Non-invasive Stimulation of Brain Networks and Cognition in Alzheimer's Disease and Frontotemporal Dementia

Alzheimer's Disease Clinical Trial

— NetCogBs  

Official title:

A Non-invasive, Multimodal Approach to Restore Functional Networks and Cognition in Alzheimer's Disease and Frontotemporal Dementia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03422250
• Other study ID #: GR-2011-02349787
• Status: Completed
• Phase: N/A
• Start date: June 8, 2015
• Est. completion date: November 3, 2018

Study information

• Verified date: April 2021
• Source: IRCCS Centro San Giovanni di Dio Fatebenefratelli
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This pilot study aims to test clinical and connectivity changes following non-invasive stimulation of disease-specific networks in Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Brain network stimulation will be carried out with transcranial direct current stimulation (tDCS). Target networks will be the default mode network (DMN) and salience network (SN). Twenty AD and 20 bvFTD patients will be recruited and assessed with a comprehensive clinical, behavioral and cognitive battery, and 3 Tesla MRI scan (including resting-state functional MRI, arterial spin labeling, diffusion tensor imaging, structural MRI) at three time-points: baseline, after tDCS, and after 6 months. Patients will be randomized to 2 arms: anodal stimulation of the disease-specific network (DMN in AD, SN in bvFTD) or cathodal stimulation of the anti-correlated network (SN in AD, DMN in bvFTD). The intervention will consist of 10 tDCS sessions over two weeks. Cerebrospinal fluid (CSF) samples will be collected at baseline for biomarker's assessment; blood samples will be collected at each time-point to assess changes in peripheral inflammatory markers. Blood and CSF collection will be optional. A sample of 20 elderly controls will be included for baseline comparisons.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 45
• Est. completion date: November 3, 2018
• Est. primary completion date: November 3, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 50 Years to 85 Years

Eligibility

Inclusion Criteria:

• Diagnosis of AD or bvFTD according to current clinical criteria (Albert et al., 2011; Rascovsky et al., 2011)
• Ability to provide written informed consent
• Availability of a collateral source

Exclusion Criteria:

• Moderate/severe dementia
• Presence of any medical or psychiatric illness that could interfere in completing assessments

Exclusion Criteria for MRI and tDCS:

• metal implants, pace-makers, prosthetic heart valves
• claustrophobia
• history of epilepsy
• pregnancy

Exclusion Criteria for controls:

• Current or past history of clinical, neurological, or psychiatric conditions that could interfere with the assessment (e.g., transient ischemic attack, ictus, head trauma, epilepsy, multiple sclerosis, neuropathy, mood disorders, substance abuse)

Related Conditions & MeSH terms

• Alzheimer Disease
• Alzheimer's Disease
• Aphasia, Primary Progressive
• Dementia
• Frontotemporal Dementia
• Frontotemporal Dementia, Behavioral Variant
• Pick Disease of the Brain

Intervention

Device:
• transcranial direct current stimulation (tDCS)
10 daily 25-minutes tDCS sessions over two weeks.

Locations

Country	Name	City	State
Italy	IRCCS Centro San Giovanni di Dio Fatebenefratelli	Brescia

Sponsors (1)

Lead Sponsor	Collaborator
IRCCS Centro San Giovanni di Dio Fatebenefratelli

Country where clinical trial is conducted

Italy, 

References & Publications (1)

