Rehabilitative Trial for the Rescue of Neurophysiological Parameters in Progranulin Deficient Subjects

Not Applicable

Completed

• Conditions: Frontotemporal Dementia; GRN Related Frontotemporal Dementia
• Interventions: Device: Anodal transcranial direct current stimulation; Device: Sham transcranial direct current stimulation

• Registration Number: NCT02999282
• Lead Sponsor: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia

Brief Summary

In this randomized, double-blind, sham-controlled study, the investigators will evaluate the effects of frontal and prefrontal anodal transcranial direct current stimulation (tDCS) on neurophysiological parameters of cortical connectivity, assessed by transcranial magnetic stimulation (TMS), in asymptomatic subjects bearing a pathogenic GRN mutation and in symptomatic patients with frontotemporal dementia.

Detailed Description

In this randomized, double-blind, sham-controlled study, the investigators will evaluate the effects of frontal and prefrontal anodal transcranial magnetic stimulation (tDCS) on neurophysiological parameters of cortical connectivity, assessed by transcranial magnetic stimulation (TMS), in asymptomatic subjects bearing a pathogenic GRN mutation and in symptomatic patients with frontotemporal dementia.

All patients will undergo genetic screening for progranulin mutations, a baseline neuropsychological and neurophysiological evaluation, including assessment of short interval intracortical inhibition, intracortical facilitation, short interval intracortical facilitation and long interval intracortical inhibition. Subjects will then be randomized in two groups, one receiving a 10 day (5 days/week for 2 weeks) treatment with anodal frontal and prefrontal anodal tDCS and the other receiving sham stimulation with identical parameters. After the intervention, patients will be reassessed with a neuropsychological and neurophysiological evaluation at 2 weeks, 1 month (only neurophysiological evaluation), 3 months and 6 month after treatment.

Study Timeline

• Study Start: 2016-10-31
• Study First Submitted: 2016-12-02
• Study First Submitted QC: 2016-12-17
• Study First Posted: 2016-12-21
• Primary Completion: 2019-06-30
• Study Completion: 2019-06-30
• Status Verified: 2020-03
• Last Update Submitted: 2020-03-01
• Last Update Posted: 2020-03-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 70

Inclusion Criteria

presymptomatic carriers, symptomatic genetic FTD patients, symptomatic sporadic FTD patients.

• Presymptomatic carriers: defined as participants who are known carriers of a pathogenic mutation in the GRN gene, who do not fulfill current criteria for the behavioral variant FTD (bvFTD) (Rascovsky et al. 2011) or for the Primary Progressive Aphasias (PPA) (Gorno-Tempini et al. 2011). All subjects will be genotyped for known pathogenic mutations for FTD (GRN, C9orf72, MAPT, TDP-43) before participation.
• Symptomatic genetic FTD: defined as patients who are known carriers of pathogenic mutation in the GRN gene, fulfilling current clinical criteria for behavioral variant FTD (bvFTD) (Rascovsky et al. 2011) or the agrammatic variant of Primary Progressive Aphasia (avPPA) (Gorno-Tempini et al. 2011).
• Symptomatic sporadic FTD: defined as patients fulfilling current clinical criteria for behavioral variant FTD (bvFTD) (Rascovsky et al. 2011) or the agrammatic variant of Primary Progressive Aphasia (avPPA) (Gorno-Tempini et al. 2011), with a negative screening for pathogenic mutations in known FTD genes (GRN, C9orf72, MAPT, TDP-43). CSF analysis or amyloid PET imaging will be carried out to exclude focal variants of AD.

Exclusion Criteria

• Cerebrovascular disorders, previous stroke, hydrocephalus, and intra-cranial mass documented by MRI.
• History of traumatic brain injury or other neurological diseases.
• Serious medical illness other than FTD
• History of seizures
• Pregnancy
• Metal implants in the head (except dental fillings)
• Electronic implants (i.e. pace-maker, implanted medical pump)
• Age <18 years

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Presymptomatic real tDCS	Anodal transcranial direct current stimulation	Asymptomatic subjects - 10 days anodal transcranial direct current stimulation
Symptomatic sham tDCS	Sham transcranial direct current stimulation	Symptomatic patients - 10 days sham transcranial direct current stimulation
Symptomatic real tDCS	Anodal transcranial direct current stimulation	Symptomatic patients - 10 days anodal transcranial direct current stimulation
Presymptomatic sham tDCS	Sham transcranial direct current stimulation	Asymptomatic subjects - 10 days sham transcranial direct current stimulation

Primary Outcome Measures

Name	Time	Method
Change in SICI measurements from Baseline	Baseline - 2 weeks	By using transcranial magnetic stimulation (TMS), the investigators will evaluate the effects of frontal and prefrontal anodal transcranial magnetic stimulation on short interval intracortical inhibition (SICI)
Change in ICF measurements from Baseline	Baseline - 2 weeks	By using transcranial magnetic stimulation (TMS), the investigators will evaluate the effects of frontal and prefrontal anodal transcranial magnetic stimulation on intracortical facilitation (ICF).

