Personalized Repetitive Transcranial Magnetic Stimulation (rTMS) in Cognitive Fluctuations of Dementia With Lewy Bodies (DLB): Proof of Concept

Study Overview
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Brief Summary
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The present study is a monocentric, therapeutic clinical trial involving forty patients diagnosed with Dementia with Lewy Bodies (DLB). The aim of this clinical trial is to evaluate the feasibility and relevance of repetitive transcranial magnetic stimulation (rTMS); a non-invasive neuromodulation technique, with a main emphasis on the evaluation of the outcome on cognitive fluctuations. For this purpose, we will compare two distinct rTMS conditions (control and experimental) in a pre-post rTMS setting. The experimental condition will be targeting the insular cortex which has been shown to be affected at prodromal DLB stages, in the form of decreased grey matter concentration and a decreased regional Cerebral Blood Flow (rCBF hypoperfusion) [Blanc et al., 2015 ; Roquet et al., 2016 ; Roquet et al., 2017]. Furthermore, these insular alterations are correlated to cognitive fluctuations [Chabran et al., 2020]. In DLB, cognitive fluctuations are particularly pervasive and manifest in the form of alertness alterations and modifications of arousal states. Participants will repeatedly undergo a series of clinical and cognitive assessments in addition to several neuroimaging examinations, namely multimodal Magnetic Resonance Imaging (MRI) and electroencephalogram (EEG) recordings, in order to evaluate potential physiological modifications and clinical changes of symptoms, pre-/post-rTMS.

Detailed Description
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Objectives: To provide a proof of concept by validating the hypoactivity (hypoperfusion) of the anterior insula (AI biomarker) as a causal factor of the instability of arousal states in DLB. To evaluate if improvement of arousal translates clinically into a reduction of cognitive fluctuations and an improvement of other functional parameters (clinical measures of symptoms). Evaluation of the relevance of the AI biomarker as a predictive tool for clinical response. Assessment of reproducibility of the AI hypoperfusion (biomarker) at an individual level and thereby its potential as a diagnostic or therapeutic biomarker. Collection, description and analysis of all adverse events and required information for the implementation of future phase II and III studies Methodological approach: The present study will be conducted at the non-invasive neurostimulation center of Strasburg (Centre de Neuromodulation Non-invasive de Strasbourg ; CEMNIS) in collaboration with the Memory Clinic of Strasbourg (Centre Mémoire de Ressources et de Recherches ; CM2R) of the University Hospitals of Strasbourg (HUS) and the ICube laboratory (Team IMIS, UMR 7357, CNRS). We propose a single-centre, two-arm, randomized, crossover, double-blind comparative study. N=40 patients will be prospectively recruited in order to create two experimental groups (arms) (Group A and Group B) in a cross-over study design, following two experimental phases (I and II). The protocol will include two rTMS conditions: (1) verum stimulation (target: insular cortex) and (2) control stimulation (target: occipital cortex). The running order for each participant will be counterbalanced: Group A will start with the verum rTMS in phase I, followed by the control rTMS in phase II. Group B will start with the control rTMS in phase I, followed by the verum rTMS in phase II. One phase of rTMS will consist of a total of ten visits. One visit will include two sessions of rTMS, summing up to a total of twenty sessions of rTMS for each patient. Participants will undergo multiple EEG recordings and multimodal cerebral MRI scans, as well as several different clinical assessments (self-reported, reported by the investigator and the patients' main caregiver) numerous times during the protocol, pre- and post-rTMS sessions. In sum, each patient will undergo five MRI scans and three clinical assessments. The clinical trial schedules a total of N=37 visits for each patient.

Official Title
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Personalized Repetitive Transcranial Magnetic Stimulation (rTMS) in Cognitive Fluctuations of Dementia With Lewy Bodies (DLB): Proof of Concept

Conditions
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Dementia With Lewy Bodies Diagnosis, Significant Cognitive Fluctuations in DLB

Intervention / Treatment
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* Device: rTMS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patient aged ≥ 45 years Enrolled in a social health insurance scheme Diagnosed with probable DLB according to McKeith et al. criteria, 2017, or McKeith et al. 2020 criteria for the prodromal stage A Mini Mental State Examination (MMSE; Folstein et al., 1983) score ≥ to 18 in the last 6 months (prodromal stage or a major neurocognitive disorder (dementia syndrome) at moderate stage) MMSE score ≥ to 15 at the inclusion visit Presence of clinically significant cognitive fluctuations Caregivers of eligible patients do have to be able to stay with the patient for at least 4 hours a day, 3 days a week, and have to be able to provide requested information and accompany the patient to the certain visits. The patient must be able to understand the objectives and risks of the study and has to be able to give dated and signed informed consent. In the case of a designed guardian or curator, the guardian or curator will sign the consent. For women of childbearing age, effective contraception throughout the study is required Exclusion criteria: History of generalized seizures (epilepsy) Pharmacological treatment for cognitive fluctuations in DLB with dose modifications that have taken place less than 2 months before the first visit of the protocol (anticholinesterase and neuroleptics) Anti-epileptic drug treatment Keppra (Levetiracetam) History of psychosis or severe depression unrelated to DLB History of brain surgery (tumour removal, electrode implantation, certain strokes as judged by the investigator, oedema...) Patients with any contraindication for MRI scans (claustrophobia, pacemaker, cochlear implant, mechanical heart valve, metallic prostheses, neurostimulators, other non-removably implanted electronic medical devices etc.) Subject unable to understand the aims and risks of the study and patients unable to give full informed consent Having a MMSE score < to 18 in the last 6 months (prodromal stage or mild to moderate dementia) MMSE score < to 15 at the inclusion visit Patients in an emergency or life-threatening situation Patients under court protection Pregnancy Breastfeeding Patients in exclusion period (determined by a previous or current study)

Ages Eligible for Study
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Minimum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VERUM<br>In the verum experimental condition, participants will receive the experimental rTMS stimulation sessions, meaning the rTMS sessions targeting the insular cortex, taking into account the insular hypoperfusion (through MRI images) of each patient. | Device: rTMS<br>* For each subject, a verum condition and a control condition will be programmed. We will use the QPS-5 method (4 pulses, Inter-Stimulation Interval; ISI: 5 seconds).<br>* Other names: Repetitive Magnetic Transcranial Stimulation is a non-invasive neuromodulation technique based on the principle of electromagnetic induction.;|
| Sham Comparator: CONTROL<br>In the control experimental condition, participants will receive the control rTMS stimulation sessions, meaning the rTMS sessions will target the occipital cortex. | Device: rTMS<br>* For each subject, a verum condition and a control condition will be programmed. We will use the QPS-5 method (4 pulses, Inter-Stimulation Interval; ISI: 5 seconds).<br>* Other names: Repetitive Magnetic Transcranial Stimulation is a non-invasive neuromodulation technique based on the principle of electromagnetic induction.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Electroencephalogram measures | The primary endpoint will be the comparison of the intensity of fluctuations in arousal level | Primary outcome measures will be realized one week before each rTMS stimulation phase. | 
| Electroencephalogram measures | The primary endpoint will be the comparison of the intensity of fluctuations in arousal level | Primary outcome measures will be realized one week after each rTMS stimulation phase. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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insula, rTMS, arousal, DLB, fluctuations