Physiological Mechanisms Inherent to Diabetes Involved in the Development of Dementia: Alzheimer’s Disease

Round 1

Reviewer 1 Report

In this study, Authors quested possible relationships underlying type two diabetes (T2D), along with Alzheimer’disease (AD) and/or vascular dementia (VaD). Growing evidence has been found that T2D may increase the risk of AD. Also, insulin resistance and metabolic dysfunction associated with T2D negatively affects the brain and increases the accumulation of βA. The outline suggests reciprocal relationships between causes and consequences as associated with T2D and AD/VaD.

The review is informative, attractive and useful, impacting wider audience. In order to further attention, Authors are invited to add historical legends to the development of AD and VaD, as well.

I strongly suggest the re-editing of the MS, to improve style, typography, clarity and precision of the description.

Selected examples:

Style: Line 20 & 23 - On the other hand

Typography:

Line 53 ­- affecting the ability to make decisions and to make decisions

Line 241 - Among the links between T2D y la dementia

 

Clarity:

Line 147 - The pathophysiology of AD involves changes at the brain level, including the   abnormal accumulation of two proteins: beta-amyloid (βA) plaques and neurofibrillary tangles ...

Line 230 - Although it is only recently that it has been suggested that the key between the two diseases is the cerebrovascular dysfunction and insulin resistance caused by T2D, which would provide a favorable environment for the development of VaD ...

Precision:

Line 151- neuronal and synaptic terminal loss

Line 250 - the relationship between diabetes and dementia

Line 280 - insulin like growing hormone

Line 351 - T2D-AD-VaD relationship

Line 391 - T2D-AD-VaD relationship

Line 402 - chy-myokines (CCL1, CCL5, CXCL1)

Line 445 - prevention and treatment of AD

 

Author Response

Dear Reviewer,

 

We would like to thank you for the opportunity you have given us to improve our work and make it more suitable and interesting for the journal and for the scientific community. We are sincerely grateful for the time you have taken to read, comment and suggest corrections, which have greatly improved the understanding of the paper.

We have made all the changes suggested by the reviewers to improve the manuscript. Thus, the article has been significantly modified and we believe it is now of high quality for publication.  Attached you can find the new version of the manuscript, in which the changes are indicated in red colour. We hope that this new version of the article is now suitable for publication in the Neurology International

 

 Reviewer 1

 

In this study, Authors quested possible relationships underlying type two diabetes (T2D), along with Alzheimer’disease (AD) and/or vascular dementia (VaD). Growing evidence has been found that T2D may increase the risk of AD. Also, insulin resistance and metabolic dysfunction associated with T2D negatively affects the brain and increases the accumulation of βA. The outline suggests reciprocal relationships between causes and consequences as associated with T2D and AD/VaD.

The review is informative, attractive and useful, impacting wider audience. In order to further attention, Authors are invited to add historical legends to the development of AD and VaD, as well.

Authors :We would like to thank you for your review work and your efforts to try to improve our work.

Following your recommendations we have added the section:

1.3 Historical development of dementia: Alzheimer's disease (see its content in the manuscript)

I strongly suggest the re-editing of the MS, to improve style, typography, clarity and precision of the description.

Selected examples:

Style: Line 20 & 23 - On the other hand

Authors: ok. we have change it

Typography:

Line 53 ­- affecting the ability to make decisions and to make decisions

Authors: thanks, we have change it

Line 241 - Among the links between T2D y la dementia

 

Authors: thanks, we have change it

 

Clarity:

Line 147 - The pathophysiology of AD involves changes at the brain level, including the   abnormal accumulation of two proteins: beta-amyloid (βA) plaques and neurofibrillary tangles ...

Authors: thanks, we have change it

Line 230 - Although it is only recently that it has been suggested that the key between the two diseases is the cerebrovascular dysfunction and insulin resistance caused by T2D, which would provide a favorable environment for the development of VaD ...

Authors: thanks, we have change it

Precision:

Line 151- neuronal and synaptic terminal loss

Authors: thanks, ok we have change it

 

Line 250 - the relationship between diabetes and dementia

Authors: thanks, ok. we have change it

 

Line 280 - insulin like growing hormone

Authors: thanks, ok. we have change it

 

Line 351 - T2D-AD-VaD relationship

Authors: thanks, ok. we have change it

 

Line 391 - T2D-AD-VaD relationship

Authors: thanks, ok. we have change it

 

 

Line 402 - chy-myokines (CCL1, CCL5, CXCL1)

Authors: thanks, ok. we have change it

 

Line 445 - prevention and treatment of AD

Authors: thanks, ok. we have change it

 

Authors: Thank you for all the appreciations and recommendations you have given us. We have followed his advice and asked colleagues to review the language of the manuscript. We hope that the corrections made have left the English language in optimal conditions.

Reviewer 2 Report

Major comments

In this study, the authors summarized previous findings and discussed the pathological implications of diabetes in Alzheimer’s disease (AD) and vascular dementia (VaD). The manuscript is well written and easy to follow. For experts as well as beginners, this review would be helpful for gaining a comprehensive understanding of the relevant area of expertise. However, I think that the manuscript needs improvement for publication; I have several suggestions as follows.

 

1.       The Future perspectives section

The contents in this section are too general, superficial, and commonplace and lack the novelty and originality. I suggest that the authors address these issues, which would significantly increase the attractiveness of the work. For instance, the current manuscript has no description concerning the therapeutic potentials of certain agents; however, growing evidence highlights the possibility that some medications for type 2 diabetes and/or bioactive molecules for glucose metabolism may have beneficial effects on cognitive impairment. In terms of the mechanisms underlying diabetes-related AD and VaD, drug repositioning and/or new agents could be innovative strategies for AD and VaD.

