Abstract
To investigate the clinical effect of donepezil combined with hydrogen–oxygen mixture inhalation in the treatment of patients with Alzheimer disease (AD), a total of 273 AD patients admitted to our hospital from March 2018 to March 2022 were retrospectively analyzed and assigned into an observation group (n = 138) and a control group (n = 135) according to the different treatment that they received. The control group was treated with donepezil tablets, while the observation group was treated with donepezil tablets combined with hydrogen–oxygen mixture inhalation. The scores of mini-mental state examination (MMSE), Montreal Cognitive Assessment (MoCA), Alzheimer’s Disease Assessment Scale-Cognition, activity of daily living scale (ADL) and the P300 event-related potential were compared between the 2 groups. After treatment, MMSE score, MoCA score, and ADL score in both groups increased after treatment (P < .01), while the improvement in the observation group was more significant than that in the control group (P < .001 for MMSE, P = .003 for MoCA, and P = .013 for ADL). The scores of Alzheimer’s Disease Assessment Scale-Cognition in the observation group decreased after treatment (P < .05), while the improvement in the observation group was more significant than that in the control group (P = .005). After treatment, the latency of P300 in both groups was shortened (P < .01), and the improvement in the observation group was more significant than that in the control group (P < .001). The amplitude of the observation group increased after treatment (P < .01), and the improvement of the observation group was significant than that of the control group (P = .007). The clinical efficacy of donepezil combined with hydrogen–oxygen mixture inhalation in the treatment of AD is better than that of donepezil alone, which is worthy of further study.
Keywords: Alzheimer disease, donepezil, efficacy, hydrogen–oxygen mixture
1. Introduction
Alzheimer disease (AD) is a common neurodegenerative disorder in the elderly population, characterized by progressive impairment of memory and other higher cognitive functions, accompanied by mental and behavioral symptoms and diminished capacity for life.[1] AD is characterized by an inflammatory response and oxidative stress, with pathological features of amyloid peptide deposition and neurofibrillary tangles in the brain, for which effective treatments are urgently needed.[2] The therapeutic medical gas hydrogen, as a drug gas molecule, has the potential to be a new adjunctive treatment for AD.[3,4] In recent years, hydrogen molecules have been found to have a wide range of antioxidant, anti-inflammatory, anti-apoptotic, and rapid diffusion effects, selectively reducing reactive oxygen species and being an antioxidant with neuroprotective properties.[5,6] Hydrogen was found to improve memory loss in AD model mice and to have a therapeutic effect on cognitive dysfunction.[7] Therefore, we believe that hydrogen–oxygen mixture inhalation is a good adjuvant therapy for early intervention. Our study aimed to explore the clinical efficacy of donepezil combined with hydrogen–oxygen mixture inhalation in the treatment of AD.
2. Materials and methods
2.1. General information
The study scheme is shown in Figure 1. A total of 273 AD patients admitted to our hospital from March 2018 to March 2022 were retrospectively analyzed and assigned into an observation group (n = 138) and a control group (n = 135) according to the different treatment that they received. Inclusion criteria: the diagnostic criteria of Alzheimer disease in the 2018 Chinese Guidelines for the Diagnosis and Treatment of Dementia and Cognitive Disorder (II): Guidelines for the Diagnosis and Treatment of Alzheimer’s Disease[8]; mild to moderate AD, with a score of 10 to 27 on the mini-mental state examination (MMSE)[9]; be able to cooperate to complete all tests; not taken anti-dementia drugs, antipsychotics, sedative and hypnotic drugs, and other related treatments before enrollment. Exclusion criteria: patients with uncontrolled hypertension, cardiopulmonary failure, thrombophlebitis, severe bleeding tendency, and risk of massive bleeding (esophageal varices with bleeding history); patients with serious mental diseases (schizophrenia, severe depression and other mental disorders); have a family history of mental diseases such as head trauma, craniocerebral disease, alcoholism or epilepsy; previous history of Parkinson disease or Huntington disease. This study was approved by the Medical Ethics Committee of our hospital (no. 2021053).
Figure 1.
A scheme of the study design.
