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

Rehabilitative Trial for the Recovery of Neurophysiological Parameters in Progranulin Mutation Carriers Through the Use of Transcranial Direct Current Stimulation (tDCS)

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.

Study Overview

• Status: Completed
• Conditions: Frontotemporal Dementia; GRN Related Frontotemporal Dementia
• Intervention / Treatment: Device: Anodal transcranial direct current stimulation; Device: Sham transcranial direct current stimulation

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 Type: Interventional
• Enrollment (Actual): 70
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • Brescia, Italy, 25123
    • Azienda Ospedaliera Spedali Civili di Brescia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Presymptomatic real tDCS; Asymptomatic subjects - 10 days anodal transcranial direct current stimulation	Device: Anodal transcranial direct current stimulation; 10 sessions of anodal transcranial direct current stimulation (5 days/week for 2 weeks)
Sham Comparator: Presymptomatic sham tDCS; Asymptomatic subjects - 10 days sham transcranial direct current stimulation	Device: Sham transcranial direct current stimulation; 10 sessions of sham transcranial direct current stimulation (5 days/week for 2 weeks)
Experimental: Symptomatic real tDCS; Symptomatic patients - 10 days anodal transcranial direct current stimulation	Device: Anodal transcranial direct current stimulation; 10 sessions of anodal transcranial direct current stimulation (5 days/week for 2 weeks)
Sham Comparator: Symptomatic sham tDCS; Symptomatic patients - 10 days sham transcranial direct current stimulation	Device: Sham transcranial direct current stimulation; 10 sessions of sham transcranial direct current stimulation (5 days/week for 2 weeks)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	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).	Baseline - 2 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	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).	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).	Baseline - 1 month - 3 months - 6 months
Change in SICF 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 facilitation (SICF).	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.	Baseline - 2 weeks - 3 months - 6 months
Change in phonemic fluencies scores from Baseline	Produce as many words as possible beginning with a specified letter in 60 seconds	Baseline - 2 weeks - 3 months - 6 months
Change in semantic fluencies scores from Baseline	Produce as many words as possible from a category in 60 seconds	Baseline - 2 weeks - 3 months - 6 months
Change in digit span forward scores from Baseline	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.	Baseline - 2 weeks - 3 months - 6 months
Change in digit span backward scores from Baseline	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.	Baseline - 2 weeks - 3 months - 6 months
Change in camel and cactus test scores from Baseline	Evaluates associative semantic memory with 64 items presented for naming and word-picture matching.	Baseline - 2 weeks - 3 months - 6 months
Change in TMTA scores from Baseline	The task requires a subject to connect a sequence of 25 consecutive targets on a sheet of paper to examine cognitive processing speed.	Baseline - 2 weeks - 3 months - 6 months
Change in TMTB scores from Baseline	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.	Baseline - 2 weeks - 3 months - 6 months
Change in Stroop test scores from Baseline	Measure a person's selective attention capacity and skills, as well as their processing speed ability.	Baseline - 2 weeks - 3 months - 6 months
Change in Symbol Digit test scores from Baseline	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.	Baseline - 2 weeks - 3 months - 6 months
Change in Block Design test scores from Baseline	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.	Baseline - 2 weeks - 3 months - 6 months
Change in The modified EkmanFaces Test from Baseline	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.	Baseline - 2 weeks - 3 months - 6 months

Collaborators and Investigators

• Sponsor: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 31, 2016
• Primary Completion (Actual): June 30, 2019
• Study Completion (Actual): June 30, 2019

Study Registration Dates

• First Submitted: December 2, 2016
• First Submitted That Met QC Criteria: December 17, 2016
• First Posted (Estimate): December 21, 2016

Study Record Updates

• Last Update Posted (Actual): March 3, 2020
• Last Update Submitted That Met QC Criteria: March 1, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: Rehabilitation; tDCS; TMS
• Additional Relevant MeSH Terms: Mental Disorders; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Neurocognitive Disorders; Neurodegenerative Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Language Disorders; Communication Disorders; Speech Disorders; Aphasia; Dementia; Frontotemporal Dementia; Aphasia, Primary Progressive; Pick Disease of the Brain; Frontotemporal Lobar Degeneration
• Other Study ID Numbers: NP2441

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: All data, including outcome measure results, study protocol and statistical analysis plan, will be shared.
• IPD Sharing Time Frame: Data will be shared after the study completion indefinitely.
• IPD Sharing Access Criteria: Reasonable request
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP)