Effects of Electrical Stimulation on Verbal Learning in Typical and Atypical Alzheimer's Disease

Not Applicable

Recruiting

• Conditions: Atypical Alzheimer's Disease; Alzheimer Disease, Early Onset; Logopenic Progressive Aphasia
• Interventions: Device: Active HD-tDCS; Device: Sham; Other: Word List Learning Intervention (WordLLI)

• Registration Number: NCT04122001
• Lead Sponsor: Johns Hopkins University

Brief Summary

Alzheimer's disease (AD) is the leading neurodegenerative disease of aging characterized by multiple cognitive impairments. Given the recent failures of disease-modifying drugs, the current focus is on preventing or mitigating synaptic damage that correlates with cognitive decline in AD patients. Transcranial Direct Current Stimulation (tDCS) is a safe, non-invasive, non-painful electrical stimulation of the brain that is shown to act as a primer at the synaptic level when administered along with behavioral therapy, mostly involving language, learning and memory. Previous studies have shown that tDCS over the left angular gyrus (AG) improves language associative learning in the elderly through changes in functional connectivity between the AG and the hippocampus. The investigators' previous clinical trial on the effects of tDCS in neurodegenerative disorders has also shown augmented effects of lexical retrieval for tDCS. In the present study the investigators will compare the effects of active vs. sham tDCS over the AG-an area that is part of the default mode network but also a language area, particularly important for semantic integration and event processing-in two predominant AD variants: probable AD with amnesic phenotype (amnesic/typical AD) and probable AD with non-amnesic (language deficit) phenotype also described as logopenic variant PPA with AD pathology (aphasic/atypical AD). The investigators aim to: (1) determine whether active high-definition tDCS (HD-tDCS) targeting the left AG combined with a Word-List Learning Intervention (WordLLI) will improve verbal learning; (2) identify the changes in functional connectivity between the stimulated area (AG) and other structurally and functionally connected areas using resting-state functional magnetic resonance imaging; (3) identify changes in the inhibitory neurotransmitter GABA at the stimulation site using magnetic resonance spectroscopy. Furthermore, the investigators need to determine the characteristics of the people that may benefit from the new neuromodulatory approaches. For this reason, the investigators will evaluate neural and cognitive functions as well as physiological characteristics such as sleep, and will analyze the moderating effects on verbal learning outcomes. Study results can help provide treatment alternatives as well as a better understanding of the therapeutic and neuromodulatory effects of tDCS in AD, thus improving patients' and caregivers' quality of life.

Detailed Description

The investigation implements a double-blind, sham-controlled, within-subject, cross-over design that allows for the evaluation of the cognitive and neural effects of word-list learning as modulated by tDCS compared to sham stimulation. Participants in all groups will receive word-list learning intervention (WordLLI)+ High-Definition tDCS (HD-tDCS) or WordLLI+ sham in Period 1 or 2, randomized for the Period 1 stimulation condition. Each learning Period will last 2 weeks, with 5 learning sessions per week (for a total of 10 learning sessions per Period) with a 3-month (stimulation-free) wash-out period between the two Periods. The intensity, total number of learning sessions and number of learning items is consistent with most other tDCS studies in neurodegenerative disorders and the investigators have used this design successfully over the past 7 years in neurodegenerative disorders (PPA, mild AD). Stimulation is implemented every weekday to take advantage of the long-term potentiation induced by tDCS as found in early multi-session studies. A tDCS-only condition (without any intervention) is not implemented in this design because no study to date has shown improvement on motor, cognitive, or language performance after anodal tDCS-only for 2 or even more weeks. After each period the investigators will perform 1-month and 3-month follow-up sessions for evaluation purposes. For those participants who are long-distance, at the 1-month time point only the investigators may use a video conferencing tool such as GoToMeeting to administer the assessments. This is to mitigate the costs of travel for a short appointment.

Study Timeline

• Study First Submitted: 2019-10-08
• Study First Submitted QC: 2019-10-08
• Study First Posted: 2019-10-10
• Study Start: 2020-08-17
• Status Verified: 2025-05
• Last Update Submitted: 2025-05-06
• Last Update Posted: 2025-05-09
• Primary Completion: 2026-05-31
• Study Completion: 2026-05-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 90

Inclusion Criteria

For the aphasic/atypical AD participants:

• Must be between 45-85 years of age.
• Must be right-handed.
• Must be proficient in English.
• Must have a minimum of high-school education.
• Must be diagnosed as logopenic variant Primary Progressive Aphasia (PPA) with Alzheimer's Disease (AD) biomarkers. Other possible diagnosis for the 'aphasic AD' variant would be Mild Cognitive Impairment (MCI) or 'possible AD' according to 2011 guidelines with AD biomarkers (CSF or positron emission tomography (PET) amyloid-beta or fluorodeoxyglucose (FDG)-positron emission tomography (PET) with unihemispheric atrophy).
• Participants will be diagnosed from PPA and early dementias clinics at Johns Hopkins University or other specialized centers in US using current consensus criteria. Diagnosis will be based on neuropsychological testing, language testing (most commonly the Western Aphasia Battery), MRI and clinical assessment. The investigators will also use two new variant classification tests the investigators have developed at the lab which discriminate PPA variants with great accuracy (above 80%): a spelling test and a speech production test (i.e.,Cookie Theft picture description task).

For the amnesic/typical AD participants:

• Must be between 45-85 years of age.
• Must be right-handed.
• Must be proficient in English.
• Must have a minimum of high-school education.
• Must be diagnosed with 'probable AD' in specialized diagnostic centers with neuropsychological (e.g., RAVLT) and AD biomarkers according to 2011 guidelines.
• The investigators will also perform extensive testing in the investigators' test battery including the Mnemonic Similarity Test (MST) that discriminates and measures the most salient hippocampal deficit-pattern separation (PS).

