Associations between Sleep Duration and Autonomic Nervous System Regulation in Patients with Probable Alzheimer’s Disease: A Cross-Sectional Pilot Study

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This study explores the relationship between sleep duration and ANS regulation in older patients with probable AD. The authors aimed to identify how varying sleep durations affect ANS function, focusing on HRV as a measure of ANS activity. Although there are some limitations, including a small sample size, cross-sectional design, and failure to control for factors such as obstructive sleep apnea, beta-blocker use, restless legs syndrome, REM sleep behavior disorder, and other biological factors that may affect ANS regulation, this study contributes to the limited literature on the relationship between sleep duration and ANS regulation in AD patients. As a pioneering and exploratory study, it deserves encouragement. It is recommended that the authors be allowed to revise and deepen the article's content to improve its depth and breadth. The following suggestions are provided for the author's consideration.

To enhance the depth and background of the research on sleep duration and ANS regulation in patients with probable AD, it is recommended that relevant studies be integrated. Expanding the scope to include neurodegenerative diseases is recommended if relevant research is challenging. Parkinson's disease and AD share common features in their neurodegenerative processes and sleep disturbances. Comparing findings from these two conditions may provide a broader understanding of the mechanisms underlying sleep duration and autonomic nervous system regulation. The following two references are suggested for consideration: Memon, Adeel A., et al. "Heart rate variability during sleep in synucleinopathies: a review." Frontiers in Neurology 14 (2024): 1323454.; Yu et al. "Mild cognitive impairment in patients with Parkinson’s disease: An updated mini-review and future outlook." Frontiers in aging neuroscience 14 (2022): 943438. Including these references will enhance the scholarly depth of this study and position these findings within the broader context of neurodegenerative disease research. This will facilitate a more comprehensive understanding of the interactions between sleep, cognitive impairment, and autonomic regulation.

This study did not consider certain factors, including obstructive sleep apnea, REM sleep behavior disorder, and other biological factors (e.g., genes) affecting sleep. It is recommended that these limitations be acknowledged to remind readers of the study's constraints, thereby enhancing the discussion and ensuring the research results are not perceived as overly conclusive. For example, By discussing the influence of genetic polymorphisms on sleep disturbances, this study can help highlight the potential genetic factors contributing to the variability in sleep duration and ANS regulation in AD patients. The following articles are provided for further reference: Musiek, Erik S., David D. Xiong, and David M. Holtzman. "Sleep, circadian rhythms, and the pathogenesis of Alzheimer disease." Experimental & molecular medicine 47.3 (2015): e148-e148.; Uddin, Md Sahab, et al. "Circadian and sleep dysfunction in Alzheimer’s disease." Ageing Research Reviews 60 (2020): 101046. ; Lin et al. "Effect of ALDH2 on sleep disturbances in patients with Parkinson’s disease." Scientific reports 9.1 (2019): 18950.

Lastly, relying on sleep diaries to assess sleep duration may introduce subjectivity. Future studies should employ more objective sleep assessment methods, such as polysomnography.

Author Response

1. Thank you for your valuable time in reviewing our manuscript and giving us the opportunity for revision Including these references will enhance the scholarly depth of this study and position these findings within the broader context of neurodegenerative disease research. This will facilitate a more comprehensive understanding of the interactions between sleep, cognitive impairment, and autonomic regulation.

Response: Thank you for your comments. As suggested, we have revised the Introduction (please see pp. 1-2).

Sleep deprivation, prolonged sleep duration, and circadian rhythm delay are associated with neurodegenerative changes. Amyloid plaques are linked to synaptic loss, neuronal death, and cognitive impairment in Alzheimer's disease (AD), primarily involving the accumulation of β-amyloid protein (Aβ), neurofibrillary tangles (NFTs), neuroinflammation, oxidative stress, circadian rhythm dysfunction, and reduced aldehyde dehydrogenase 2 (ALDH2) enzyme activity. These factors may exacerbate monoaminergic neuronal loss and synucleinopathies, which may be related to the degradation of brain regions control-ling autonomic nervous system (ANS) functions (Uddin, 2020; Park, 2021; Lin, 2019). Sleep is a natural and crucial biological process, and sleep disturbances can lead to neurodegenerative by products that not only affect disease progression but also cause cognitive impairment. Additionally, sleep disturbances may be considered a marker of neurodegeneration (Memon, 2024). In patients with all types of dementia, particularly in the case of AD, PSNS activity during both NREM and REM sleep stages is lower than that in healthy individuals. This may be related to the degeneration of brain regions that control the ANS (Cheng, 2022; Memon, 2024).

2. This study did not consider certain factors, including obstructive sleep apnea, REM sleep behavior disorder, and other biological factors (e.g., genes) affecting sleep. It is recommended that these limitations be acknowledged to remind readers of the study's constraints, thereby enhancing the discussion and ensuring the research results are not perceived as overly conclusive.

