Persistence of Cognitive Difficulties in Adults Three Years After COVID-19 Infection

Round 1

Reviewer 1 Report

The manuscript (ID: covid-3858344) of de Pádua Serafim and Collogues aims to investigate the persistent cognitive difficulties following infection with the SARS-CoV-2 virus, which induces the Long COVID. Through both a previous study and the present one, the authors highlight the need to better understand this new condition in order to implement appropriate rehabilitation strategies, thereby improving patients’ quality of life. According to the authors, long-term neuropsychological assessment combined with individualized rehabilitation strategies is essential to lessen the impact of Long COVID on patients’ autonomy and well-being.

The article is well structured, clearly written, and presented in a fluent style, making it accessible even to a non-specialist audience. The topic is highly relevant and timely, as it explores the long-term effects of COVID-19 infection on cognitive functioning, an issue of considerable interest for both the scientific community and clinical practice. The bibliography is up to date, coherent with the subject matter, and consistent with the most recent international evidence. A thorough proofreading of the manuscript is suggested to address minor typographical or grammatical inaccuracies and ensure overall clarity. 

Overall, this is a solid article with interesting results that could be highly useful in guiding future longitudinal studies on patients affected by post-COVID cognitive disorders. With the suggested corrections and additions, the manuscript could become even clearer, more comprehensive, and impactful for the scientific literature.

There are some aspects that could be improved to make the manuscript even clearer and more rigorous:

1. Table 1: I suggest replacing the terms masculine and feminine with men and women, in line with what is already reported in the text (line 159). This would ensure greater consistency and immediate comprehensibility for the reader.
2. Aim section (line 72-77): It would be useful to explicitly point out that the authors have already published a preliminary study on the same patients, reporting cognitive disorders observed 18 months after infection. The present study therefore represents a longer-term follow-up, with data collected approximately three years post-infection, thus providing an original and valuable contribution to understanding the temporal evolution of post-COVID cognitive deficits. This contextualization would enrich the introduction and clarify the added value of the current work.
3. Tables and figures: Whenever tables and/or figures are included, they should always be explicitly cited and discussed in the text, so that readers can better follow the results and appreciate their clinical and statistical relevance. Clear referencing would improve readability and highlight the value of the data presented.

Author Response

We greatly appreciate your thorough review and insightful comments, which have significantly improved our manuscript. Below, we detail our responses to each of your suggestions.

1. Table 1: I suggest replacing the terms masculine and feminine with men and women, in line with what is already reported in the text (line 159). This would ensure greater consistency and immediate comprehensibility for the reader.

Response: Applied in Table 1.

2. Aim section (line 72-77): It would be useful to explicitly point out that the authors have already published a preliminary study on the same patients, reporting cognitive disorders observed 18 months after infection. The present study therefore represents a longer-term follow-up, with data collected approximately three years post-infection, thus providing an original and valuable contribution to understanding the temporal evolution of post-COVID cognitive deficits. This contextualization would enrich the introduction and clarify the added value of the current work.

Response: Lines 97-104 were added in order to clarify that question.

3. Tables and figures: Whenever tables and/or figures are included, they should always be explicitly cited and discussed in the text, so that readers can better follow the results and appreciate their clinical and statistical relevance. Clear referencing would improve readability and highlight the value of the data presented.

Response: We added citations to tables where there were no citations (lines 354, 358, 415-416 and 426).

 

            Thank you.

Reviewer 2 Report

INTRODUCTION

The introduction is well-structured; however, in comparison with the discussion, it seems too brief. I suggest the authors elaborate on several key aspects within the introduction to provide a more comprehensive context.Specifically, greater terminological precision is needed regarding Long COVID, which is most commonly referred to as Post-Acute COVID-19 Syndrome (PACS). While this condition encompasses a broad spectrum of multi-organ sequelae, the focus of this manuscript is on the more debilitating neurological manifestations, namely the so-called Neuro-Long Covid. The most predominant, extensively documented neurological condition of PACS is Brain fog (mental fatigue and cognitive dysfunctions), which is not addressed in this study. I suggest the authors add this symptom to the description of PACS sequelae with the relevant bibliography.Furthermore, the discussion on the pathophysiology of Long COVID is currently limited to structural modifications identified through neuroimaging techniques like MRI. I suggest the authors incorporate findings related to functional alterations, particularly those revealed by electrophysiological methods such as EEG and TMS, as there is a growing body of literature linking these electrophysiological abnormalities to cognitive domains of Long COVID.

DISCUSSION

Similar to the introduction, this discussion would benefit from a more comprehensive exploration of brain fog (mental fatigue) and the neurophysiological correlates of this phenomenon.

 

MATERIALS AND METHODS

I suggest the authors add subparagraphs to enhance the readability of the section.

Row 102:  Please, move this point (g) to the end of the paragraph. The requirement for informed consent is not considered an inclusion criterion in itself.

RESULTS

Row 269: I suggest the authors avoid throughout the text colloquial expression, such as ‘one again’.

