Clinical study of acupuncture combined with medication for the elderly with Alzheimer disease

PANG Jing (逄静), YⅠN Hongna (尹洪娜), SUN Zhongren (孙忠人), XⅠA Kunpeng (夏昆鹏)

1 Heilongjiang University of Chinese Medicine, Harbin 150040, China

2 The Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin 150001, China

Abstract

Keywords: Acupuncture Therapy; Acupuncture Medication Combined; Donepezil; Alzheimer Disease; Activities of Daily Living; Event-related Potentials, P300

Alzheimer disease (AD), a sneaky neurodegenerative disorder significantly affecting the quality of life of the aged population, has become a real challenge to geriatrics[1]. AD’s typical clinical manifestation is cognitive impairment. In the long term, AD may also bring negative emotions, including depression, anxiety,agitation, etc., which will, in turn, aggravate AD’s clinical symptoms[2]. According to the ancient physicians’elaboration of the Governor Vessel-brain-mind theory,when people are old and fragile, the marrow sea will become deficient, and the mind will lack nourishment,subsequently leading to AD. The Governor Vessel charges Yang Qi of the whole body, connects the brain,kidney, and marrow, and is an essential meridian for treating brain disorders[3]. Traditional Chinese medicine(TCM) holds that the priority should fixate on treating the mind in acupuncture treatment. Consequently,some doctors propose treating the mind first to treat brain diseases. Based on these theories, this trial adopted mind-regulating acupuncture by selecting points from the Governor Vessel plus donepezil to treat AD.

1 Clinical Materials

1.1 Diagnostic criteria

We referred to the diagnostic criteria for AD jointly stipulated by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association(NINCDS-ADRDA)[4].

1.2 Inclusion criteria

Met the diagnostic criteria for AD; age ≥60 and ≤80 years old, males or females; scored 10-25 points by the mini-mental state examination (MMSE); approved by the ethics committee and the written informed consent obtained; not taking any medications to treat AD within the previous 2 weeks.

1.3 Exclusion criteria

Showed poor compliance and failed to stick with the treatment protocol; serious hearing or visual impairment; severe organic or mental disorders; allergic to donepezil or with a history of fainting during acupuncture.

1.4 Statistical methods

The SPSS version 23.0 software was used for data analysis. The normally distributed measurement data were described as mean ± standard deviation (±s),checked by the paired samplest-test in intra-group comparisons or groupt-test in between-group comparisons. If not meeting normal distribution, the measurement data would be expressed as median(interquartile range) [M (IQR)], checked by the paired samples rank-sum test in intra-group comparisons or the two independent samples rank-sum test in between-group comparisons. The enumeration data were expressed as rates and analyzed using the Chi-square test.P＜0.05 indicated statistical significance.

1.5 General data

Sixty AD patients visiting the Second Affiliated Hospital of Heilongjiang University of Chinese Medicine between January 2019 and February 2021 were recruited. The Ethics Committee of the Second Affiliated Hospital of Heilongjiang University of Chinese Medicine approved the trial protocol (Approval No. 2019-27). We adopted the envelope method using a computer to randomly assign the patients to a treatment group or a control group at a ratio of 1:1, with 30 cases in each group. The general data were statistically equal between the two groups (P＞0.05), suggesting comparability. The details are shown in Table 1.

Table 1 Comparison of the general data

2 Treatment Methods

The patients received interventions for primary diseases, including reducing blood pressure, blood glucose, and lipids. They also received health education on diet and living habits.

2.1 Treatment group

Patients in the treatment group were intervened by mind-regulating acupuncture plus donepezil.

Points: Fengfu (GV16), Baihui (GV20), and Shenting(GV24).

Operation: The patient took a sitting position. The physician used disposable acupuncture needles of Hwato brand (Suzhou Medical Appliance Factory, Co.,Ltd., China) for acupuncture. Fengfu (GV16) should be punctured with the needle tip toward the lower jaw,and the needle should go slowly 15-20 mm in depth.Baihui (GV20) and Shenting (GV24) were punctured using the subcutaneous needling method, with needles insertion for 20-30 mm under the epicranial aponeurosis. Then, the physician performed smallamplitude high-frequency (200 r/min or higher) twirling needling manipulations while puncturing the needle,15 min later, and before removing the needle, 2 min each time. The stimulating intensity should be within the patient’s tolerance, and the needles should be remained for 30 min. The treatment was offered by the same senior physician once daily, 7 times as a course of treatment for 4 courses.

