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High Frequency Repetitive Transcranial Magnetic Stimulation Combined with Cognitive Training Improves Cognitive Function and Cortical Metabolic Ratios in Alzheimer's DiseaseBackground:Various studies report discordant results about the efficacy,parameters,and underlying mechanisms of repetitive transcranial magnetic stimulation(rTMS)combined with cognitive training(CT)on Alzheimer's disease(AD).Objective:To assess the effect of rTMS-CT on cognition,the activities of daily life,neuropsychiatric behavioral symptoms,and metabolite levels beneath the stimulated areas of the brain in patients with Alzheimer's disease,and to investigate the correlation of metabolic changes(measured with proton magnetic resonance spectroscopy[1H-MRS])with clinical outcomes after treatment.Methods:Thirty consecutive patients with mild or moderate AD were enrolled and randomly divided into one of two intervention groups:(1)real rTMS with CT(i.e.,real group)and(2)sham rTMS with CT(i.e.,sham group).10 Hz rTMS was used to stimulate the left dorsolateral prefrontal cortex(DLPFC)and then stimulate the left lateral temporal lobe(LTL)for 20 minutes each day for 4 weeks.Each patient underwent neuropsychological assessment at baseline(T0),immediately after treatment(T1),and 4 weeks after treatment(T2).The ratios of N-acetylaspartate/creatine(NAA/C r),myoinositol/creatine(mI/Cr),and choline/creatine(Cho/Cr)in the stimulated cortex were measured using 1H-MRS at T0 and T1.Results:Twenty-eight patients were treated with rTMS-CT for 4 weeks.Two patients in the sham group withdrew after being treated several times.Compared with the sham group,the cognitive function and behavior in the real rTMS group improved significantly at T1 and T2.In the real group,compared with the sham group,the NAA/Cr ratio in the left DLPFC was significantly elevated(p=0.045);however,in the left LTL,it only showed a tendency toward increase(p=0.162).The change in the NAA/Cr ratio in the left DLPFC was negatively correlated with the change in the cognitive scales of the Alzheimer's Disease Assessment Scale-cognitive.Conclusion:This study indicated a possible modest effect of rTMS-CT on preventing clinical and neuronal functional deterioration in the left DLPFC of patients with AD The left DLPFC is a better candidate area than the left LTL.Part ? High Frequency Repetitive Transcranial Magnetic Stimulation Combined with Cognitive Training Improves Cognitive Function and Intensity of Resting Brain Function in Alzheimer's DiseaseObjective:To investigate the effects of high-frequency repetitive transcranial magnetic stimulation(TMS)on the cortical activity in Alzheimer's disease(AD)and its correlation with cognitive alteration were studied by fractional amplitude of low-frequency fluctuation(fALFF)technique.Methods:Twenty consecutive patients with mild or moderate AD were enrolled and randomly divided into one of two intervention groups:(1)real rTMS with CT(i.e.,real group)and(2)sham rTMS with CT(i.e.,sham group).10 Hz rTMS was used to stimulate the left dorsolateral prefrontal cortex(DLPFC)and then stimulate the left lateral temporal lobe(LTL)for 20 minutes each day for 4 weeks.Each patient underwent neuropsychological assessment at baseline(T0),immediately after treatment(T4),and 4 weeks after treatment(T8).At the same time,resting state functional magnetic resonance(rsfMRI)was performed at T0 and T4 to detect the changes in cortical brain functional activity.Results:Seventeen patients were treated with rTMS-CT for 4 weeks.Two patients in the sham group and one patient dropped out after being treated several times Compared with the sham group,the cognitive function and behavior in the real rTMS group improved significantly at T4 and T8.No significant baseline(pre-stimulation condition)fALFF difference was observed between the two groups,regressing out the covariates of age,gender and education years.rTMS induced significant fALFF changes in the real rTMS group,but the sham group didn't show any significant change.Comparing the results before and after rTMS in the real group,significant fALFF increase after 10 Hz rTMS was found in right cerebellum(peak MNI coordinates:x=9,y=-66,z=-24),left lingual and cuneus(peak MNI coordinates:x=-3,y=-63,z=6),and left cingulate gyrus(peak MNI coordinates:x=-12,y=-9,z=39).However,significant fALFF decrease after 10 Hz rTMS was found in left middle frontal gyrus(peak MNI coordinates:x=-30,y=-3,z=-69).Seed-based functional connectivity analysis of the above four brain regions,showed that the right cerebellum connectivity with the left side of the central anterior gyrus and the central posterior gyrus was enhanced in real group.The sham group did not change.Conclusion:Repetitive high-frequency transcranial magnetic stimulation can improve the cognitive function of patients with mild to moderate Alzheimer's disease,and can improve the intensity of functional activity of distant cortical brain stimulated.Due to the small sample size of the present study,it is necessary to further expand the sample size in the future to reveal the mechanism of rTMS.Part ? Effect of Repetitive Transcranial Magnetic Stimulation on Plasma miR-125b in Patients with Alzheimer's diseaseObjective:High frequency repetitive transcranial magnetic stimulation(rTMS)has been used to improve memory,cognition and activity of daily life in patients with Alzheimer's disease.However,the measurements are almost just including subjective scales,the objective evidence was lacking in most studies.In the present study,objective indicators such as miRNA,A? 1-42,and p-tau 181 in plasma were used to further explain mechanism of rTMS,so as to provide clinical evidence and evaluate indicators for the application of rTMS in AD.Methods:Twenty patients with mild to moderate AD diagnosed in neurology department of Tongji hospital from September 2015 to June 2017,were selected and randomly divided into the rTMS active stimulation group or the rTMS placebo stimulation group.10Hz rTMS stimulated the left dorsolateral prefrontal lobe and left temporal lobe,and each stimulation area was stimulated for about 10 minutes,once a day,five times a week,for a total of 20 times in 4 weeks.Cognitive assessment was performed before treatment(T0)and 4 weeks after treatment(T4).At the same time,patients' fasting blood was extracted at T0 and T4 in the morning,plasma was obtained by centrifugation,miRNA was detected by fluorescence quantitative PCR,and plasma concentrations of A ?1-42 and p-tau 181 were detected by ELISA kit.In addition,22 blood samples from healthy old persons with gender and age matching the AD were selected at the physical examination center,and the process is the same as AD.Results:Before treatment with rTMS,there were statistically significant difference of miR-125b,miR-132,miR-107,miR-29b-1 and miR-26b in patients with Alzheimer's disease compared with the normal control group.After the treatment with rTMS,the expression of miR-125b in the active stimulation group(real rTMS)and the placebo stimulation group(sham rTMS)was statistically significant.Before the treatment with rTMS,the concentration of AD plasma p-tau181 increased compared with the normal control group,which was statistically significant.There was no significant difference in A? 1-42 concentration between AD and normal control.After treatment with rTMS,plasma p-tau181 showed a decreasing trend in real rTMS group compared with the sham rTMS group(p=0.079).Compared with baseline within group,A? 1-42 in the real rTMS group showed an upward trend(p=0.086)and a downward trend(p=0.066)in the p-tau181 group after treatment,while no change trend was observed in the pseudo-stimulation group.Conclusion:rTMS can improve the cognitive function and neuropsychiatric behavioral symptoms in AD patients.What's more,rTMS can promote the expression of miR-125b,which is related to the production of A? and tau in AD patients.Therefore,rTMS may improve the metabolism of AD pathological products by affecting the expression of miR-125b in the brain,thereby promoting the recovery of clinical functions.In the future,it is necessary to increase the sample size of clinical cases to further study the in-depth mechanism of rTMS in AD. |
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