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Repetitive Transcranial Magnetic Stimulation for Alzheimer's Disease Based on Apolipoprotein E Genotyping: Protocol for a Randomized Controlled Study.

ABSTRACT: 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].

SUBMITTER: Wei N

PROVIDER: S-EPMC8675398 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundSeveral 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.MethodsForty-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)].ResultsIn 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.ConclusionThis 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.

Project description:BackgroundDepression is a chronic illness that generally requires lifelong therapy. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive technique with few side effects that has been reported to be useful in the treatment of depression. However, no studies to date have evaluated in a randomized controlled trial (RCT) the efficacy of rTMS for maintenance treatment of depression.Methods/designIn this article, we report the design and protocol of a randomized, single-blind, placebo-controlled, parallel-group, multicenter study in China to evaluate the efficacy of rTMS in the prevention of relapse of depressive symptoms. In total, 540 patients, aged 18 to 60 years, diagnosed with depression and experiencing an acute exacerbation of depressive symptoms, will be enrolled. The study will consist of four phases: a screening/tolerability phase of up to 7 days; an open-label, flexible-dose lead-in phase of 8 weeks; an open-label, fixed-dose stabilization phase of 6 weeks; and a single-blind relapse prevention phase of 12 months. During the open-label phase, all patients will be treated with venlafaxine. Remitters with Hamilton Rating Scale for Depression (HAM-D₁₇) score ≤7 will be eligible to enter the single-blind phase and will be randomly assigned to one of three groups: group 1 on active rTMS and venlafaxine; group 2 on sham rTMS and venlafaxine; and group 3 on venlafaxine alone. Efficacy will be evaluated during the study using relapse assessment (time between subject randomization to treatment and the first occurrence of relapse). Secondary outcome measures will include: symptom changes, measured by the HAM-D₁₇; illness severity changes, measured by the Clinical Global Impression of Severity for Depression (CGI-S-DEP); and changes in subject functioning, assessed with the Personal and Social Performance (PSP)scale. Safety will be assessed throughout the study by monitoring of adverse events, clinical laboratory tests, electrocardiography (ECG), and measurements of vital signs (temperature, pulse, and blood pressure) and weight. Suicidality will be assessed by the Columbia Suicide Severity Rating Scale (C-SSRS).DiscussionThe result of this trial will assess the efficacy of rTMS in the prevention of relapse of symptoms of depression by determining whether rTMS in combination with an antidepressant is more efficacious than the antidepressant alone for maintenance of the clinical response.Trial registrationClinicalTrials.gov, NCT01516931.

Project description:BackgroundEvaluation of repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant major depression (TRMD) in Veterans offers unique clinical trial challenges. Here we describe a randomized, double-blinded, intent-to-treat, two-arm, superiority parallel design, a multicenter study funded by the Cooperative Studies Program (CSP No. 556) of the US Department of Veterans Affairs.MethodsWe recruited medical providers with clinical expertise in treating TRMD at nine Veterans Affairs (VA) medical centers as the trial local investigators. We plan to enroll 360 Veterans diagnosed with TRMD at the nine VA medical centers over a 3-year period. We will randomize participants into a double-blinded clinical trial to left prefrontal rTMS treatment or to sham (control) rTMS treatment (180 participants each group) for up to 30 treatment sessions. All participants will meet Diagnostic and statistical manual of mental disorders, 4 th edition (DSM-IV) criteria for major depression and will have failed at least two prior pharmacological interventions. In contrast with other rTMS clinical trials, we will not exclude Veterans with posttraumatic stress disorder (PTSD) or history of substance abuse and we will obtain detailed history regarding these disorders. Furthermore, we will maintain participants on stable anti-depressant medication throughout the trial. We will evaluate all participants on a wide variety of potential predictors of treatment response including cognitive, psychological and functional parameters.DiscussionThe primary dependent measure will be remission rate (Hamilton Rating Scale for Depression (HRSD24) ≤ 10), and secondary analyses will be conducted on other indices. Comparisons between the rTMS and the sham groups will be made at the end of the acute treatment phase to test the primary hypothesis. The unique challenges to performing such a large technically challenging clinical trial with Veterans and potential avenues for improvement of the design in future trials will be described.Trial registrationClinicalTrials.gov, NCT01191333 . Registered on 26 August 2010. This report is based on the protocol version 4.6 amended in February 2016. All items from the World Health Organization Trial Registration Data Set are listed in Appendix A.

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Repetitive Transcranial Magnetic Stimulation for Alzheimer's Disease Based on Apolipoprotein E Genotyping: Protocol for a Randomized Controlled Study.

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