2.2. Grouping and treatment methods
Patients received donepezil combined with hydrogen–oxygen mixture inhalation were assigned to the observation group. The hydrogen–oxygen mixture is mainly prepared by the hydrogen–oxygen atomizer (model AMS-H-03, Asclepius Meditec Co., Ltd., Shanghai, China [3 L of hydrogen–oxygen mixture is produced per minute, with hydrogen accounting for 66.67% and oxygen accounting for 33.33%]). Donepezil (Weisai [China] Pharmaceutical Co., Ltd., batch number H20050978, specification: 5 mg) was given 5 mg/time, once a day, orally. Patients who received only donepezil treatment were assigned to the control group. Treatment course: both groups took donepezil orally for 4 weeks, the observation group was treated with hydrogen–oxygen mixture inhalation once a day and 6 times a week (1 day off every Sunday) for a total of 4 weeks. After the treatment, video phone and outpatient follow-up were carried out (after 3 months of treatment).
2.3. Outcome indicators
Cognitive assessment was evaluated by using the scores of MMSE,[10] Montreal Cognitive Assessment (MoCA),[11] Alzheimer’s Disease Assessment Scale-Cognition (ADAS-Cog),[12] and capability of daily living activities was evaluated by using activity of daily living scale (ADL)[13] and the P300 event-related potential[14] were compared between the 2 groups.
2.4. Data collection
Data collected from our institutional electronic medical record system. Demographic characteristics (age, gender, disease duration, and education level), MMSE, MoCA, ADAS-Cog, ADL, and the P300 event-related potential were recorded.
2.5. Statistical analysis
Data analyzed by using were SPSS 25.0 software. The counting data was expressed as n (%) and compared by using χ2 test. The measurement data was expressed as mean ± standard deviation (SD) and compared by using t-test. The significance level was set at α < 0.05.
3. Results
The observation group had 77 males and 61 females, and the control group had 63 males and 72 females. The mean age of the observation group was 65.28 ± 12.78 years, and the control group was 65.07 ± 13.10 years. The mean disease duration of the observation group was 4.28 ± 2.17 years, and the control group was 4.62 ± 1.98 years. The observation group had 30 subjects with illiteracy, 35 subjects with primary school, 30 subjects with junior high school, and 43 subjects with high school. The control group had 22 subjects with illiteracy, 32 subjects with primary school, 36 subjects with junior high school, and 45 subjects with high school. There was no significant difference in the baseline data (all P > .05) (Table 1).
Table 1.
Comparison of clinical data between the 2 groups.
| Groups | n | Gender | Age (years) | Disease duration | Education | ||||
|---|---|---|---|---|---|---|---|---|---|
| Male | Female | Illiteracy | Primary school | Junior high school | High school | ||||
| Observation group | 138 | 77 | 61 | 65.28 ± 12.78 | 4.28 ± 2.17 | 30 | 35 | 30 | 43 |
| Control group | 135 | 63 | 72 | 65.07 ± 13.10 | 4.62 ± 1.98 | 22 | 32 | 36 | 45 |
| t/χ2 | 2.277 | 1.139 | 0.511 | 1.923 | |||||
| P | .131 | .257 | .683 | .59 | |||||
3.1. Comparison of the score of MMSE, MoCA, ADAS-Cog, and ADL between the 2 groups
There was no significant difference in MMSE, MoCA, ADAS-Cog, and ADL scale scores between the 2 groups before treatment (P > .05). After treatment, the MMSE scores of the observation group and the control group were significantly higher than those before treatment (P < .01), and the MMSE scores of the observation group were significantly higher than those of the control group after treatment (P < .001). After treatment, the MoCA score of the observation group and the control group were significantly higher than that before treatment (P < .01), and the MoCA score of the observation group was significantly higher than that of the control group after treatment (P = .003). After treatment, the ADAS-Cog score in the observation group was significantly lower than that before treatment (P < .05), and the ADAS-Cog score in the observation group was significantly lower than that in the control group (P = .005). After treatment, the ADL score of the observation group was significantly higher than that of the control group (P = .013) (Table 2).
Table 2.
Comparison of clinical data between the 2 groups.
| Groups | n | MMSE | MoCA | ADAS-Cog | ADL | ||||
|---|---|---|---|---|---|---|---|---|---|
| Before treatment | After treatment | Before treatment | After treatment | Before treatment | After treatment | Before treatment | After treatment | ||
| Observation group | 138 | 21.76 ± 2.86 | 26.90 ± 3.16# | 20.63 ± 2.65 | 25.34 ± 2.57# | 27.63 ± 5.95 | 24.34 ± 5.83* | 35.69 ± 5.08 | 39.01 ± 5.11* |
| Control group | 135 | 22.15 ± 2.12 | 24.81 ± 2.95# | 21.01 ± 2.86 | 23.69 ± 2.73# | 27.58 ± 5.86 | 27.52 ± 5.59 | 34.76 ± 5.57 | 37.89 ± 5.16 |
| P | .327 | <.001 | .912 | .003 | .473 | .005 | .337 | .013 | |
Compared with before treatment, *P < .05, #P < .01.
