The Evolving Role of Ophthalmology Clinics in Screening for Early Alzheimer’s Disease: A Review

Round 1

Reviewer 1 Report

In this review, the authors proposed that eye clinics and ophtalmology facilities could be helpful for early diagnosis of AD. The topic is quite interesting, contemporary and recent findings are providing intriguing insights into this field. In particular, the authors suggested that VOSP test may be helpful for detecting visuospatial impairment in mild AD patients. Do you think it might also be useful for other neurodegenerative disorders over AD?
I believe that the review would appear more complete by extending the paragraph concerning the involvement of retina in neurodegenerative changes and providing some examples of imaging and/or molecular biomarkers that could be utilized or are being investigated.
Moreover, the scope and the data discussed in the review should be contextualized in the era of omics, big data and network medicine, since the use of eye clinics and ophtalmology facilities can be part of the scientific and medical effort to achieve a precision medicine for neurodegenerative disorders, especially for AD.

Author Response

Dear reviewer 

I have addressed  the issues you have raised.  please see the attachment  

Author Response File: Author Response.pdf

Reviewer 2 Report

Thank you for choosing me to review this paper.

Indeed, OCT use in the diagnosis of Alzheimer disease is a very interesting topic

Here are my comments:

Abstract

1.Well written

2. “An early diagnosis of AD can be potentially beneficial…” I am not sure this statement is true and is not proven yet. it might be that early diagnosis will indeed affect all these parameters but it might as well increase financial burden. I suggest saving this to the discussion and not the second line in the abstract.
3. this is a review but it is not mentioned in the abstract- I will add in the tittle maybe also so the reader would know it is not original study

Intro

1. “The pathogenic process of AD however remains unclear and controversial;” I will just cite and maybe add a little bit about the ubiquitin-proteasome system. This was discovered recently, the founders got a Nobel price and it might just be the key. This system was found to be faulty in removing proteins and leading to their accumulation –int the discussion or shortly in the intro

(https://pubmed.ncbi.nlm.nih.gov/18266959/)

2. I also think that multidomain interventions should be started early as possible and that early diagnosis and interventions are indeed a possible solution (this paragraph is very well written)
3. “Medical—nomadism” = I was not aware of this term. Thank you. You could also add ref

https://pubmed.ncbi.nlm.nih.gov/21365179/

4. But- will early diagnosis/ multidomain intervention will reduce the risk of AD patient's institutionalization? This is the main issue.
5. “A recent literature review examined studies and models that addressed economic benefits of early diagnosis and treatment” –just one/ two examples are given. I would use ref 12 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4927869/) and maybe edit the point that early detection of AD can reduce the cost of this medical nomadism, for example, from ref 12:

 Weimer and Sager [45] performed a cost-benefit analysis (Monte Carlo model) of early identification and treatment of Alzheimer’s dementia. The model estimated the net social benefits and net fiscal savings of early intervention with drug treatment, a caregiver intervention program, and a combination of both interventions. The results showed that the net benefits could be highest when patients received a diagnosis at the initial symptomatic stage of the disease and when drug treatment was combined with caregiver intervention: the mean net social, state fiscal, and federal fiscal benefits of drug treatment plus caregiver intervention for a 70-year-old married woman with a Mini-Mental State Examination (MMSE) score of 28 were estimated as $US125,000, $16,000, and $34,000, respectively.

That’s mean that if we had more tools for early diagnosis, we could reduce the cost.

Vision and visual functional abnormalities in AD

1. cognitive resource hypothesis- very interesting- please add a [ref] for further reading
2. common factor- [ref is needed [
3. what about the hypothesis that low sight affect the test = is there a study with pre cataract removal---trial---post cataract removal design?

Retina, macular and optic nerve

1. I think you could cite a lot more here- there is plethora of studies on OCT retina and AD.

https://pubmed.ncbi.nlm.nih.gov/30114417/

2. How will you assess visuospatial impairment in the clinic?
3. " his preliminary shape detection test requires patients to identify whether there is a
   degraded ‘X’ on 20 patterned sheets of paper, with one point being given for each correct answer. Scores of 15 or lower effectively exclude participants from performing the VOSP "battery. The full VOSP battery is comprised of four tests of object perception and four tests of space perc" can you add these tests as supplemental material so we could use them in the clinic? I think all the test in table 1 should be accessible – that will be great value for the reader

Justification for screening for AD by eye clinics

1. I think its a great idea. Were all the tests I table 1 proved to be reliable? Because in the intro you mention that “there is no screening for AD” visuospatial difficulties may offer a tool to screen for early-stage AD. However, I thought this review would be about the validity of the VOSP to detect early AD.
2. How are we sure the VOSP really detect AD etc—I would suggest elaborating on this
3. As discussed, the benefits of early AD diagnosis are numerous and extend to patients, carers,
   healthcare professionals, and society.”----the issue I am not convinced we can detect early AD.
4. So it seems reasonable to screen AD in the eyes clinic (while no clinical data had been showing to prove this) with VOSP questioner (again no clinical data is given to support this).
5. In your suggestion protocol, the optician will do the VOSP. How long does it take? Who will pay for it?

Conclusion

1. This review/suggestion was nice to read.
2. No new data is presented here
3. It is well written and give concepts to think about
4. I think it merits a publication but the tone needs to be changed to less affirmative as no data is there to show that indeed this will do any benefit.
5. I suggest actually performs some clinical studies: screen in different clinics (orthopedics/ ophthalmology etc) and see if indeed the AD incidence is higher in eyes clinic or questionnaire regarding optician attitude towards this?
6. I would also suggest discussing opticians training and approval for giving AD diagnosis- this is a hard talk to no? they will need to interpret the VOSP and discuss this

Author Response

many thanks for your very constructive comments.  trust the changes we have made are satisfactory. 

Author Response File: Author Response.pdf