Dataset Information

Randomized, sham-controlled, clinical trial of repetitive transcranial magnetic stimulation for patients with Alzheimer's dementia in Japan.

ABSTRACT:

Background

Several medications have been applied to Alzheimer's dementia patients (AD) but their efficacies have been insufficient. The efficacy and safety of 4 weeks of repetitive transcranial magnetic stimulation (rTMS) in Japanese AD were evaluated in this exploratory clinical trial.

Methods

Forty-two patients, aged 60-93 years (average, 76.4 years), who were taking medication (> 6 months) and had Mini-Mental State Examination (MMSE) scores ≤ 25 and Clinical Dementia Rating Scale scores (CDR-J) of 1 or 2, were enrolled in this single-center, prospective, randomized, three-arm study [i.e., 120% resting motor threshold (120% RMT), 90% RMT for the bilateral dorsolateral prefrontal cortex, and Sham]. Alzheimer's Disease Assessment Scale-Japanese Cognitive (ADAS-J cog), Montreal Cognitive Assessment (MoCA-J), Clinical Global Impression of Change (CGIC), Neuropsychiatric inventory (NPI), and EuroQOL 5 Dimensions 5-Level (EQ-5D-5L) were administered. The primary endpoint was the mean change from baseline in the MMSE score (week 4). An active rTMS session involved applying 15 trains bilaterally (40 pulses/train at 10 Hz; intertrain interval, 26 s). Participants received ≥ 8 interventions within the first 2 weeks and at least one intervention weekly in the 3rd and 4th weeks. Full Analysis set (FAS) included 40 patients [120% RMT (n = 15), 90% RMT (n = 13), and Sham (n = 12)].

Results

In the FAS, MMSE, ADAS-J cog, MoCA-J, CDR-J, CGIC, NPI, and EQ-5D-5L scores between the three groups were not significantly different. Two patients were erroneously switched between the 120% RMT and 90% RMT groups, therefore, "as treated" patients were mainly analyzed. Post hoc analysis revealed significant treatment efficacy in participants with MMSE scores ≥ 15, favoring the 120% RMT group over the Sham group. Responder analysis revealed 41.7% of the 120% RMT group had a ≥ 3-point improvement in the ADAS-J cog versus 0% in the Sham group (Fisher's exact test, p = 0.045). The MoCA-J showed the same tendency but was not significant. Efficacy disappeared in week 20, based on the ADAS-cog and MoCA-J. No intervention-related serious adverse events occurred.

Conclusion

This paper is the first report of using rTMS in Japanese AD patients. The treatment seems safe and moderate-mild stage AD should be target population of pivotal clinical trial with 120% RMT rTMS.

SUBMITTER: Saitoh Y

PROVIDER: S-EPMC9606646 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

Randomized, sham-controlled, clinical trial of repetitive transcranial magnetic stimulation for patients with Alzheimer's dementia in Japan.

Saitoh Youichi Y Hosomi Koichi K Mano Tomoo T Takeya Yasushi Y Tagami Shinji S Mori Nobuhiko N Matsugi Akiyoshi A Jono Yasutomo Y Harada Hideaki H Yamada Tomomi T Miyake Akimitsu A

Frontiers in aging neuroscience 20221013

<h4>Background</h4>Several medications have been applied to Alzheimer's dementia patients (AD) but their efficacies have been insufficient. The efficacy and safety of 4 weeks of repetitive transcranial magnetic stimulation (rTMS) in Japanese AD were evaluated in this exploratory clinical trial.<h4>Methods</h4>Forty-two patients, aged 60-93 years (average, 76.4 years), who were taking medication (> 6 months) and had Mini-Mental State Examination (MMSE) scores ≤ 25 and Clinical Dementia Rating Sca ...[more]

PMID: 36313021

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Project description:Repetitive transcranial magnetic stimulation (rTMS) is emerging as a non-invasive therapeutic strategy in the battle against Alzheimer's disease. Alzheimer's disease patients primarily show alterations of the default mode network for which the precuneus is a key node. Here, we hypothesized that targeting the precuneus with TMS represents a promising strategy to slow down cognitive and functional decline in Alzheimer's disease patients. We performed a randomized, double-blind, sham-controlled, phase 2, 24-week trial to determine the safety and efficacy of precuneus stimulation in patients with mild-to-moderate Alzheimer's disease. Fifty Alzheimer's disease patients were randomly assigned in a 1:1 ratio to either receive precuneus or sham rTMS (mean age 73.7 years; 52% female). The trial included a 24-week treatment, with a 2-week intensive course in which rTMS (or sham) was applied daily five times per week, followed by a 22-week maintenance phase in which stimulation was applied once weekly. The Clinical Dementia Rating Scale-Sum of Boxes was selected as the primary outcome measure, in which post-treatment scores were compared to baseline. Secondary outcomes included score changes in the Alzheimer's Disease Assessment Scale-Cognitive Subscale, Mini-Mental State Examination and Alzheimer's Disease Cooperative Study-Activities of Daily Living scale. Moreover, single-pulse TMS in combination with EEG was used to assess neurophysiological changes in precuneus cortical excitability and oscillatory activity. Our findings show that patients that received precuneus repetitive magnetic stimulation presented a stable performance of the Clinical Dementia Rating Scale-Sum of Boxes score, whereas patients treated with sham showed a worsening of their score. Compared with the sham stimulation, patients in the precuneus stimulation group also showed also significantly better performances for the secondary outcome measures, including the Alzheimer's Disease Assessment Scale-Cognitive Subscale, Mini-Mental State Examination and Alzheimer's Disease Cooperative Study-Activities of Daily Living scale. Neurophysiological results showed that precuneus cortical excitability remained unchanged after 24 weeks in the precuneus stimulation group, whereas it was significantly reduced in the sham group. Finally, we found an enhancement of local gamma oscillations in the group treated with precuneus stimulation but not in patients treated with sham. We conclude that 24 weeks of precuneus rTMS may slow down cognitive and functional decline in Alzheimer's disease. Repetitive TMS targeting the default mode network could represent a novel therapeutic approach in Alzheimer's disease patients.

