The Effects of a Multimodal Approach for the Treatment of Primary Progressive Aphasia

Study Overview
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Brief Summary
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Primary Progressive Aphasia (PPA) is an untreatable neurodegenerative disorder that disrupts language functions. Available therapies are mainly symptomatic and recently attention has been gained by new techniques that allow for noninvasive brain stimulation such as transcranial direct current stimulation (tDCS). The primary objective of this study is to evaluate whether the application of Active tDCS (anode over the left dorsolateral prefrontal cortex- DLPFC with the cathode over the right supraorbital region) to the scalp during individualized language training, would improve naming abilities in the agrammatic variant of PPA (avPPA) more than use of one methodology alone. The effect of treatment on the clinical symptoms will be related to changes in brain activity (Magnetic Resonance Imaging, MRI and Functional near-infrared spectroscopy fNIRS) and in biological markers, using a multimodal approach. Finally, we will assess the long-term effects of this approach.

Detailed Description
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45 patients with avPPA, will be recruited from IRCCS Istituto Centro San Giovanni di Dio Brescia, Italy and ASST Spedali Civili Brescia, Italy . Inclusion criteria will be a diagnosis avPPA according to the current clinical criteria (Gorno-Tempini et al., 2011) and a FTD Clinical Dementia Rating score >0.5 and <2. Exclusion criteria will be the presence of any medical or psychiatric illness that could interfere in completing assessments and the presence of any medical condition that represents a contraindication to tDCS. All the patients will undergo five consecutive days a week for two weeks of treatment sessions: 15 patients will receive Active tDCS over DLPFC while performing a language training; 15 patients will receive placebo tDCS during language training; 15 patients will receive Active tDCS over DLPFC during unstructured cognitive training. Two trained neuropsychologists will administer the neuropsychological testing in two sessions. At baseline (T0), post-treatment (T1) and 3-months (T2) follow-up assessments were conducted by the same assessor. Blood sample withdrawal at baseline (T0) and after the DLPFC-tDCS intervention (T1) will be assessed. To elucidate the mechanisms underlying tDCS effects, structural imaging, functional connectivity (fMRI) alterations and concentration changes of hemoglobin (fNIRS) will be collected off-line. Each avPPA patient will undergo an MRI scan at the ASST Spedali Civili Brescia, Italy at T0 and T1 and a fNIRS acquisition at the IRCCS Istituto Centro San Giovanni di Dio Brescia, Italy at T0, T1 and T2.

Official Title
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The Effects of a Multimodal Approach for the Treatment of Primary Progressive Aphasia

Conditions
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Primary Progressive Aphasia

Intervention / Treatment
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* Device: Active tDCS
* Device: Placebo tDCS
* Behavioral: Language training
* Behavioral: Unstructured cognitive training


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis avPPA according to the current clinical criteria (Gorno-Tempini et al., 2011) FTD Clinical Dementia Rating (FTD-CDR) score >0.5 and <2 Exclusion Criteria: Presence of any medical or psychiatric illness that could interfere in completing assessments Presence of any medical condition that represents a contraindication to tDCS.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 95 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active tDCS plus individual language training<br>Active tDCS plus individual language training | Device: Active tDCS<br>* Active tDCS anode is applied over the left DLPFC with the cathode over the right supraorbital region.<br>Behavioral: Language training<br>* patients receive language training<br>|
| Active Comparator: placebo tDCS plus individual language training<br>placebo tDCS plus individual language training | Device: Placebo tDCS<br>* Placebo tDCS is applied but the current is turned off 10 seconds after the beginning and turned on for the last 10 seconds of the stimulation period.<br>Behavioral: Language training<br>* patients receive language training<br>|
| Active Comparator: Active tDCS plus unstructured cognitive stimulation<br>Active tDCS plus unstructured cognitive stimulation | Device: Active tDCS<br>* Active tDCS anode is applied over the left DLPFC with the cathode over the right supraorbital region.<br>Behavioral: Unstructured cognitive training<br>* patients receive unstructured cognitive training.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in naming test scores on Picture Naming Task | Picture Naming Task: percentage of correct responses (0-100) | Baseline up to 2 weeks and 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in quality of life on Stroke and Aphasia Quality of Life | Stroke and Aphasia Quality of Life (0-5; higher scores=better quality of life) | Baseline up to 2 weeks and 3 months | 
| Change in dementia severity on Frontotemporal Dementia-modified Clinical Dementia Rating Scale | Frontotemporal Dementia-modified Clinical Dementia Rating Scale (0-3; higher scores=greater dementia severity) | Baseline up to 2 weeks and 3 months | 
| Change in cognitive impairment on Mini Mental State Examination | Mini Mental State Examination (0-30; higher scores=better cognitive abilities) | Baseline up to 2 weeks and 3 months | 
| Change in verbal long term memory on Story Recall | Story Recall (0-28; higher scores=better memory abilities) | Baseline up to 2 weeks and 3 months | 
| Change in nonverbal long term memory on Rey-Osterrieth Complex Figure-Recall | Rey-Osterrieth Complex Figure-Recall (0-36; higher scores=better abilities) | Baseline up to 2 weeks and 3 months | 
| Change in attentional abilities on Trial Making Test | Trial Making Test (milliseconds; higher scores=worse abilities) | Baseline up to 2 weeks and 3 months | 
| Change in constructional praxia on Rey-Osterrieth Complex Figure-Copy | Rey-Osterrieth Complex Figure-Copy (0-36; higher scores=better abilities) | Baseline up to 2 weeks and 3 months | 
| Change in fluency abilities on Verbal Fluency (semantic and phonemic) | Verbal Fluency (semantic and phonemic) Test (higher scores=better abilities) | Baseline up to 2 weeks and 3 months | 
| Change in aphasia severity on Screening for Neurodegenerative Aphasia | Screening for Neurodegenerative Aphasia Battery (higher scores=better abilities) | Baseline up to 2 weeks and 3 months | 
| Change in naming on naming subtest from Aachener Aphasie Test | naming subtest from Aachener Aphasie Test (0-120; higher scores=better abilities) | Baseline up to 2 weeks and 3 months | 
| Change in language impairment on Mini Language State Examination | Mini Language State Examination Battery (higher scores=better abilities) | Baseline up to 2 weeks and 3 months | 
| Change in molecular biomarkers on neurogranin | neurogranin | Baseline up to 2 weeks | 
| Change in imaging biomarkers on fMRI and fNIRS | fMRI and fNIRS | Baseline up to 2 weeks |