pathways by which inflammation is linked to brain health- while assessing long-term and short-term effects of systemic low-grade inflammation” You may wish to re-write this as it is not clear and potentially not substantiated within this review.

Within the discussion on page 9: please explain why plasticity does not occure, this maybe introduced earlier within the paper to give relevance, why geographical areas have been chosen to conduct the studies, Why studies only seriously look at IQ and how is this measured. Also, it is important to clearly indicate the proposition that inflammatory responses and their repation to neurocognitive disorders,

Why is Leptin of interest?  Why is copper introduced into the discussion??

Line 83 page 10 you state” The variation in biomarker associations underscores the complexity of cognitive development and the need for further investigation into the role of these markers in children's cognitive function, however, according to this review, CRP and TNF-α appear to be the most prac-86 tical and effective biomarker for assessing neurocognitive deficits.” Please highlight how you have come to this conclusion, based on what papers reviewed, and what is biomarker underscores??

Author Response

Please see attachment 

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

Even though the idea of this review may seem interesting, the manuscript requires some improvements. There are some important points that need to be improved.

1.      Abstract: The manuscript needs writing and language editing. This abstract must be improved. Reformulate the main objective of this literature review, for example, “to review the primary evidence on biomarkers of diet-related neurocognitive development/disorder in children”. The main aim must be direct and the same throughout the manuscript (abstract, introduction, results/discussion. The first time that an abbreviation appears, the full name must be entered. Please delete what has been crossed out throughout this manuscript. Authors should not use the words that appear in the title as keywords.

2.      The introduction section should be rewritten. A proper presentation and a good and clear justification (reason) for conducting this study should be given. The introduction section should guide readers to understand why they undertook this review. Why did the authors carry out this study? What does "biomarker of diet-related neurocognitive deficit" mean? Examples, specify. It would be better if the authors justified this study, moving from the general issues (neurocognitive deficits related to diet, useful biomarkers related to diet and neurocognitive development) to the specific issue that the authors investigated (health/nutritional biomarkers related to neurocognitive development/disorders in childhood). What are the authors trying to convey with this phrase “their influence” on neurocognitive disorders in children”? The authors must delve deeper into the topics covered, especially in the diet-related biomarkers. The introduction should be concise and concrete, providing the most important information on which the hypothesis of this study is based. It would be better if the authors offered a hypothesis at the end of the introduction section and before the main objective of this study. Why is this study important? The main aim must be direct and the same throughout the manuscript. It would be a good idea for the authors to reformulate the hypothesis and the main aim.  

3.      The material and methods section: Why did the authors choose these biomarkers and not others? The description must be clear, concise, and detailed. Who conducted this study? Why did the authors discard the TRIAL? It would be best to write “in all searches we used” “(Cognition OR Executive Function OR Neurocognitive Deficit or Intellectual Ability*) AND (Children)” AND: (Serum Biomarkers*), etc. Lines 93, 130: Specify

4.      Results:  How many children/teenagers are there in these 9 articles in total? The 3.6 subsection should be described as part of the discussion section.

5.      The discussion section should be improved and more argumentative. It should start with the main objective of this study and the most significant results found. The results must be discussed from multiple angles and placed in context without being over-interpreted. The authors should focus their discussion on the central theme of the study and avoid repeating the information given. The authors should indicate why their results are important and to what extent they contribute to current knowledge of this topic. A paragraph of limitations and suggestions for this study should be written before the conclusion.

6.      The conclusion must improve and be the same throughout the manuscript.

I would like to encourage the authors to rewrite this manuscript, thinking about the main objective of this study, its design and responding with the results and arguments of the discussion to the most appropriate conclusion of this research work.

Comments for author File: Comments.pdf

Comments on the Quality of English Language

Minor editing of English language required.

Author Response

Please see the attachment 

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Authors,

Thank you for considering the changes suggested within the manuscript.

It has certainly enabled a more precise manuscript to be considered.

Author Response

Thank you

Reviewer 2 Report

Comments and Suggestions for Authors

Unfortunately, the manuscript has not improved sufficiently for publication. There are too many points that need to be clarified.