3.2. Comparison of P300 latency and amplitude between the 2 groups
After treatment, the P300 latency of the observation group and the control group were significantly lower than those before treatment (P < .01), and the P300 latency of the observation group were significantly lower than those of the control group after treatment (P < .001). The wave amplitude in the observation group after treatment was significantly higher than that before treatment (P < .01), and the wave amplitude in the observation group after treatment was significantly higher than that in the control group (P = .007) (Table 3).
Table 3.
Comparison of P300 latency and amplitude between the 2 groups
| Groups | n | Incubation (ms) | Amplitude (μV) | ||
|---|---|---|---|---|---|
| Before treatment | After treatment | Before treatment | After treatment | ||
| Observation group | 138 | 397.15 ± 36.16 | 349.35 ± 28.25# | 18.92 ± 6.25 | 24.02 ± 5.23# |
| Control group | 135 | 398.21 ± 45.76 | 366.36 ± 25.81# | 19.10 ± 5.73 | 21.11 ± 4.07 |
| P | .752 | <.001 | .259 | .007 | |
Compared with before treatment, *P < .05, #P < .01.
4. Discussion
AD is the most common type of dementia in the elderly, with an estimated 50 million people living with dementia worldwide, and the number of people living with AD has continued to increase in recent years as the population ages, severely affecting the quality of life of patients and families and imposing an excessive economic and social burden.[15] AD is now a global public health issue and one of the most important neuropsychiatric disorders. There is no curative treatment and only some improvement in symptoms.[16] Early intervention of AD is essential to improve symptoms and slow down the progression of the disease.[17] Currently, the main pharmacological treatments for AD are donepezil and memantine, which can slow down the progression of the disease to a certain extent, but the adverse effects of the drugs, the financial acceptability of the patients and the compliance are not to be underestimated.[18,19] In addition, most of the drugs used to treat the cerebral nervous system have difficulty reaching the foci of brain tissue damage due to the blood-brain barrier, and there are many difficult problems in treatment. Therefore, there is an urgent need for new and effective strategies for early intervention in AD.
The pathogenesis of AD is related to chronic oxidative stress and inflammatory responses, with excess reactive oxygen species contributing to the formation of amyloid plaques.[20] The formation and propagation of tau is associated with the interaction between brain tissue inflammation and amyloid pathology, ultimately leading to extensive brain tissue damage and cognitive impairment.[21,22] Hydrogen, the lightest and smallest gas molecule, is an antioxidant that selectively reduces reactive oxygen species, has good distribution properties, has the physical ability to penetrate cell membranes and diffuse into the cytoplasm, rapidly reaches the nucleus and mitochondria, and also crosses the blood-brain barrier to directly reach the site of injury, scavenging excess surrounding free radicals, and repairing neurological damage.[4,23] It has anti-inflammatory and anti-apoptotic effects and is neuroprotective in neurological diseases such as stroke and AD.[4,23] Experiments have shown that administration of hydrogen-containing water can significantly reduce oxidative stress indicators and improve cognitive, motor and memory abilities of animals in AD model rats.[24,25] Hydrogen as a drug gas molecule is therefore an ideal adjunct to oxygen inhalation, and inhalation of a hydrogen–oxygen mixture is a new adjunctive treatment for AD with a good safety profile.[3,4]
Our study showed that the improvement of MMSE score, MoCA score and ADAS-Cog score of the patients in the observation group after treatment was better than that in the control group, indicating that donepezil combined with hydrogen-oxygen mixture inhalation in the treatment of patients with AD can better improve the cognitive function of the patients. Meanwhile, the improvement of ADL score of patients in the observation group was better than that in the control group after treatment, indicating that donepezil combined with hydrogen–oxygen mixture inhalation can better improve the ability of daily living of patients with AD. Event P300 event-related potential, also known as cognitive evoked potential, is an objective neuroelectrophysiological examination method with the strongest specificity and is closely related to the cognitive process. It has very important clinical application value for early determination of patients’ cognitive impairment, assessment of the severity of cognitive impairment and prediction of the prognosis of cognitive impairment.[26] This study showed that the P300 latency of patients in the observation group was shortened and the wave amplitude was increased after treatment, indicating that the combination of inhalation of hydrogen and oxygen mixture and donepezil oral treatment of AD can better improve the cognitive function of patients.