Medication: Donepezil tablets [State Food and Drug Administration Approval No. H2007081, Eisai China Inc.,China] were taken orally, 5 mg each time, once daily, for 4 weeks.

2.2 Control group

Patients in the control group only took donepezil for treatment with the same dosage and duration.

3 Efficacy Observation

3.1 Observation items

3.1.1 MMSE score[5]

MMSE is known for its reliability and validity; a lower score indicates a worse cognitive ability.

3.1.2 Alzheimer disease assessment scale-cognitive part (ADAS-Cog)[6]

ADAS-Cog can assess the level of cognitive impairment. The higher the score, the more serious the cognitive impairment.

3.1.3 Activities of daily living (ADL)[7]

The ADL evaluates activities such as toilet use,feeding, and mobility. The lower the score, the worse the self-care ability.

3.1.4 Detection of event-related potential (ERP) P300

The ERP P300 was detected one day before treatment and the next day of the final session using the KEYPOINT electromyograph and evoked potential equipment (Medtronic Inc., USA). P300 is an endogenous core member of ERPs. A shorter latency and larger amplitude of P300 suggest better cognitive function.

3.1.5 Transcranial Doppler (TCD)

The CV550 Philips color Doppler ultrasonography(frequency 2 MHz) was used to measure the mean blood flow velocity of bilateral middle cerebral arteries(MCA), anterior cerebral arteries (ACA), bilateral posterior cerebral arteries (PCA), bilateral vertebral arteries (VA), and the basilar artery (BA) before and after treatment.

3.1.6 Adverse reactions

The adverse reactions of acupuncture treatment included fainting, ecchymosis, sustained needling sensations after needle removal, etc. The adverse reactions of the pharmaceutical treatment included dizziness, nausea, vomiting, diarrhea, etc. These reactions were kept a record by the physician who conducted acupuncture treatments.

3.2 Results

3.2.1 Comparison of the scores of MMSE, ADAS-Cog,and ADL

There were no significant differences in the MMSE,ADAS-Cog, or ADL scores between the two groups before treatment (P＞0.05), indicating the comparability.After treatment, the MMSE and ADL scores increased in both groups (P＜0.05) and were markedly higher in the treatment group than in the control group (P＜0.05). The ADAS-Cog score dropped after treatment in both groups (P＜0.05) and was significantly lower in the treatment group than in the control group (P＜0.05).Please find the details in Table 2.

3.2.2 Comparison of the latency and amplitude of P300

The latency and amplitude of P300 were statistically equal between the two groups before treatment(P＞0.05), suggesting comparability. After treatment, the latency of P300 was shortened, and the amplitude was extended in both groups, all showing statistical significance (P＜0.05); the latency of P300 was shorter,and the amplitude was larger in the treatment group than in the control group, presenting significant between-group differences (P＜0.05). The data are detailed in Table 3.

3.2.3 Comparison of the mean cerebral blood flow velocity

There were no significant differences in the mean cerebral blood flow velocities between the two groups before treatment (P＞0.05), suggesting comparability.After treatment, the mean cerebral blood flow velocities increased after treatment in both groups,showing notable intra-group differences (P＜0.05); the improvements were more significant in the treatment group than in the control group (P＜0.05). The details are shown in Table 4 and Table 5.

Table 2 Comparison of the MMSE, ADAS-Cog, and ADL scores before and after treatment ( ±s) Unit: point

Table 2 Comparison of the MMSE, ADAS-Cog, and ADL scores before and after treatment ( ±s) Unit: point

Note: MMSE=Mini-mental state examination; ADAS-Cog=Alzheimer disease assessment scale-cognitive part; ADL=Activities of daily living; compared with the same group before treatment, 1) P＜0.05; compared with the control group after treatment, 2) P＜0.05.

