The Effects of a Multimodal Approach for the Treatment of PPA (ACROSS)

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

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.

Study Overview

• Status: Completed
• Conditions: Primary Progressive Aphasia
• Intervention / Treatment: Device: Active tDCS; Behavioral: Language training; Device: Placebo tDCS; Behavioral: Unstructured cognitive training

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • BS
    • Brescia, BS, Italy, 25125
      • IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 95 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active tDCS plus individual language training	Device: Active tDCS; Active tDCS anode is applied over the left DLPFC with the cathode over the right supraorbital region.; Behavioral: Language training; patients receive language training
Active Comparator: placebo tDCS plus individual language training	Behavioral: Language training; patients receive language training; Device: Placebo tDCS; 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.
Active Comparator: Active tDCS plus unstructured cognitive stimulation	Device: Active tDCS; Active tDCS anode is applied over the left DLPFC with the cathode over the right supraorbital region.; Behavioral: Unstructured cognitive training; patients receive unstructured cognitive training.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: IRCCS Centro San Giovanni di Dio Fatebenefratelli
• Collaborators: Asst Degli Spedali Civili Di Brescia
• Investigators: Principal Investigator: Rosa Manenti, PhD, IRCCS Istituto Centro San Giovanni di Dio- Fatebenefratelli

Study record dates

Study Major Dates

• Study Start (Actual): January 15, 2020
• Primary Completion (Actual): March 31, 2024
• Study Completion (Actual): March 31, 2024

Study Registration Dates

• First Submitted: November 29, 2019
• First Submitted That Met QC Criteria: December 3, 2019
• First Posted (Actual): December 5, 2019

Study Record Updates

• Last Update Posted (Actual): October 3, 2024
• Last Update Submitted That Met QC Criteria: October 1, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• 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; Dementia; Language Disorders; Communication Disorders; Speech Disorders; Frontotemporal Lobar Degeneration; Aphasia; Frontotemporal Dementia; Aphasia, Primary Progressive; Pick Disease of the Brain
• Other Study ID Numbers: GR 2018 12365105

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No