To sum up, donepezil combined with hydrogen–oxygen mixture inhalation in the treatment of patients with AD can better improve the cognitive function and ability of daily living of patients. The curative effect is better than that of donepezil alone in the treatment of AD. However, the number of samples in this clinical study is small, and the efficacy evaluation standard is mainly based on the scale evaluation, lacking more accurate objective evaluation indicators. In the process of continuing clinical research, the number of samples will be further increased, and some objective evaluation indicators will be included to improve the accuracy of efficacy evaluation. The ultimate goal of this clinical study was to establish a standardized operating procedure and clinical evaluation system for the treatment of Alzheimer disease with hydrogen and oxygen mixture gas, delay the disease process of Alzheimer disease patients, enable patients to achieve maximum cognitive function recovery, improve their ability of daily life, and better serve patients with this disease.
Author contributions
Conceptualization: Haifeng Li, Jin Xie.
Data curation: Haifeng Li, Jin Xie.
Formal analysis: Haifeng Li.
Funding acquisition: Haifeng Li, Jin Xie.
Investigation: Haifeng Li.
Methodology: Haifeng Li, Jin Xie.
Project administration: Haifeng Li.
Resources: Zhaojun Dan, Haifeng Li, Jin Xie.
Software: Zhaojun Dan, Haifeng Li, Jin Xie.
Supervision: Zhaojun Dan, Haifeng Li, Jin Xie.
Validation: Zhaojun Dan, Jin Xie.
Visualization: Zhaojun Dan.
Writing—original draft: Zhaojun Dan.
Writing—review & editing: Zhaojun Dan.
Abbreviations:
- AD
- Alzheimer disease
- ADAS-Cog
- Alzheimer’s Disease Assessment Scale-Cognition
- ADL
- activity of daily living
- MMSE
- mini-mental state examination
- MoCA
- Montreal Cognitive Assessment
This study was supported by Hospital level project of Shiyan Taihe Hospital (2020JJXM097).
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
How to cite this article: Dan Z, Li H, Xie J. Efficacy of donepezil plus hydrogen–oxygen mixture inhalation for treatment of patients with Alzheimer disease: A retrospective study. Medicine 2023;102:30(e34382).
Contributor Information
Haifeng Li, Email: 12545974@qq.com.
Jin Xie, Email: 632514251@qq.com.
References
- [1].Sun Y, Wang Y, Lu J, et al. Disrupted functional connectivity between perirhinal and parahippocampal cortices with hippocampal subfields in patients with mild cognitive impairment and Alzheimer’s disease. Oncotarget. 2017;8:99112–24. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [2].He XF, Xu JH, Li G, et al. NLRP3-dependent microglial training impaired the clearance of amyloid-beta and aggravated the cognitive decline in Alzheimer’s disease. Cell Death Dis. 2020;11:849. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [3].Huang C-S, Kawamura T, Toyoda Y, et al. Recent advances in hydrogen research as a therapeutic medical gas. Free Radic Res. 2010;44:971–82. [DOI] [PubMed] [Google Scholar]
- [4].Htun Y, Nakamura S, Kusaka T. Hydrogen and therapeutic gases for neonatal hypoxic–ischemic encephalopathy: potential neuroprotective adjuncts in translational research. Pediatr Res. 2021;89:753–9. [DOI] [PubMed] [Google Scholar]
- [5].Ishibashi T. Molecular hydrogen: new antioxidant and anti-inflammatory therapy for rheumatoid arthritis and related diseases. Curr Pharm Des. 2013;19:6375–81. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [6].Kawamura T, Higashida K, Muraoka I. Application of molecular hydrogen as a novel antioxidant in sports science. Oxid Med Cell Longevity. 2020;2020:1–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [7].Hou C, Peng Y, Qin C, et al. Hydrogen-rich water improves cognitive impairment gender-dependently in APP/PS1 mice without affecting Aβ clearance. Free Radic Res. 2018;52:1311–22. [DOI] [PubMed] [Google Scholar]
- [8].China Dementia and Cognitive Disorders Writing Group, Cognitive Disorders Committee of the Neurologist Branch of the Chinese Medical Association. 2018 Chinese guidelines for the diagnosis and treatment of dementia and cognitive disorders (II): guidelines for the diagnosis and treatment of Alzheimer’s disease. Chin Med J (Engl). 2018;98:971–97. [Google Scholar]
