PONE-D-22-00239Protocol: A Randomised Controlled Trial to Compare the Efficacy of Music Therapy and Physical Activity on Brain Plasticity, Depressive Symptoms, and Cognitive Decline, in a Population With and At Risk for Alzheimer’s DiseasePLOS ONE

Dear Dr. Flo,

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Burak Yulug

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Yes

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3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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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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

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors well designed a study protocol that is aimed to evaluate the pro-cognitive cognitive role of music therapy and exercise.

However, there are some minor points that would help to increase the impact and hence the relevance of the expected results of the study

1-There are no defined pulse/heart zone criteria for the exercise regimen that would be better to determine since there are strong correlations between the aeorobic exercise and heart zones (for instance, that the heart rate should be least 50% elevated than the resting state for a pro-cognitive role through various neurochemicals including also dopamine and BDNF etc.)

2-How the authors plan to discriminate the isolated effect of music therapy or exercise (it can be partly isolated ) from the general pro-cognitive effect of the social engagement (enriched environment effect?). This is an issue that should be clarified.

3-Do they plan to evaluate also some metabolic parameters which could have a role in mediating the beneficial effects. Hence, all basic and after-intervention parameters should be determined, such as glucose, and BMI, which have an isolated pro-cognitive effect if regulated properly.

Reviewer #2: General Summary: The authors present a study protocol aiming at demonstrating the effects of music therapy in a three arm RCT.

Study duration is planned for 12 months with the music therapy intervention group, an active control group (physical activity) and a passive control group (no intervention).

Theoretical background:

The study focusses on an immensely important and vulnerable patient group (AD). In my opinion the importance of this study is increased by recent developments in pharmaceutical industry reducing financial means to explore treatment options.

In general, the introduction is well written and includes up to date scientific evidence.

Methods/ design:

The three armed RCT design is sound and well planned. Inclusion criteria and exclusion criteria are well defined. Primary and secondary outcomes a clear described. The measurement of the primary outcomes includes valid MRT and test psychological methods. Power calculation using G* Power 3 is well done. The interventions are clear defined and well described.

I just like to raise three questions concerning the methods

1) the main outcome parameters Brain Age and depressives symptoms are from a clinical perspective not independent. Hence a participant with a faster

progression of the AD (= a faster progression of the Brain age gap) is more likely to develop depressive symptoms. Therefor the authors might think about how to statistically correct for this interaction

2) It is known that AD and vascular dementia often co-occur. How will the authors proceed if the inclusion criteria are met in the primary assessment, but after 12 months signs of Leukencephalopathy or similar are found?

3) The authors mention in the introduction that pharmacological interventions have limited effects in AD (And they are totally right). However psychopharmacological interventions concerning depressive symptoms are well established. Further it is known that Psychotherapy and Psychopharmacological inventions show additive effects. It might be likely that this goes as well for MT. The issue of psychopharmacology should be clearly stated in methods. Because in the worst case MT might work better but the other groups receive more Antidepressants. On how to deal with this issue valuable insight might come from Prof. Munkholm or Prof. Leucht (just a suggestion)

Conclusion:

The study protocol is sound, the study motivation well established and methods and study design are based on up to date scientific standards.-

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Reviewer #1: No

Reviewer #2: Yes: Christian Mikutta

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Study protocol for the Alzheimer and Music Therapy study: an RCT to compare the efficacy of Music therapy and physical activity on brain plasticity, depressive symptoms, and cognitive decline, in a population with and at risk for Alzheimer's Disease

PONE-D-22-00239R1

Dear Dr. Flo,

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.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Burak Yulug

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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 and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The manuscript is acceptable in its current form and the authors well reponded to my major concerns.

Reviewer #2: Dear Authors,

Thank you for clarifying the issues raised in the review process.

From my siede there are nor further hindrances for publication

Congratulations for this important and well planed project

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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: Christian Mikutta

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