DISCUSSION

Row 459-469: I suggest the authors acknowledge as a limitation the use of a limited, online-only neuropsychological test battery, which may not be as comprehensive or exhaustive as an in-person assessment.

Author Response

Dear Reviewer 2,

Thank you for your detailed review and valuable suggestions. We have addressed each of your comments as follows:

1. I suggest the authors add subparagraphs to enhance the readability of the section.

Response: Applied in ‘Materials and Methods’.

2. Row 102: Please, move this point (g) to the end of the paragraph. The requirement for informed consent is not considered an inclusion criterion in itself.

Response: Applied (lines 129-130).

3. Row 269: I suggest the authors avoid throughout the text colloquial expression, such as ‘one again’.

Response: Applied in all text.

4. Row 459-469: I suggest the authors acknowledge as a limitation the use of a limited, online-only neuropsychological test battery, which may not be as comprehensive or exhaustive as an in-person assessment.

Response: Applied (added paragraph in lines 522-531).

 

            Thank you.

Reviewer 3 Report

The manuscript by Antonio de Pádua Serafim et al. presents a study examining the neuropsychological correlates of SARS-CoV-2 infection after a significant time period, specifically 36 months. The data are intriguing and provide insights into the infection's effects, categorized by severity, on cognitive functions tested using a comprehensive battery of tests. Although it has some limitations, such as its retrospective design and the absence of a control group (i.e., individuals who did not contract Covid-19), which prevents definitive attribution of the observed effects solely to the infection, I believe the results are worth discussing. 

Please see the comments provided in each section. Specifically: 

- I suggest including, at the end of the Introduction, a priori hypotheses regarding expected results based on age and severity, considering what is already known from the literature.
- Moreover, I suggest citing seminal works in the context of interest, e.g., doi: 10.1016/j.tics.2023.08.008, to provide a stronger foundational background;

- It is unclear how the patients included in the study were identified and recruited; did all contacted patients agree to participate, or did some refuse? Have any patients died in the three years since the original database was created? Additional methodological details and a flow chart would be helpful.

- It is not clear to me whether influential factors, such as any comorbidities that may have developed in the meantime, therapies with potential adverse cognitive effects, etc., were considered and, if so, how.

- Line 105: I suggest replacing the term “decompensated” with a more appropriate one.

- In the Discussion, I suggest citing this work and others like it (doi: 10.3390/diagnostics12020544), as it is known that delirium is a risk factor for the subsequent onset of dementia, and citing evidence such as this on the link between COVID-19 and delirium further reinforces the demonstrated cognitive damage.

- Again in the Discussion, I recommend including practical suggestions on which neurorehabilitation or cognitive stimulation strategies could be effective and identifying the patients who have had Covid-19 most likely to benefit from these treatments, to optimize the results. 

Author Response

Dear Reviewer 3,

            We sincerely appreciate your thorough review and insightful feedback. Below, we provide our responses to each of your comments:

1. I suggest including, at the end of the Introduction, a priori hypotheses regarding expected results based on age and severity, considering what is already known from the literature.

Response: Applied (lines 183-188).

2. Moreover, I suggest citing seminal works in the context of interest, e.g., doi: 10.1016/j.tics.2023.08.008, to provide a stronger foundational background.

Response: Appliede (reference 25, first citation in line 64). Lines 58-67 were rewritten in order to contextualize that reference.

3. It is unclear how the patients included in the study were identified and recruited; did all contacted patients agree to participate, or did some refuse? Have any patients died in the three years since the original database was created? Additional methodological details and a flow chart would be helpful.

Response: Applied. Lines 97-106 were added in order to clarify that point.

4. It is not clear to me whether influential factors, such as any comorbidities that may have developed in the meantime, therapies with potential adverse cognitive effects, etc., were considered and, if so, how.

Response: Applied. Lines 183-188 e 507-521 were added in order to clarify that metodological point and discuss those limitations.

5. Line 105: I suggest replacing the term “decompensated” with a more appropriate one.

Response: Applied.

6. In the Discussion, I suggest citing this work and others like it (doi: 10.3390/diagnostics12020544), as it is known that delirium is a risk factor for the subsequent onset of dementia, and citing evidence such as this on the link between COVID-19 and delirium further reinforces the demonstrated cognitive damage.

Response: Applied. Lines 532-544 were added in order to contextualize that point.

7. Again in the Discussion, I recommend including practical suggestions on which neurorehabilitation or cognitive stimulation strategies could be effective and identifying the patients who have had Covid-19 most likely to benefit from these treatments, to optimize the results.

Response: Applied. Lines 532-544 were added also in order to contextualize that point.

Round 2

Reviewer 2 Report

All requests have been addressed.

All requests pertaining to 'Materials and methods' and 'Results' sessions  have been addressed.

Reviewer 3 Report

I would like to thank the Authors for their extensive work, which has clearly enhanced the quality of their manuscript. The paper presents a significant contribution to the field.

I have no additional suggestions.