- [9].Ikonomovic MD, Klunk WE, Abrahamson EE, et al. Precuneus amyloid burden is associated with reduced cholinergic activity in Alzheimer disease. Neurology. 2011;77:39–47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [10].Elosúa MR, Ciudad MJ, Contreras MJ. Gender differences in verbal and visuospatial working memory tasks in patients with mild cognitive impairment and Alzheimer disease. Dement Geriatr Cogn Dis Extra. 2017;7:101–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [11].Said CM, Delahunt M, Hardidge A, et al. Recumbent cycling to improve outcomes in people with hip fracture: a feasibility randomized trial. BMC Geriatr. 2021;21:394. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [12].Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry. 1984;141:1356–64. [DOI] [PubMed] [Google Scholar]
- [13].Erzigkeit H, Lehfeld H, Peña-Casanova J, et al. The Bayer-Activities of Daily Living Scale (B-ADL): results from a validation study in three European countries. Dement Geriatr Cogn Disord. 2001;12:348–58. [DOI] [PubMed] [Google Scholar]
- [14].Smith DB, Donchin E, Cohen L, et al. Auditory averaged evoked potentials in man during selective binaural listening. Electroencephalogr Clin Neurophysiol. 1970;28:146–52. [DOI] [PubMed] [Google Scholar]
- [15].Qiu T, Zeng Q, Luo X, et al. Effects of cigarette smoking on resting-state functional connectivity of the nucleus basalis of Meynert in mild cognitive impairment. Front Aging Neurosci. 2021;13:755630. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [16].Wu J, Ishikawa M, Zhang J, et al. Brain imaging of nicotinic receptors in Alzheimer’s disease. Int J Alzheimers Dis. 2010;2010:548913. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [17].Chougule PS, Najjar RP, Finkelstein MT, et al. Light-induced pupillary responses in Alzheimer’s disease. Front Neurol. 2019;10:360. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [18].Wang LY, Pei J, Zhan YJ, et al. Overview of meta-analyses of five non-pharmacological interventions for Alzheimer’s disease. Front Aging Neurosci. 2020;12:594432. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [19].Chen R, Chan PT, Chu H, et al. Treatment effects between monotherapy of donepezil versus combination with memantine for Alzheimer disease: a meta-analysis. PLoS One. 2017;12:e0183586. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [20].El Sayed NS, Ghoneum MH. Antia, a natural antioxidant product, attenuates cognitive dysfunction in streptozotocin-induced mouse model of sporadic Alzheimer’s disease by targeting the amyloidogenic, inflammatory, autophagy, and oxidative stress pathways. Oxid Med Cell Longev. 2020;2020:4386562. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [21].Shahani N, Subramaniam S, Wolf T, et al. Tau aggregation and progressive neuronal degeneration in the absence of changes in spine density and morphology after targeted expression of Alzheimer’s disease-relevant tau constructs in organotypic hippocampal slices. J Neurosci. 2006;26:6103–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [22].Cao J, Zhong MB, Toro CA, et al. Endo-lysosomal pathway and ubiquitin-proteasome system dysfunction in Alzheimer’s disease pathogenesis. Neurosci Lett. 2019;703:68–78. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [23].Ohsawa I, Ishikawa M, Takahashi K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 2007;13:688–94. [DOI] [PubMed] [Google Scholar]
- [24].Chen C, Chen Q, Mao Y, et al. Hydrogen-rich saline protects against spinal cord injury in rats. Neurochem Res. 2010;35:1111–8. [DOI] [PubMed] [Google Scholar]
- [25].Wang C, Li J, Liu Q, et al. Hydrogen-rich saline reduces oxidative stress and inflammation by inhibit of JNK and NF-κB activation in a rat model of amyloid-beta-induced Alzheimer’s disease. Neurosci Lett. 2011;491:127–32. [DOI] [PubMed] [Google Scholar]
- [26].He B, Lu GH, Yang ZY, et al. Effects of cognitive intervention training on cognitive function and event-related potential P300 in patients with mild cognitive impairment. Chin J Rehabil Med. 2013;28:1006–9. [Google Scholar]