Repetitive Transcranial Magnetic Stimulation in Frontotemporal Lobar Degeneration

Overview

The aim of the study is to evaluate the safety, feasibility, clinical and biological efficacy, and predictors of efficacy of an intervention consisting of repetitive transcranial magnetic stimulation (rTMS) in patients with frontotemporal dementia (FTLD) or in asymptomatic persons at risk of FTLD (i.e., persons familiar with FTLD patients). rTMS is a non-invasive brain stimulation technique, and has demonstrated the ability to modulate neuronal activity by applying high-frequency magnetic fields to the surface of the skull. rTMS offers a potentially effective means to influence neural networks involved in the pathogenesis of neurodegenerative diseases, with benefits that could extend beyond symptomatic relief. Its safety has been widely documented in a variety of clinical conditions, making it an ideal candidate for application in neurodegenerative diseases. In the present study, participants will undergo the following procedures: (i) clinical and neuropsychological assessment, (ii) TMS, and (iii) blood sampling. The occurrence of adverse events will be monitored throughout the duration of the study. The study is structured in two phases. In the first phase, double-blind, randomised and placebo-controlled, participants will be randomised into two groups: group 1, participants will receive real rTMS for 2 weeks; and group 2, placebo rTMS for 2 weeks. In the second, open-label phase, after 10 weeks, both group 1 and group 2 participants will receive real rTMS for 2 weeks. Each participant will receive a total of 4 weeks of intervention (4 weeks of real stimulation in group 1, or 2 weeks of real stimulation and 2 weeks of placebo stimulation in group 2), with 5 sessions per week (Monday to Friday) lasting approximately 30 minutes each. Visits will take place at the beginning of the study (T00) and after 2 weeks (T02, end of the first phase), 12 weeks (T12, beginning of the second phase), 14 weeks (T14, end of the second phase), 24 weeks (T24, follow-up). During each visit, participants underwent the following procedures: (i) clinical and neuropsychological assessment, (ii) blood sampling, and (iii) TMS. Specific biomarker analyses will be performed on the blood samples to study the pathophysiological mechanisms of the disease and the effect of the experimental intervention.

Interventions

• Device Theta burst stimulation
  10 sessions (5 days/week for 2 weeks) of 20 trains of 10 bursts, each containing 3 pulses at 50 Hz, applied at a frequency of 5 Hz (total pulses: 600, total duration: approx. 3 minutes); this protocol will be repeated twice within each single session.
• Device Sham Theta burst stimulation
  10 sessions (5 days/week for 2 weeks) of sham theta burst stimulation.The device providing Theta Burst Stimulation can be placed in the same position and turned on, creating a similar experience for the participant, without providing any neural stimulation.

Primary outcome measures

• Safety of repetitive Transcranial Magnetic Stimulation Protocol [Time frame: Through study completion, at week 24]
• Feasibility of repetitive Transcranial Magnetic Stimulation Protocol [Time frame: Through study completion, at week 24]
• Effectiveness in restoring neurotransmission [Time frame: Through study completion, at week 24]

Secondary outcome measures (3)

• Clinical effectiveness [Time frame: Change from baseline to week 2, 12, 14, 24]
• Biological efficacy [Time frame: Change from baseline to week 2, 12, 14, 24]
• Predictors of efficacy [Time frame: Change from baseline to week 2, 12, 14, 24]

Eligibility criteria

Inclusion criteria

• diagnosis of FTLD (bvFTD, avPPA, svPPA, CBS, or PSP)
• global CDR plus NACC FTLD ≤ 1

Exclusion criteria

• presence of cerebrovascular disease, hydrocephalus, intracranial masses identified by MRI, history of head trauma, serious medical conditions unrelated to FTLD, history of epilepsy, and presence of electronic (e.g., pacemaker) or metallic implants in the head.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

