PONE-D-19-31892

RE-PERG in early-onset Alzheimer’s Disease. A double-blind, electrophysiological pilot study

PLOS ONE

Dear Dr. Mavilio,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration by 2 Reviewers and an Academic Editor, all of the critiques of both Reviewers must be addressed in detail in a revision to determine publication status. If you are prepared to undertake the work required, I would be pleased to reconsider my decision, but revision of the original submission without directly addressing the critiques of the two Reviewers does not guarantee acceptance for publication in PLOS ONE. If the authors do not feel that the queries can be addressed, please consider submitting to another publication medium. A revised submission will be sent out for re-review. The authors are urged to have the manuscript given a hard copyedit for syntax and grammar.

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. 

Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously? 

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Introduction:

1. Authors should explain in more detail what Alzheimer's disease is and how it differs from (VD) -related MCI, describe changes in the CNS, retina, and why eye biomarkers may be useful.

2. How do we confirm the diagnosis of AD in sMRI?

MATERIALS AND METHODS:

1. The authors described that neurologic exclusion criteria were: „neurological / psychiatric conditions other than mild AD"- what about patients who had vascular dementia? After all, they were included in the study.

2. Did all participants have an MRI? How on the basis of sMRI diagnosed and distinguish patients with AD and VD.

3. The description of the statistics should be more detailed, paying attention to the tests used.

Results:

1. „ANOVA analysis showed no difference between groups for age. MD. PSD RNFL and GCC.”- errors in punctuation

2. Please specify the number and characteristics of excluded subjects to reduce the selection bias.

Discussion:

1. Epidemiology, diagnosis and pathogenesis should be included in the introduction (not in the discussion).

2. Unfortunately, the most effective tests for the diagnosis of AD are expensive and invasive.”- e.g. MRI is not an invasive test, therefore this sentence should be formulated more precisely

3. "Since the neurodegeneration of RGCs shows similar features in both glaucoma and AD, we performed this study in order to evaluate the ability of RE-PERG in the identification of the early stage of AD. "- How can RE-PERG distinguish AD from glaucoma? Since the PERG test is used in glaucoma diagnosis why the authors did not compare glaucoma, AD and HC?

4. The authors did not describe the limitations of their research

5. MMSE may not be the best cognitive test with which to measure AD related cognitive impairment. This should be acknowledged and the limitations explored in the discussion.

6. Why do the authors compare patients with VD to AD and NC if the problem is to distinguish AD from glaucoma? I think that vascular changes in the retina in AD patients should be mentioned (Bulut, M., Kurtuluş, F., Gözkaya, O., Erol, M. K., Cengiz, A., Akıdan, M., & Yaman, A. (2018). Evaluation of optical coherence tomography angiographic findings in Alzheimer’s type dementia. British Journal of Ophthalmology, 102(2), 233-237.) and describe differences in microvascularization between AD, POAG and NC (Zabel, P., Kaluzny, J. J., Wilkosc-Debczynska, M., Gebska-Toloczko, M., Suwala, K., Zabel, K., ... & Araszkiewicz, A. (2019). Comparison of Retinal Microvasculature in Patients With Alzheimer's Disease and Primary Open-Angle Glaucoma by Optical Coherence Tomography Angiography. Investigative ophthalmology & visual science, 60(10), 3447-3455.)

References:

1. Kamila K., Wojciech L., Andrzej P. Pattern electroretinogram (PERG) and pattern visual evoked potential (PVEP) in the early stages of Alzheimer’s disease Doc Ophthalmol. 2010 435 Oct; 121(2): 111–121.”- these are not the author's' last names

Reviewer #2: Manuscript n.: PONE-D-19-31892

TITLE: RE-PERG in early-onset Alzheimer’s disease. A double-blind electrophysiological pilot study.

Article Type: Research Article.

