Clinical Evaluation Of Electroacupuncture Combined With Donepezil In The Treatment Of Alzheimer’s Disease And Investigation On Its Mechanism Based On FALFF And Functional Connectivity Analysis Of FMRI Technology

ObjectiveTo evaluate the clinical effect on cognitive function and safety of electro-acupuncture combined with donepezil in the treatment of Alzheimer’s disease(AD)based on a multi-center randomized controlled study,and the fractional amplitude of low frequency fluctuation(f ALFF)and functional connectivity obtained by resting state functional magnetic resonance imaging technology(f MRI)was used to investigate its influences on the neuron spontaneous activity.To provide evidence for the electro-acupuncture effects,prognosis and central mechanism of AD.MethodsParticipants were recruited from the Acupuncture Department of Longhua Hospital,Shanghai University of Traditional Chinese Medicine,the Geriatrics Department of Huashan Hospital,Fudan University,and the Geriatrics Department of Mental Health Center,School of Medicine,Shanghai Jiaotong University,from March2019 to September 2020.The enrolled 176 mild-to-moderate AD patients were randomly assigned to electro-acupuncture combined with donepezil group(treatment group)and donepezil group(control group),with 88 cases in each group.The control group received Donepezil hydrochloride,with an initial treatment dosage of 5mg/time,once a day,orally before going to bed for 12 weeks;the treatment group received additional electro-acupuncture program "Bu shen tian jing,Yi zhi tiao shen”(BSTJ-YZTS).The main points included Shen Ting(DU24),Yin Tang(EX-HN3),Bai Hui(DU20),Si Shencong(EX-HN1),Wan Gu(GB12),Shen Men(HT7),San Yinjiao(SP6),Zhao Hai(KI6)and Xuan Zhong(GB39).Tai Xi(KI3)and Shen Shu(BL23)were added for patients with syndrome of deficiency of sea of marrow.Pi Shu(BL20)and Shen Shu(BL23)were added for patients with syndrome of deficiency of spleen and kidney.Nei Guan(PC6)and Zu Sanli(ST36)were added for patients with syndrome of insufficiency of qi and blood.Zhong Wan(RN12)and Feng Long(ST40)were added for patients with syndrome of phlegm turbidity clouding the orifices.A dilatational electrical wave was applied to EX-HN1 connected with GB12 and HT7 connected with SP6,and maintained within a tolerable range for patients.The electro-acupuncture program was carried out 3 times a week for 12 weeks.The primary outcome index was the changed score of Alzheimer’s Disease Assessment Scale-cognitive section(ADAS-cog)measured after the end of treatment(Week 12).The secondary outcome index is the changed score of ADAS-cog measured after the end of follow-up(Week 24),the changed score of Alzheimer’s Disease Cooperative Study-activities of daily living(ADCS-ADL)and Quality of Life-Alzheimer’s Disease(QOL-AD)measured at Week 12 and Week 24.22 patients from the treatment group and control group in the clinical trial were further selected according to the inclusion and exclusion criteria of f MRI study,and22 subjects with normal cognitive function(normal group)matched with AD patients by age,gender and education backgrounds were also included.Both the treatment group and the control group received f MRI scans before treatment(Week 0)and after treatment(Week 12).The normal group did not undergo any intervention,and only one f MRI scan was performed after enrollment.The f ALFF value in the frequency range of 0.01-0.08 Hz was calculated,and statistical methods of one-sample t-test,paired t-test,and two-sample t-test were used to analyze the changes in the neuron spontaneous activities within and between groups.Based on the results of f ALFF analysis,the right precuneus was set as the seed point,and the above analysis method was used to investigate the changes of functional connectivity between the whole brain and the right precuneus.Results1.The scores of ADAS-cog,ADCS-ADL,and QOL-AD at week 12 in both treatment and control group were significantly improved compared to the baseline,and there were still long-term effects at follow-up(Week 24).The differences were statistically significant(P<0.05);2.The difference in ADAS-cog,ADCS-ADL and QOL-AD scores before and after treatment in the treatment group was significantly higher than that in the control group,and there were still long-term effects during follow-up(Week 24).The differences were statistically