Secondary Outcome Measures

Name	Time	Method
Change in SICI measurements from Baseline	Baseline - 1 month - 3 months - 6 months	By using transcranial magnetic stimulation (TMS), the investigators will evaluate the effects of frontal and prefrontal anodal transcranial magnetic stimulation on short interval intracortical inhibition (SICI)
Change in ICF measurements from Baseline	Baseline - 1 month - 3 months - 6 months	By using transcranial magnetic stimulation (TMS), the investigators will evaluate the effects of frontal and prefrontal anodal transcranial magnetic stimulation on intracortical facilitation (ICF).
Change in LICI measurements from Baseline	Baseline - 1 month - 3 months - 6 months	By using transcranial magnetic stimulation (TMS), the investigators will evaluate the effects of frontal and prefrontal anodal transcranial magnetic stimulation on long interval intracortical inhibition (LICI).
Change in SICF measurements from Baseline	Baseline - 1 month - 3 months - 6 months	By using transcranial magnetic stimulation (TMS), the investigators will evaluate the effects of frontal and prefrontal anodal transcranial magnetic stimulation on short interval intracortical facilitation (SICF).
Change in MMSE scores from Baseline	Baseline - 2 weeks - 3 months - 6 months	The Mini Mental State Examination (MMMSE) is a 30-point questionnaire that is used to measure cognitive impairment.
Change in phonemic fluencies scores from Baseline	Baseline - 2 weeks - 3 months - 6 months	Produce as many words as possible beginning with a specified letter in 60 seconds
Change in semantic fluencies scores from Baseline	Baseline - 2 weeks - 3 months - 6 months	Produce as many words as possible from a category in 60 seconds
Change in digit span forward scores from Baseline	Baseline - 2 weeks - 3 months - 6 months	Participants hear a sequence of numerical digits and are tasked to recall the sequence correctly, with increasingly longer sequences being tested in each trial. The participant's span is the longest number of sequential digits that can accurately be remembered.
Change in digit span backward scores from Baseline	Baseline - 2 weeks - 3 months - 6 months	Participants hear a sequence of numerical digits and are tasked to recall the sequence correctly in reverse order, with increasingly longer sequences being tested in each trial. The participant's span is the longest number of sequential digits that can accurately be remembered.
Change in camel and cactus test scores from Baseline	Baseline - 2 weeks - 3 months - 6 months	Evaluates associative semantic memory with 64 items presented for naming and word-picture matching.
Change in TMTA scores from Baseline	Baseline - 2 weeks - 3 months - 6 months	The task requires a subject to connect a sequence of 25 consecutive targets on a sheet of paper to examine cognitive processing speed.
Change in TMTB scores from Baseline	Baseline - 2 weeks - 3 months - 6 months	The task requires a subject to connect a sequence of 25 consecutive targets on a sheet of paper, alternating between numbers and letters, to examine executive functioning.
Change in Stroop test scores from Baseline	Baseline - 2 weeks - 3 months - 6 months	Measure a person's selective attention capacity and skills, as well as their processing speed ability.
Change in Symbol Digit test scores from Baseline	Baseline - 2 weeks - 3 months - 6 months	It consists of digit-symbol pairs followed by a list of digits. Under each digit the subject should write down the corresponding symbol as fast as possible. The number of correct symbols within the allowed time is measured.
Change in Block Design test scores from Baseline	Baseline - 2 weeks - 3 months - 6 months	To evaluated spatial visualization ability and motor skills. The test-taker uses hand movements to rearrange blocks that have various color patterns on different sides to match a pattern. The items in a block design test are scored both by accuracy in matching the pattern and by speed in completing each item.
Change in The modified EkmanFaces Test from Baseline	Baseline - 2 weeks - 3 months - 6 months	Each face is presented on a sheet with six labels of basic emotions below the photograph. The patient was required to respond verbally, deciding the label that best described the facial expression shown.

Trial Locations

Locations (1)

Azienda Ospedaliera Spedali Civili di Brescia; 🇮🇹 Brescia, Italy