In this study, the Authors investigate the ability RE-PERG (retest PERG) in detection inner retinal bioelectric function abnormalities in patients with early-onset Alzheimer Disease (AD). They investigated a series of pt. (17 pt.) with AD and report mean RE-PERG amplitude significantly lower and phase of 2nd harmonic (PERG SDPh) higher in AD pts. compared with controls. Moreover, they affirm that RE-PERG can be useful to identify early AD stages and that changes may be imputable to magnocellular pathway dysfunction not present in other conditions, like vascular dementia and conclude that RE-PERG could be a new promising biomarker of neurodegenerative disease.

The study is well conducted and written, results are clear, sound well and could be interesting for the readership of the journal, even if not at all new (see previous paper on the same field reported in references).

The manuscript has some issues needed to be addressed.

Major criticism are:

- First, the AA address the magnocellular pathway (M pathway), but it should be kept in mind that there are other pathway subsystems (Parvo-, P and Konio-cellular, K subsystem; see Paper of Livingstone, Porciatti, van Essen etc. on this topic). The AA should add some information concerning these subsystems and their propriety. In fact whereas color information is processed mainly by the P system, luminance by both P and M subsystem. Moreover, the stimulus employed by the AA is not selective for the Magno and result could be aspecific. The AA should add some informations on visual pathways subsystem and property.

- Second the AA to exclude a bias in their study should exclude involvement of other subsystem before to affirm an exclusive magnocellular dysfunction in their conclusions. Please clarify.

- Third, How can the AA exclude that a lower RE-PERG and a higher SDPh RE-PERG are not an aspecific changes

Keywords: I suggest add visual pathway subsystem.

Abstract: modify according the above criticisms.

Introduction: see major criticisms.

In line 89 they affirm that “ … this parameter is not influenced by optical …”; I suggest “scarcely influenced by refraction “

Materials and methods: -

Discussion and Concluding remarks: they have to be rewritten following the above suggestions and comments.

References: there are only few typing mistaken and two reference in my opinion seems the same (n. 14 and 56): check.

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Reviewer #1: Yes: Przemyslaw Zabel

Reviewer #2: Yes: Ferdinando Sartucci

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

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Kind regards,

Stephen D. Ginsberg, Ph.D.

Section Editor

PLOS ONE

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PONE-D-19-31892R1

RE-PERG in early-onset Alzheimer’s disease:  A double-blind, electrophysiological pilot study

PLOS ONE

Dear Dr. Mavilio,

Thank you for resubmitting your work to PLOS ONE. Please make the corrections posed by Reviewer #2 so I can render a decision on this manuscript.

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Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. 

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously? 

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: All the concerns have been addressed. The authors corrected the manuscript in accordance with the suggestions of the reviewers, which made the manuscript suitable for publication.

Reviewer #2: Manuscript n.: PONE-D-19-31892

TITLE: RE-PERG in early-onset Alzheimer’s disease. A double-blind electrophysiological pilot study.

Article Type: Research Article.

I revised again with pleasure the interesting manuscript that in many aspects has been significantly improved. The Authors were able to overcome most of criticisms.

Therefore I only have only two minor comments:

-Changes in Re-PERG were they also accompanied in parallel by changes in the so-called apparent latency or not?

-The main conclusion that Re-PERG changes may be attributable predominantly to magnocellular pathway should be softened because the other two visual stream (Konio and Parvo) were not investigated; in my opinion their study prove an alteration in RE-PERGs more evident in AD compared with VD. Otherwise it seems that the AA want to prove forcedly that an involvement of the RE-PERG means diagnosis of AD and instead may also be present in other diseases or depend from common visual changes age-related, e.g. presbyopia, cataract and so on.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Ferdinando Sartucci

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

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We look forward to receiving your revised manuscript.

Kind regards,

Stephen D. Ginsberg, Ph.D.

Section Editor

PLOS ONE

RE-PERG in early-onset Alzheimer’s disease:  A double-blind, electrophysiological pilot study

PONE-D-19-31892R2

Dear Dr. Mavilio,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Stephen D. Ginsberg, Ph.D.

Section Editor

PLOS ONE