First, the meaning of biomarker: “A biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process, or a condition or disease.” That is, the biomarker is a tool that shows whether what is evaluated, for example the CRP, is in the normal range or not. If the CRP is higher than the normal range, it indicates that there is an inflammatory process. What the authors had reported in their results is that there are several biomarkers (CRP, BDNF, TNF-α, etc.) related to the neurocognitive parameters studied in cross-sectional studies. However, they did not explain to what extent (positive/negative) this association exists and, obviously, they could not demonstrate cause-effect. Secondly, another aspect to consider is what is the definition of a dietary biomarker? Furthermore, the authors did not demonstrate that the biomarkers studied are related to any nutritional status or nutritional deficiency. That is, CRP was associated with behavioral and emotional functioning, but what was the nutritional status of these children, did they have any risk or disease or were they healthy? Third, the authors cannot say that they evaluated "the effect of biomarkers" because biomarkers cannot have any effect on the body. They only show whether what they evaluated is at an adequate level or function, for example, the PCR shows that there is or is not an inflammatory response/state. What they evaluated shows whether there is a body response such as an inflammatory process. So, another question would be what causes this inflammatory state?

Fortunately, this study can be improved if the authors rewrite it with the following points in mind.

1. The main objective of this literature review is to report which inflammatory biomarkers have been associated with cognitive parameters in children (healthy?) so far. Delete what is crossed out.

2. The study design should be rewritten with this idea in mind. The authors should no mention any dietary biomarkers, no nutritional biomarkers, and no neurocognitive deficits (only if the authors had found whether any of the 9 studies show a child population with neurocognitive problems).

3. Highlight and discuss your results in this context.

Comments for author File: Comments.pdf

Comments on the Quality of English Language

Minor editing of English language required.

Author Response

Please see attachment

Author Response File: Author Response.docx

Round 3

Reviewer 2 Report

Comments and Suggestions for Authors

Even though the manuscript has improved, here are important issues that require modification before publication. Crucially, the authors should highlight that in these studies collected, children under 15 years of age were healthy. They must clearly describe (discussion) whether the associations found between the biomarkers (BDNF, TNF-alpha, TNF receptor and leptin) studied and the cognitive parameters were significant or not, positive or negative. What is the relevance of this review study?

Abstract: Line 13: ... to include all published data from 2000 to October 2023. Line 15: Avoid repeating the same information. Line 21-23, 59-62: Please delete what is crossed out.

Introduction: It would be better to add in line 43: ... like mood disorders, learning difficulties, and Attention Deficit Hyperactivity Disorder (ADHD) [17, 18]. Blood-based biomarkers can successfully predict cognitive decline and pathological progression of neurocognitive disorders such as Alzheimer’s disease [19]. Line 43: …for instant, vitamin D levels, iron status, omega-3 fatty acids, homocysteine levels, C-reactive protein (CRP), brain-derived neurotrophic factor (BDNF), glucose, insulin, and antioxidant levels, …. child's health a nutritional status... Confirm the reference Nº 19. Line 53-58: References on which the authors rely. Please write the hypothesis before the goal of this study: We hypothesize that some inflammatory biomarkers are associated with neurocognitions in children.  Therefore, the main aim....

Material and methods: Line 69: It would be better to write: the relationship between inflammatory biomarkers and neurocognition in children. Line 71: from 2000 to October 2023? Lines 73-74: Avoid repeating the same information given on Line 85. Lines 76-77: Avoid repeating the same information given on Line 70. Line 82: What happened to the other criteria highlighted in the previously reviewed document? (i) the articles had to constitute original research, (ii) they needed to be composed in English, (iii) access to the full text of the article was required… Line 84: Authors should specify which biomarkers and cognitive functions were searched.

Results: It would be a good idea to write line 120: The studies found considered the following inflammatory biomarkers...

Discussion: Line 52: Why? Because they were healthy? Because they did not suffer from another inflammatory condition? Because the authors did not know if the participants had any nutritional deficiencies related to an inflammatory condition? Specify. Argue. Line 102: It would be better to write “may be” instead of “is”.

Comments for author File: Comments.pdf

Comments on the Quality of English Language

This manuscript requires language editing.

Author Response

Please see the attachment

Author Response File: Author Response.docx