Group n MMSE score ADAS-Cog score ADL score Pre-treatment Post-treatment Pre-treatment Post-treatment Pre-treatment Post-treatment Treatment 30 16.48±1.23 29.16±2.111)2) 38.15±4.95 28.45±3.751)2) 33.59±1.87 65.56±1.631)2)Control 30 16.42±1.34 23.27±2.131) 38.35±4.23 33.46±4.011) 34.32±1.81 45.87±1.591)

Table 3 Comparison of the latency and amplitude of P300 before and after treatment ( ±s)

Table 3 Comparison of the latency and amplitude of P300 before and after treatment ( ±s)

Note: Compared with the same group before treatment, 1) P＜0.05; compared with the control group after treatment, 2) P＜0.05.

Group n Time Latency/ms Amplitude/μⅤTreatment 30 Pre-treatment 369.78±18.54 4.85±0.56 Post-treatment 336.54±14.101)2) 7.98±0.591)2)Control 30 Pre-treatment 368.94±17.65 4.91±0.52 Post-treatment 352.18±15.281) 5.85±0.651)

Table 4 Comparison of the mean blood flow velocities of the anterior circulation ( ±s) Unit: cm/s

Table 4 Comparison of the mean blood flow velocities of the anterior circulation ( ±s) Unit: cm/s

Note: Compared with the same group before treatment, 1) P＜0.05; compared with the control group after treatment, 2) P＜0.05.

Group n Time Anterior cerebral artery Middle cerebral artery Treatment 30 Pre-treatment 36.85±3.68 40.25±3.21 Post-treatment 46.25±3.141)2) 50.27±2.971)2)Control 30 Pre-treatment 36.57±3.51 41.07±3.15 Post-treatment 42.35±3.241) 45.37±2.681)

Table 5 Comparison of the mean blood flow velocities of the posterior circulation ( ±s) Unit: cm/s

Table 5 Comparison of the mean blood flow velocities of the posterior circulation ( ±s) Unit: cm/s

Note: Compared with the same group before treatment, 1) P＜0.05; compared with the control group after treatment, 2) P＜0.05.

Group n Time Ⅴertebral artery Basilar artery Posterior cerebral artery Treatment 30 Pre-treatment 16.52±2.57 18.36±2.87 19.24±2.61 Post-treatment 26.12±2.741)2) 28.57±2.671)2) 28.97±2.541)2)Control 30 Pre-treatment 17.21±2.69 18.25±2.94 19.19±2.74 Post-treatment 20.38±2.781) 23.27±2.471) 24.19±2.581)

3.2.4 Adverse reactions

During the study, the treatment group had 1 case of needle fainting and 1 case of ecchymosis, which made the adverse reaction rate 6.67% in this group. One case of nausea happened in the control group during the treatment, and the adverse reaction rate was 3.33%.The symptoms were relieved after management, not affecting the following treatment. There was no significant difference in the adverse reaction rate between the two groups (P＞0.05).

4 Discussion

AD is a neurodegenerative disease, clinically manifesting as declined learning ability and memory and progressive cognitive impairment, often accompanied by mental symptoms[8-9]. Each year, more and more people are diagnosed with AD in the rapidly aging society[10]. As the condition aggravates, AD dramatically affects the quality of daily life amongst older patients. Regarding the treatment of AD,pharmaceutical treatment alone acts slowly but costs high, let alone various adverse reactions. Therefore,finding a safe and effective treatment for AD becomes urgent. Donepezil, the medication selected in this study,is one of the principal drugs used to treat AD. Donepezil is a cholinesterase inhibitor that improves the patient’s cognitive function by boosting the level of acetylcholine[11].

