Progressive Age-Associated Blood–Brain Barrier Leak/Dysfunction-Nexus of Neurodegenerative Disease Using MRI Markers to Identify Preclinical Disease and Potential New Targets for Future Treatments

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review paper focused on the upstream pertinent pathophysiology leading to neurodegenerative disease. The nexus appeared to be blood brain barrier (BBB) leakiness resulting in a two-prong inflammatory disease spectrum damaging the microvasculature and corrupted protein synthesis and degradation with accumulating misfolded toxic proteins. This review paper with 8 figures and 1 table discussed in detail the physiology and pathophysiology of the BBB, new MRI imaging techniques identifying the leak and altered fluid dynamic effects in the preclinical state. The manuscript is useful for understanding pathogenesis of brain disorders. However, the reviewer has some minor comments.

 

(Comments)

1)      Letters in Fig. 1 and table 1 are very small. Please make the letters larger.

2)      Typing mistakes are scattered.

3)      Please describe intramural periarterial drainage (IPAD) pathway and glymphatic system more. The two pathways are very important to consider when investigating the relationship between the pathogenesis of neurodegenerative diseases and BBB disruption.

Author Response

1.  Have revised the figures for readability.

2.  Have corrected typing errors.

3.  will add additional description of fluid movement through the pathway.

 

Thank you for your time and attention and excellent review.  Much appreciated.

 

Reviewer 2 Report

Comments and Suggestions for Authors

The author came up with an interesting review article linking blood-brain barrier dysfunction and neurodegenerative diseases which were well established years ago.

I have minor comments

1. The figures' quality needs to be improved as it is hard to see and read and I would suggest adding a graphical abstract to the manuscript.

2. Spacing issues have been observed throughout the manuscript.

3. In some paragraphs, some words are highlighted without mentioning...This will confuse readers.

4. Table 1 is pixelated and hard to read the content

5. It would be better to add more author's thoughts in conclusion section.

Author Response

1. Have improved the figures for readability
2. Have addressed the spacing issues
3. Have removed the highlighting
4. Have improved readability of the table
5. Have added more comments in the conclusion.

Thank you for your thoughtful and excellent review.