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

Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia70 enrolled

Overview

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.

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

Conditions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

Change in SICI measurements from Baseline

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)

Time frame: Baseline - 2 weeks

Change in ICF measurements from Baseline

By using transcranial magnetic stimulation (TMS), the investigators will evaluate the effects of frontal and prefrontal anodal transcranial magnetic stimulation on intracortical facilitation (ICF).

Time frame: Baseline - 2 weeks

Secondary Outcomes

Change in SICI measurements from Baseline

Time frame: Baseline - 1 month - 3 months - 6 months

Change in ICF measurements from Baseline

By using transcranial magnetic stimulation (TMS), the investigators will evaluate the effects of frontal and prefrontal anodal transcranial magnetic stimulation on intracortical facilitation (ICF).

Time frame: Baseline - 1 month - 3 months - 6 months

Change in LICI measurements from Baseline

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).

Time frame: Baseline - 1 month - 3 months - 6 months

Change in SICF measurements from Baseline

Time frame: Baseline - 1 month - 3 months - 6 months

Change in MMSE scores from Baseline

The Mini Mental State Examination (MMMSE) is a 30-point questionnaire that is used to measure cognitive impairment.