Response: Thank you for pointing this out. As suggested, we have revised the Discussion (please see pp. 6-7.).

3. Lastly, relying on sleep diaries to assess sleep duration may introduce subjectivity. Future studies should employ more objective sleep assessment methods, such as polysomnography.

Response: Thank you for your comments. As suggested, we have revised the Feasibility of this Study in the Discussion (please see p 8).

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript entitled “Associations between sleep duration and autonomic nervous system regulation in patients with probable Alzheimer's disease: A cross-sectional pilot study" by Liu et al is potentially an important study. The following are some points that the authors should consider.

 

1.  In the Introduction, authors should briefly describe ANS function during NREM and REM sleep and write the full form of ANS and PNS.

2.    The ANS activity pattern is different during REM and NREM sleep. Authors should report HRV data during REM and NREM separately.

3.     In Figure 1. LF and HF is no clearly described, the authors should describe it and also correct the very confusing sentence in the figure caption. And also write the full form LF and HF.  

4.     In Table 2, authors claim that longer sleep duration was associated with more severe impairment of ANS regulation than was a shorter sleep duration. Please check it again make sure it is correct.

5.     The authors have shown the exclusion criteria of patients that affect the sleep. Several other factors that affect HRV. Did the authors check the addiction and phycological disorder status of the patients?

6.     In method (line 319-321), “psychiatric nurse observed eye movement, depth of breathing, and frequency of body movements”. Authors should also include this information in the results section.

7.     The authors divided four groups with different ages and three groups with different sleep duration.  Did the authors compare HRV within these age groups?

8.     The methodology seems little confusing like experimental design, group division etc, it is not written properly, write it in representative form.

9.     Check the full manuscript for punctuation, spelling errors, grammatical errors and long sentences.

 

Thanks

Author Response

1. In the Introduction, authors should briefly describe ANS function during NREM and REM sleep and write the full form of ANS and PNS.

Response: Thank you for your comments. As suggested, we have revised the Introduction (please see pp. 1–2).

The autonomic nervous system (ANS) plays a crucial role during sleep and is divided into two branches: the sympathetic nervous system (SNS) and parasympathetic nervous system (PNS). Sleep consists of two distinct states: non-rapid eye movement (NREM) and rapid eye movement (REM). During NREM sleep, ANS activity is characterized by lower sympathetic activity and higher parasympathetic (PNS) activity. In contrast, REM sleep is characterized by more variable ANS activity, with periods of both sympathetic and parasympathetic influences.

 

2. The ANS activity pattern is different during REM and NREM sleep. Authors should report HRV data during REM and NREM separately.

Response: Thank you for the insightful comment. Since polysomnography was not used in this study, we were not able to differentiate the HRV data between REM and NREM sleep. We recommend future research to include polysomnography to address this gap in the Discussion (see p. 8).

3. In Figure 1. LF and HF is no clearly described, the authors should describe it and also correct the very confusing sentence in the figure caption. And also write the full form LF and HF.

Response: Thank you for your comments. As suggested, we have revised the Figure 1 caption and provided the full form LF and HF.

4. In Table 2, authors claim that longer sleep duration was associated with more severe impairment of ANS regulation than was a shorter sleep duration. Please check it again make sure it is correct.

Response: Thank you for pointing this out; we have revised the sentence. A longer sleep duration was associated with more severe impairment of ANS regulation than was a sleep duration of 6–9 hours.

5. The authors have shown the exclusion criteria of patients that affect the sleep. Several other factors that affect HRV. Did the authors check the addiction and phycological disorder status of the patients?

Response: Thank you for your suggestion. According to the literature, monitoring HRV during sleep may be more accurate and reliable for measuring ANS activity, as there is less influence from factors such as addiction and psychological disorders. This point has been added to the Discussion (see p. 7).

6. In method (line 319-321), “psychiatric nurse observed eye movement, depth of breathing, and frequency of body movements”. Authors should also include this information in the results section.

Response: We appreciate your feedback. In the revised Results section, we have included details on sleep duration based on the psychiatric nurse's observations of eye movement, depth of breathing, and frequency of body movements (see p. 9).

7. The authors divided four groups with different ages and three groups with different sleep duration. Did the authors compare HRV within these age groups?

Response: Thank you for your comments. Yes, we compared HRV within these age groups. However, the statistical analysis indicates that the effect of age on HRV results was not significant (p > 0.05).

8. The methodology seems little confusing like experimental design, group division etc, it is not written properly, write it in representative form.

Response: Thank you for meticulously reviewing our manuscript. We have revised the Materials and Methods according to your suggestion (please see p. 9).

9. Check the full manuscript for punctuation, spelling errors, grammatical errors and long sentences.

Response: We have revised the manuscript for punctuation, spelling errors, grammatical errors, and long sentences.