significant(P<0.05).3.Syndrome types of AD patients were correlated with baseline score of ADAS-cog(P<0.05),but not with the improvement of ADAS-cog after the interventions(P>0.05).4.During the treatment period,adverse events in the treatment group was less than that in the control group.5.In f MRI experiment,f ALFF analysis showed that compared with healthy subjects,the areas where the f ALFF value decreases in AD patients were the right inferior temporal gyrus,middle/inferior frontal gyrus,postcentral gyrus,middle occipital gyrus,cerebellar declive,left cingulate gyrus,precuneus,bilateral superior temporal gyrus.6.After 12 weeks of electroacupuncture combined with donepezil treatment,the areas where the f ALFF values increased in the treatment group mainly included the left orbitofrontal gyrus,lingual gyrus,fusiform gyrus and cerebellar tonsils,and the right precuneus and middle frontal gyrus;the area where the f ALFF value decreases is the left cerebellar culmen,the right superior temporal gyrus and cuneus lobe.After 12 weeks of treatment with donepezil,the areas where the f ALFF value increased in the control group mainly included the left inferior temporal gyrus,inferior parietal lobule,and the right lingual gyrus;the areas where the f ALFF value decreased were the right middle frontal gyrus and bilateral cerebellar declive.7.Compared with the control group,the areas where the treatment group demonstrated greater changed value of f ALFF were located in the left orbitofrontal gyrus,inferior temporal gyrus,lingual gyrus,thalamus,and the right insula,precuneus,middle frontal gyrus,and bilateral cerebellar tonsils.8.The difference of ADAS-cog after interventions was positively correlated with the difference of f ALFF in the left temporal lobe,and negatively correlated with the difference of f ALFF in the right middle temporal gyrus.9.Functional connectivity analysis showed that compared with healthy subjects,the area of enhanced functional connectivity between the whole brain and the right precuneus lobe in AD patients was located in the right cerebellar declive;The lowered areas were located in the right superior frontal gyrus and the left cerebellar tonsil.10.After 12 weeks of electroacupuncture combined with donepezil treatment,the areas where the functional connectivity increased in the treatment group mainly included the right inferior frontal gyrus,middle temporal gyrus and left superior frontal gyrus;the area where the functional connectivity decreased was left precuneus lobe and right calcarine fissure.After 12 weeks of treatment with donepezil,the areas where the functional connectivity increased in the control group mainly included the right middle frontal region.No decreased functional connectivity was detected.11.Compared with the control group,the areas where the treatment group demonstrated greater changed functional connectivity were located in the bilateral middle temporal gyrus and left middle frontal gyrus.12.The difference of ADAS-cog after interventions was negatively correlated with the difference of functional connectivity between the right precuneus and the left precuneus,right superior temporal gyrus and right superior occipital gyrus.Conclusions1.Electro-acupuncture(BSTJ-YZTS program)combined with donepezil effectively could improve the cognitive dysfunction,ability of daily living and quality of life of mild-to-moderate AD patients,with a definite long-term effect.The reliable clinical safety can make up for donepezil’s shortcomings of obvious adverse reactions.The results provided a forward-looking acupuncture comprehensive program for the promotion and application of the three-level network of AD prevention and treatment in hospitals,communities,and families.2.Using resting state f MRI technology,based on the f ALFF and functional connectivity analysis method,it was found that the central mechanism of electro-acupuncture(BSTJ-YZTS program)combined with donepezil improving the cognitive dysfunction of AD patients lied in regulation of the abnormal reduction of spontaneous neuron activity in AD patients in middle/inferior frontal gyrus,middle occipital gyrus,lingual gyrus and precuneus gyrus and the regulation of functional connection between superior frontal gyrus and right precuneus lobe;Temporal lobe may be the key brain regions of cognitive function regulation in AD patients.