 

2.       Figure 4

Why do both increase in the levels of insulin in type 2 diabetes and decrease in those in type 1 diabetes result in the same shift regarding the balance between insoluble amyloid-b (Ab) and soluble Ab? I suggest that the authors explain the underlying mechanisms with the relevant citations.

 

3.       Relevant citations

The following sentence needs the relevant citations:

 

a)       “Insulin acts as… (lines 288–289)” (Insulin is not the same to Insulin-like Growth Factor.)

b)       “In that sense… (lines 322–324)”

c)       “In addition, insulin… (lines 332–333)”

d)       “Insulin plays an… (lines 352–354)”

e)       “In addition, insulin… (lines 354–355)”

 

Minor comments

1.       Both Ab and bA are described; the description should be consistent.

2.       Where is the “Figure 1 (lines 160–161)” that describes amyloid precursor protein processing?

3.       The title “Results (line 236)” should be rephrased to describe the contents of the 2^nd section appropriately.

4.       Typo should be corrected regarding “to make decisions and to make decisions (lines 53–54)” and “Nervius (line 256).”

5.       “AD y VaD (line 237)” and “T2D y la dementia (line 241)” should be described in English appropriately.

I think that the quality of English language is almost fine, but minor editing is required.

Author Response

Dear Reviewer,

We would like to thank you for the opportunity you have given us to improve our work and make it more suitable and interesting for the journal and for the scientific community. We are sincerely grateful for the time you have taken to read, comment and suggest corrections, which have greatly improved the understanding of the paper.

 

Major comments

In this study, the authors summarized previous findings and discussed the pathological implications of diabetes in Alzheimer’s disease (AD) and vascular dementia (VaD). The manuscript is well written and easy to follow. For experts as well as beginners, this review would be helpful for gaining a comprehensive understanding of the relevant area of expertise. However, I think that the manuscript needs improvement for publication; I have several suggestions as follows.

 Authors: Dear reviewers,

Many thanks to the reviewer for his comments on our work. The effort and time invested in reviewing a paper is always appreciated. Your feedback is of great help to us to improve the development of this review so that our publications can be useful to the scientific community. We believe that the article has been greatly improved and now has the quality to be published in the Neurology International. Below, we detail the changes that the paper has undergone, so that you can re-evaluate our article.

1. The Future perspectives section

 

The contents in this section are too general, superficial, and commonplace and lack the novelty and originality. I suggest that the authors address these issues, which would significantly increase the attractiveness of the work. For instance, the current manuscript has no description concerning the therapeutic potentials of certain agents; however, growing evidence highlights the possibility that some medications for type 2 diabetes and/or bioactive molecules for glucose metabolism may have beneficial effects on cognitive impairment. In terms of the mechanisms underlying diabetes-related AD and VaD, drug repositioning and/or new agents could be innovative strategies for AD and VaD.

Authors: Thank you very much for your suggestion, we have added two paragraphs including T2D drugs currently being studied that seem to have beneficial effects in the treatment of AD and VaD (lines 486-502)

 

 

2. Figure 4

 

Why do both increase in the levels of insulin in type 2 diabetes and decrease in those in type 1 diabetes result in the same shift regarding the balance between insoluble amyloid-b (Ab) and soluble Ab? I suggest that the authors explain the underlying mechanisms with the relevant citations.

Authors: Thank you very much for the observation. It is a point that was not really fully clarified in the text. We have added in point 2.5 a new paragraph (paragraph 3) where we explain the mechanisms that converge in T1D and T2D that may be leading to a shift in the way AB accumulates. Lines 400-417

 

 

3. Relevant citations

 

The following sentence needs the relevant citations:

1. a) “Insulin acts as… (lines 288–289)” (Insulin is not the same to Insulin-like Growth Factor.)

Authors: thanks, ok. we have done it.

1. b) “In that sense… (lines 322–324)”

Authors: thanks, ok. we have done it.

 

1. c) “In addition, insulin… (lines 332–333)”

Authors: thanks, ok. we have done it.

 

1. d) “Insulin plays an… (lines 352–354)”

Authors: thanks, ok. we have done it.

 

1. e) “In addition, insulin… (lines 354–355)”

Authors: thanks, ok. we have done it.

Minor comments

 

1. Both Ab and bA are described; the description should be consistent.

Authors: thanks for your appreciation. we have corrected it.

 

2. Where is the “Figure 1 (lines 160–161)” that describes amyloid precursor protein processing?

Authors: Thank you for detecting the error. we have corrected it

 

3. The title “Results (line 236)” should be rephrased to describe the contents of the 2nd section appropriately.

Authors: thanks for the recommendation. We have renamed the "result" section as: Link between Diabetes Mellitus, Alzheimer's disease and Vascular Dementia

 

4. Typo should be corrected regarding “to make decisions and to make decisions (lines 53–54)” and “Nervius (line 256).”

Authors: thanks, ok. we have change it

 

5. “AD y VaD (line 237)” and “T2D y la dementia (line 241)” should be described in English appropriately.

Authors: thanks, ok. we have change it

 

 

Comments on the Quality of English Language

I think that the quality of English language is almost fine, but minor editing is required.

 

Authors: Thank you for all the appreciations and recommendations you have given us. We have followed his advice and asked colleagues to review the language of the manuscript. We hope that the corrections made have left the English language in optimal conditions.

Round 2

Reviewer 2 Report

I think that the authors appropriately responded to comments raised previously.