Project description:BackgroundTo examine the antidepressant efficacy and response predictors of R-DLPFC-LF rTMS for antidepressant-nonresponding BD.MethodsWe conducted a single-blind randomized sham-controlled trial for 54 (28 sham, 26 active) patients with antidepressant-nonresponding BD (baseline MADRS ≥ 20). Patients received 15 daily sessions of active or sham neuronavigated rTMS (Figure-of-8 coil, five 1 Hz 60 s 110% RMT trains). Outcome measures included depressive response (≥ 50% MADRS reduction, CGI ≤ 2) and remission (MADRS < 7, CGI = 1) rates, treatment emergent hypo/mania (YMRS), depressive and anxiety symptoms (HAM-A).Results48 patients (25 sham, 23 active) completed treatment, with 3 drop-outs each in active and sham groups. Active rTMS did not produce superior response or remission rates at endpoint or 6 or 12 weeks (ps > 0.05). There was no significant group * time interaction (ps > 0.05) in a multivariate ANOVA with MADRS, HAMA and YMRS as dependent variables. Exploratory analysis found MADRS improvement to be moderated by baseline anxiety (p = 0.02) and melancholia (p = 0.03) at week 3, and depressive onset at weeks 6 (p = 0.03) and 12 (p = 0.04). In subjects with below-mean anxiety (HAMA < 20.7, n = 24), MADRS improvement from active rTMS was superior to sham at week 3 (ITT, t = 2.49, p = 0.04, Cohen's d = 1.05). No seizures were observed. Groups did not differ in treatment-emergent hypomania (p = 0.1).LimitationsLarger sample size might be needed to power subgroup analyses. Moderation analyses were exploratory. Single-blind design. Unblinding before follow-up assessments due to ethical reasons.Conclusions1-Hz 110% RMT (5 × 60 s trains) R-DLPFC-LF rTMS was not effective for antidepressant non-responding BD but may be further investigated at increased dosage and/or in BD patients with low anxiety. Trial registration CCRB Clinical Trials Registry, CUHK, CUHK_CCT00440. Registered 04 December 2014, https://www2.ccrb.cuhk.edu.hk/registry/public/279.

Project description:To date, there is a shortage of effective treatment strategies for Alzheimer's disease (AD), and although repetitive transcranial magnetic stimulation (rTMS) can improve AD cognitive function, there are obvious individual differences, which may be related to different apolipoprotein E (APOE) genotypes. As the risk and pathogenesis of AD varies greatly among different genotypes precise treatment strategies should be implemented depending upon genotype, which has not been proved by clinical studies. Apart from that, the published clinical studies are highly heterogeneous, and therefore, systematic and well-developed randomized controlled Trails (RCT) and demonstration of precise administration protocols are required. To verify this hypothesis, this project designed a RCT study, and randomly divided apoE4 carrier AD and non-carrier AD into high-frequency rTMS (HF-rTMS) or low-frequency rTMS (LF-rTMS) treatment groups. Specifically, 80 patients with AD, namely 48 APOE4 carriers and 32 non-APOE4 carriers will be included in the study. After that, based on different stimulation frequencies of rTMS, they will be divided into the HF-rTMS group and the LF-rTMS group, when patients with AD will be randomly assigned to different treatment groups. After AD patients are involved in the study, their memory, cognition, anxiety, depression and activities of daily living will be tested before and during 2 weeks of rTMS. Furthermore, peripheral blood will be collected before and after treatment to detect changes in pathological indexes via MSD platform (Meso Scale Discovery), while 32-channel EEG data will be also collected to detect and analyze changes in gamma oscillation. In addition, these patients will be followed up for 6 months and their neuropsychological scale was also evaluated every month. At present, our study has included 18 AD patients (10 APOE4 carriers; 8 non-carriers). Our study is still in progress. The grouping has not been unblinded. But the preliminary data demonstrated that non-carriers had better MoCA score improvement than APOE4 carriers. The results indicated that the two populations of AD patients should be treated differently. Thus, this project will provide direction for precision rTMS in AD and also promotes a shift in relevant treatment philosophy. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [ChiCTR2100041625].

Dataset Information

Randomized, sham-controlled, clinical trial of repetitive transcranial magnetic stimulation for patients with Alzheimer's dementia in Japan.

Background

Methods

Results

Conclusion

Publications

Randomized, sham-controlled, clinical trial of repetitive transcranial magnetic stimulation for patients with Alzheimer's dementia in Japan.

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