Clinical trial NCT02999282: Rehabilitative Trial for the Rescue of Neurophysiological Parameters in Progranulin Deficient Subjects
Official title: Rehabilitative Trial for the Recovery of Neurophysiological Parameters in Progranulin Mutation Carriers Through the Use of Transcranial Direct Current Stimulation (tDCS)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Frontotemporal Dementia
GRN Related Frontotemporal Dementia
Keywords: TMS
tDCS
Rehabilitation
Lead sponsor: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
Sponsor class: OTHER
First posted: 2016-12-21
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in SICI measurements from Baseline
timeFrame: Baseline - 2 weeks
measure: Change in ICF measurements from Baseline
timeFrame: Baseline - 2 weeks
Secondary outcomes:
measure: Change in SICI measurements from Baseline
timeFrame: Baseline - 1 month - 3 months - 6 months
measure: Change in ICF measurements from Baseline
timeFrame: Baseline - 1 month - 3 months - 6 months
measure: Change in LICI measurements from Baseline
timeFrame: Baseline - 1 month - 3 months - 6 months
measure: Change in SICF measurements from Baseline
timeFrame: Baseline - 1 month - 3 months - 6 months
measure: Change in MMSE scores from Baseline
timeFrame: Baseline - 2 weeks - 3 months - 6 months
measure: Change in phonemic fluencies scores from Baseline
timeFrame: Baseline - 2 weeks - 3 months - 6 months
measure: Change in semantic fluencies scores from Baseline
timeFrame: Baseline - 2 weeks - 3 months - 6 months
measure: Change in digit span forward scores from Baseline
timeFrame: Baseline - 2 weeks - 3 months - 6 months
measure: Change in digit span backward scores from Baseline
timeFrame: Baseline - 2 weeks - 3 months - 6 months
measure: Change in camel and cactus test scores from Baseline
timeFrame: Baseline - 2 weeks - 3 months - 6 months
measure: Change in TMTA scores from Baseline
timeFrame: Baseline - 2 weeks - 3 months - 6 months
measure: Change in TMTB scores from Baseline
timeFrame: Baseline - 2 weeks - 3 months - 6 months
measure: Change in Stroop test scores from Baseline
timeFrame: Baseline - 2 weeks - 3 months - 6 months
measure: Change in Symbol Digit test scores from Baseline
timeFrame: Baseline - 2 weeks - 3 months - 6 months
measure: Change in Block Design test scores from Baseline
timeFrame: Baseline - 2 weeks - 3 months - 6 months
measure: Change in The modified EkmanFaces Test from Baseline
timeFrame: Baseline - 2 weeks - 3 months - 6 months
Other outcomes:
Locations:
city: Brescia
country: Italy
facility: Azienda Ospedaliera Spedali Civili di Brescia
Study officials:
affiliation: Azienda Ospedaliera Spedali Civili, Brescia
name: Barbara Borroni, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Università degli Studi di Brescia
name: Alberto Benussi, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Benussi A, Cosseddu M, Filareto I, Dell'Era V, Archetti S, Sofia Cotelli M, Micheli A, Padovani A, Borroni B. Impaired long-term potentiation-like cortical plasticity in presymptomatic genetic frontotemporal dementia. Ann Neurol. 2016 Sep;80(3):472-6. doi: 10.1002/ana.24731. Epub 2016 Aug 10.
citation: Bikson M, Grossman P, Thomas C, Zannou AL, Jiang J, Adnan T, Mourdoukoutas AP, Kronberg G, Truong D, Boggio P, Brunoni AR, Charvet L, Fregni F, Fritsch B, Gillick B, Hamilton RH, Hampstead BM, Jankord R, Kirton A, Knotkova H, Liebetanz D, Liu A, Loo C, Nitsche MA, Reis J, Richardson JD, Rotenberg A, Turkeltaub PE, Woods AJ. Safety of Transcranial Direct Current Stimulation: Evidence Based Update 2016. Brain Stimul. 2016 Sep-Oct;9(5):641-661. doi: 10.1016/j.brs.2016.06.004. Epub 2016 Jun 15.
citation: Rossini PM, Burke D, Chen R, Cohen LG, Daskalakis Z, Di Iorio R, Di Lazzaro V, Ferreri F, Fitzgerald PB, George MS, Hallett M, Lefaucheur JP, Langguth B, Matsumoto H, Miniussi C, Nitsche MA, Pascual-Leone A, Paulus W, Rossi S, Rothwell JC, Siebner HR, Ugawa Y, Walsh V, Ziemann U. Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: Basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee. Clin Neurophysiol. 2015 Jun;126(6):1071-1107. doi: 10.1016/j.clinph.2015.02.001. Epub 2015 Feb 10.