In TCM, AD belongs to the scope of “dementia”. It is located in the brain and associated with weakness and aging, deficiency in the brain and marrow, and insufficient nutritional supply to the mind. According to TCM, the kidney’s failure to produce sufficient essence and the malnourished brain are to blame for the development of dementia. The Governor Vessel runs through the brain, which is recognized as the sea of marrow; the kidney governs bones and is in charge of producing marrow. The Governor Vessel is the sea of Yang meridians and the commander of Yang Qi of the whole body and connects with the kidney. Hence, it is suggested that the Governor Vessel is closely linked with the brain, kidney, and spinal cord[12]. The mind is the foundation for regulating body activities[13]. Also,physicians from various generations hold that the Governor Vessel should be considered first for treating brain-related disorders. Therefore, we selected Fengfu(GV16), Baihui (GV20), and Shenting (GV24) in this study to treat AD by supplementing essence and marrow and unblocking and regulating the Governor Vessel to nourish the brain and mind and harmonize the mind and spirit. Data mining analysis reveals that Governor Vessel points are commonly selected in the treatment of cognitive impairment[14-15]. Acupuncture at Governor Vessel points helps blood flow in the cerebral cortex and regulates cell metabolism to repair damaged cranial nerves[16]. In this study, we adopted the mind-regulating acupuncture method to regain the balance between Yin and Yang by modulating the patient’s mind. This is an acupuncture method that can modulate the mind, Zang-Fu organs, Qi, blood, and body fluids[17]. Ancient TCM classics all emphasize the mind’s role in the treatment process. In modern times,academician SHI Xuemin also points out that, “the mind is involved in the begging of various diseases[18]; the priority of acupuncture should lay on awakening the mind so that the flow of Qi becomes smooth and diseases can be eradicated”. Therefore, to treat AD,we should treat the mind first. In this study, the acupuncturist always communicated with the patient before treatment to ensure the patient was in a good state, physically and emotionally, not anxious or stressed but entirely focused. Small-amplitude and high-frequency twirling acupuncture manipulations were offered 3 times during a treatment session to increase the stimulation. At the same time, the physician also observed the patient’s responses and asked the patient to feel the needling sensation, which was supposed to reach the corresponding brain functional area through the epicranial aponeurosis to benefit the brain and intelligence and calm the mind[19-20]. After the acupuncture treatment, health education was offered to soothe the patient’s heart and mind and help them develop a healthy lifestyle to achieve a better treatment result finally[21].

The MMSE and ADAS-Cog, two classic scales for evaluating the cognitive function, were used in this study. They have a high sensitivity and can evaluate the patient’s cognitive function from multiple perspectives such as memory, language, and execution. The results here showed that both groups gained increases in the MMSE score after treatment, and the score was higher in the treatment group than in the control group; the ADAS-Cog score dropped after treatment in both groups and was lower in the treatment group than in the control group. Furthermore, ADL has been commonly used to evaluate AD patients’ basic daily activities such as toilet use, dressing, bathing, etc. The study results showed that the ADL score increased after treatment in both groups and was notably higher in the treatment group.

Rheoencephalogram examines blood supply,elasticity, tone, and other brain blood vessel features.Research demonstrates that cerebral circulation improves, brain cell function recovers, cerebral metabolism strengthens, and brain neurons get repaired[22]. We observed enhanced cerebral blood flow in the current study after the intervention in both groups and more significant improvements in each mean cerebral blood flow velocity in the treatment group. P300 can reflect the brain’s cognitive function[23].In this study, the latency of P300 was shortened, and its amplitude became larger in both groups after treatment, and the latency was obviously shorter, and the amplitude was larger in the treatment group than in the control group.

To conclude, this trial tells that mind-regulating acupuncture plus donepezil can accelerate cerebral blood flow and modulate P300’s latency and amplitude in AD patients to improve learning and memory abilities.However, due to the limited sample size, we did not stage long-term follow-ups in this study. Next, we will conduct multicenter studies to verify further the mechanism of mind-regulating acupuncture in treating AD.

Conflict of Interest

The authors declare that there is no potential conflict of interest in this article.

Acknowledgments

This work was supported by the Construction Project of Evidence-based Ability of Traditional Chinese Medicine(Ⅰmprovement Evidence-based Ability of Specialized Diseases) [中医药循证能力建设项目(专科专病循证能力提升), No. 2019XZZX-ZJ005]; Research Project of Health Commission of Heilongjiang Province (黑龙江省卫生健康委科研课题, No. 2019-192).

Statement of Informed Consent

Ⅰnformed consent was obtained from all individual participants or their guardians.

Received: 8 July 2021/Accepted: 4 January 2022