Italy · 1 center

• IRCCS Istituto Centro San Giovanni Di Dio - Fatebenefratelli Brescia — Brescia

Publications

• Antczak J, Kowalska K, Klimkowicz-Mrowiec A, Wach B, Kasprzyk K, Banach M, Rzeznicka-Brzegowy K, Kubica J, Slowik A. Repetitive transcranial magnetic stimulation for the treatment of cognitive impairment in frontotemporal dementia: an open-label pilot study. Neuropsychiatr Dis Treat. 2018 Mar 13;14:749-755. doi: 10.2147/NDT.S153213. eCollection 2018. PMID 29559782
• Dong K, Zhu X, Xiao W, Gan C, Luo Y, Jiang M, Liu H, Chen X. Comparative efficacy of transcranial magnetic stimulation on different targets in Parkinson's disease: A Bayesian network meta-analysis. Front Aging Neurosci. 2023 Jan 4;14:1073310. doi: 10.3389/fnagi.2022.1073310. eCollection 2022. PMID 36688161
• Wei Z, Fu J, Liang H, Liu M, Ye X, Zhong P. The therapeutic efficacy of transcranial magnetic stimulation in managing Alzheimer's disease: A systemic review and meta-analysis. Front Aging Neurosci. 2022 Sep 6;14:980998. doi: 10.3389/fnagi.2022.980998. eCollection 2022. PMID 36147701
• Siebner HR, Funke K, Aberra AS, Antal A, Bestmann S, Chen R, Classen J, Davare M, Di Lazzaro V, Fox PT, Hallett M, Karabanov AN, Kesselheim J, Beck MM, Koch G, Liebetanz D, Meunier S, Miniussi C, Paulus W, Peterchev AV, Popa T, Ridding MC, Thielscher A, Ziemann U, Rothwell JC, Ugawa Y. Transcranial magnetic stimulation of the brain: What is stimulated? - A consensus and critical position paper. Cl PMID 35738037
• Menardi A, Rossi S, Koch G, Hampel H, Vergallo A, Nitsche MA, Stern Y, Borroni B, Cappa SF, Cotelli M, Ruffini G, El-Fakhri G, Rossini PM, Dickerson B, Antal A, Babiloni C, Lefaucheur JP, Dubois B, Deco G, Ziemann U, Pascual-Leone A, Santarnecchi E. Toward noninvasive brain stimulation 2.0 in Alzheimer's disease. Ageing Res Rev. 2022 Mar;75:101555. doi: 10.1016/j.arr.2021.101555. Epub 2021 Dec 30. PMID 34973457
• Benussi A, Alberici A, Samra K, Russell LL, Greaves CV, Bocchetta M, Ducharme S, Finger E, Fumagalli G, Galimberti D, Jiskoot LC, Le Ber I, Masellis M, Nacmias B, Rowe JB, Sanchez-Valle R, Seelaar H, Synofzik M; GENFI Consortium; Rohrer JD, Borroni B. Conceptual framework for the definition of preclinical and prodromal frontotemporal dementia. Alzheimers Dement. 2022 Jul;18(7):1408-1423. doi: 10.1 PMID 34874596
• Hoglinger GU, Respondek G, Stamelou M, Kurz C, Josephs KA, Lang AE, Mollenhauer B, Muller U, Nilsson C, Whitwell JL, Arzberger T, Englund E, Gelpi E, Giese A, Irwin DJ, Meissner WG, Pantelyat A, Rajput A, van Swieten JC, Troakes C, Antonini A, Bhatia KP, Bordelon Y, Compta Y, Corvol JC, Colosimo C, Dickson DW, Dodel R, Ferguson L, Grossman M, Kassubek J, Krismer F, Levin J, Lorenzl S, Morris HR, N PMID 28467028
• Armstrong MJ, Litvan I, Lang AE, Bak TH, Bhatia KP, Borroni B, Boxer AL, Dickson DW, Grossman M, Hallett M, Josephs KA, Kertesz A, Lee SE, Miller BL, Reich SG, Riley DE, Tolosa E, Troster AI, Vidailhet M, Weiner WJ. Criteria for the diagnosis of corticobasal degeneration. Neurology. 2013 Jan 29;80(5):496-503. doi: 10.1212/WNL.0b013e31827f0fd1. PMID 23359374

Identifiers

NCT: NCT07316413 · FTLD_rTMS

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