FTLD, FTD, bvFTD, PPA, PSP, Cortical Basal Syndrome (CBS), rTMS, Theta Burst Stimulation
Conditions
Brief summary
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
DEVICETheta 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.
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.
Sponsors
Università degli Studi di Brescia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety of repetitive Transcranial Magnetic Stimulation Protocol | Through study completion, at week 24 | Safety will be assessed in terms of the frequency and severity of any adverse events. Safety will be monitored throughout the duration of the study. |
| Feasibility of repetitive Transcranial Magnetic Stimulation Protocol | Through study completion, at week 24 | Feasibility will be assessed according to the study drop-out rate. Feasibility will be monitored throughout the duration of the study. |
| Effectiveness in restoring neurotransmission | Through study completion, at week 24 | Neurotransmission will be assessed by measuring changes in glutamatergic (intracortical facilitation, ICF) and GABAergic (short-interval intracortical inhibition, SICI) neurotransmission assessed indirectly through TMS. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical effectiveness | Change from baseline to week 2, 12, 14, 24 | Clinical effectiveness will be assessed by measuring changes in clinical and cognitive measures, in behavioural and neuropsychiatric symptoms, and in caregiver burden. Specifically, the following instruments will be used: Clinical Global Impression (CGI) Severity (CGI-S) and Improvement (CGI-I) and FBI. |
| Biological efficacy | Change from baseline to week 2, 12, 14, 24 | Biological efficacy will be assessed via blood sampling by measuring changes in neurodegeneration biomarkers: neurofilament light (NfL, measured in pg/mL); astrogliosis: Serum Glial Fibrillary Acidic Protein (GFAP, measured in pg/mL). |
| Predictors of efficacy | Change from baseline to week 2, 12, 14, 24 | We will assess whether demographic characteristics (age, gender, level of education), genetic traits (comparing genetic and sporadic forms of FTD), clinical phenotype (bvFTD, avPPA, svPPA, CBS, or PSP), disease severity, markers of cognitive reserve, and plasma biomarker profile are correlated with better treatment response. |
Countries
Italy
Outcome results
None listed