Pievani M, Pini L, Cappa SF, Frisoni GB. Brain networks stimulation in dementia: insights from functional imaging. Curr Opin Neurol. 2016 Dec;29(6):756-762. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Clinical Disease Severity (CDR)	CDR - Clinical Dementia Rating score; The clinical dementia rating (CDR) is a clinical global rating scale administered to both the participant and the caregiver, assessing 6 domains of participant function: memory, orientation, judgement and problem solving, community affairs, home and hobbies and personal care. Each domain is based on a 5-point scale ranging from no impairment=0, questionable impairment=0.5, mild impairment=1, moderate impairment=2 to severe impairment=3. The global CDR score is computed via a memory-weighted averaging algorithm of the six domain scores and ranges from 0 to 5. The CDR-sum of boxes (CDR-SB) is the sum of the individual domain scores and ranges from 0 to 18. Higher scores indicate more clinical impairment. Negative changes at post tDCS compared to baseline represent an improvement on the scale.	Baseline, post tDCS (week 3)
Primary	Change in Behavioral Symptom Severity (NPI)	The Neuropsychiatric Inventory (NPI) is a behavioral scale administered to the caregiver assessing 12 dimensions: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, euphoria, apathy, disinhibition, irritability, aberrant motor activity, nighttime behaviors, and appetite/eating. Each dimension has multiple screening questions relating to symptoms. If the answer to the screening questions is "Yes", the dimensional-score is the product of frequency (1=occasionally to 4=very frequently) and severity (1=Mild to 3=Severe) of symptoms. Dimensional-scores are summed (from 0 to 144). Higher scores indicate greater behavioral disturbances. Negative changes at post tDCS compared to baseline represent an improvement on the scale.	Baseline, post tDCS (week 3)
Primary	Change in Behavioral Symptom Severity (FBI)	The Frontal Behavioral Inventory (FBI) is a 24-item inventory designed to assess behavior and personality changes via caregiver. Item-level scores range from 0=none, 1=mild/occasional, 2=moderate, 3=severe/most of the time. Item-scores are summed (from 0 to 72). Higher scores indicate greater behavioral/personality disturbances. Negative changes at post tDCS compared to baseline represent an improvement on the scale.	Baseline, post tDCS (week 3)
Primary	Change in Functional Connectivity	Default mode network (DMN) and salience network (SN) mean functional connectivity is assessed on resting state functional MRI. Functional connectivity is standardized to Z scores and thresholded at Z>2. Higher values denote greater functional connectivity. A positive change at post tDCS compared to baseline represents an increase in resting-state functional connectivity.	Baseline, post tDCS (week 3)
Primary	Change in Cerebral Blood Flow	Default mode network (DMN) and salience network (SN) mean cerebral blood flow is assessed on arterial spin labeling. Cerebral blood flow is computed by averaging values across the DMN and SN regions of interest. Cerebral blood flow is a measure of brain perfusion, higher values denoting higher perfusion. A positive change at post tDCS compared to baseline represents an increase in perfusion.	Baseline, post tDCS (week 3)
Secondary	Change in Cognition: Memory	The composite memory score consists of the averaged Z-standardized scores of 5 memory tests: immediate and delayed auditory verbal learning test recall, Rey-Osterrieth complex figure recall, story recall, digit span backward and forward tests. Each test score is normalized to an independent dataset of healthy controls. Z-scores have no minimum/maximum values. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Higher values denote better memory performance. Positive changes at post tDCS compared to baseline represent an improvement in memory.	Baseline, post tDCS (week 3)
Secondary	Change in Cognition: Language	The composite language score consists of the averaged Z-standardized scores of 2 language tests: verbal fluency and token tests. Each test score is normalized to an independent dataset of healthy controls. Z-scores have no minimum/maximum values. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Higher values denote better language performance. Positive changes at post tDCS compared to baseline represent an improvement in language.	Baseline, post tDCS (week 3)
Secondary	Change in Cognition: Executive Function	The composite executive function score consists of the averaged Z-standardized scores of 2 executive functions tests: trail making test part A and part B tests. Each test score is normalized to an independent dataset of healthy controls and inverted. Z-scores have no minimum/maximum values. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Higher values denote better executive function performance. Positive changes at post tDCS compared to baseline represent an improvement in executive functions.	Baseline, post tDCS (week 3)
Secondary	Change in Cognition: Visuospatial Function	The visuospatial function score consists of the Z-standardized scores for the Rey-Osterrieth complex figure copy test. Scores are normalized to an independent dataset of healthy controls. Z-scores have no minimum/maximum values. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Higher values denote better visuospatial performance. Positive changes at post tDCS compared to baseline represent an improvement in visuospatial functions.	Baseline, post tDCS (week 3)
Secondary	Change in Cognition: Emotion Recognition	The composite emotion recognition score consists of the averaged Z-standardized scores for 2 emotion recognition tests: reading the Mind in the Eyes and 60 Ekman faces tests. Each test score is normalized to an independent dataset of healthy controls. Z-scores have no minimum/maximum values. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Higher values denote better emotion recognition performance. Positive changes at post tDCS compared to baseline represent an improvement in emotion recognition.	Baseline, post tDCS (week 3)
Secondary	Change in Structural Connectivity: FA	Fractional anisotropy (FA) is assessed on diffusion weighted imaging. FA values are averaged in default mode network (DMN) and salience network (SN) regions of interest. FA values denote the directionality of water diffusivity, ranging from 0 (isotropic diffusion) to 1 (anisotropic diffusion). Higher values denote higher directionality and connectivity. Positive changes at post tDCS compared to baseline represent an improvement in the measure.	Baseline, post tDCS (week 3)
Secondary	Change in Structural Connectivity: MD, AxD, RaD	Mean diffusivity (MD), axial diffusivity (AxD), and radial diffusivity (RaD) are assessed on diffusion weighted imaging. MD, AxD, RaD values are averaged in default mode network (DMN) and salience network (SN) regions of interest. MD, AxD, and RaD measure water diffusion and are expressed in mm^2/s (starting from 0 with no maximum value; scaled at x10^-3). Higher values denote higher diffusion and lower connectivity. Negative changes at post tDCS compared to baseline represent an improvement in the measure.	Baseline, post tDCS (week 3)