Exclusion Criteria

• People with previous neurological disease including vascular dementia (e.g., stroke, developmental dyslexia, dysgraphia or attentional deficit).
• People with hearing loss (> 25 decibel, using audiometric hearing screen).
• People with uncorrected visual acuity loss.
• People with advanced dementia or severe language impairments (MMSE < 15, or Montreal Cognitive Assessment <10, or language Frontotemporal Dementia-specific Clinical Dementia Rating (FTD-CDR) = 3).
• Left handed individuals.
• People with pre-existing psychiatric disorders such as behavioral disturbances, severe depression, or schizophrenia that do not allow these people to comply or follow the study schedule and requirements such as repeated evaluation and therapy.

Exclusion Criteria for MRI Participation:

• People with severe claustrophobia.
• People with cardiac pacemakers or ferromagnetic implants.
• Pregnant women.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Active HD-tDCS+word intervention then Sham+word intervention	Sham	Participants will receive active HD-tDCS + Word List Learning Intervention (WordLLI) and then receive Sham + WordLLI after a three-month washout period.
Active HD-tDCS+word intervention then Sham+word intervention	Word List Learning Intervention (WordLLI)	Participants will receive active HD-tDCS + Word List Learning Intervention (WordLLI) and then receive Sham + WordLLI after a three-month washout period.
Sham+word intervention then active HD-tDCS+word intervention	Sham	Participants will receive Sham + Word List Learning Intervention (WordLLI) and then active HD-tDCS + WordLLI after a three-month washout period.
Active HD-tDCS+word intervention then Sham+word intervention	Active HD-tDCS	Participants will receive active HD-tDCS + Word List Learning Intervention (WordLLI) and then receive Sham + WordLLI after a three-month washout period.
Sham+word intervention then active HD-tDCS+word intervention	Active HD-tDCS	Participants will receive Sham + Word List Learning Intervention (WordLLI) and then active HD-tDCS + WordLLI after a three-month washout period.
Sham+word intervention then active HD-tDCS+word intervention	Word List Learning Intervention (WordLLI)	Participants will receive Sham + Word List Learning Intervention (WordLLI) and then active HD-tDCS + WordLLI after a three-month washout period.

Primary Outcome Measures

Name	Time	Method
Change in auditory recall accuracy based on the sum of words recalled in Trials 1-5 of semantically related - trained word-lists	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	Each trained word-list (practiced during the intervention period) will consist of 12 semantically related words (e.g., birds). Word lists will be constructed using psycholinguistic databases. There will be 5 Trials to learn each list. The investigators will compute the raw score of items correctly recalled by summing all scores from Trial 1 to Trial 5 and transforming to percent correct (range: 0-100%) at each time point of the study. Increase in scores is considered a benefit.
Change in auditory delayed recall accuracy of semantically related - trained word-lists	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	Each trained word-list (practiced during the intervention period) will consist of 12 semantically related words (e.g., birds). Word lists will be constructed using psycholinguistic databases. There will be 5 Trials to recall each list, and then participants will be asked to recall that list 20 minutes later (delayed recall). The investigators will compute the raw score of items correctly recalled (delayed recall) and transform to percent correct (range: 0-100%) at each time point of the study. Increase in scores is considered a benefit.
Change in auditory recall accuracy based on the sum of words recalled in Trials 1-5 of semantically unrelated - trained word-lists	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	Each trained word-list (practiced during the intervention period) will consist of 12 semantically unrelated words (as in RAVLT). Word lists will be constructed using psycholinguistic databases. There will be 5 Trials to learn each list. The investigators will compute the raw score of items correctly recalled by summing all scores from Trial 1 to Trial 5 and transforming to percent correct (range: 0-100%) at each time point of the study. Increase in scores is considered a benefit.
Change in auditory delayed recall accuracy of semantically unrelated - trained word-lists	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	Each trained word-list (practiced during the intervention period) will consist of 12 semantically unrelated words (as in RAVLT). Word lists will be constructed using psycholinguistic databases. There will be 5 Trials to recall each list, and then participants will be asked to recall that list 20 minutes later (delayed recall). The investigators will compute the raw score of items correctly recalled (delayed recall) and transform to percent correct (range: 0-100%) at each time point of the study. Increase in scores is considered a benefit.
Change in auditory recall accuracy based the sum of words recalled in Trials 1-5 of semantically related - untrained word-lists	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	Each untrained word-list (not practiced during the intervention period) will consist of 12 semantically related words (e.g., birds). Word lists will be constructed using psycholinguistic databases. There will be 5 Trials to learn each list. The investigators will compute the raw score of items correctly recalled by summing all scores from Trial 1 to Trial 5 and transforming to percent correct (range: 0-100%) at each time point of the study. Increase in scores is considered a benefit.
Change in auditory delayed recall accuracy of semantically related - untrained word-lists	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	Each untrained word-list (not practiced during the intervention period) will consist of 12 semantically related words (e.g., birds). Word lists will be constructed using psycholinguistic databases. There will be 5 Trials to recall each list, and then participants will be asked to recall that list 20 minutes later (delayed recall). The investigators will compute the raw score of items correctly recalled (delayed recall) and transform to percent correct (range: 0-100%) at each time point of the study. Increase in scores is considered a benefit.
Change in auditory recall accuracy based on the sum of words recalled in Trials 1-5 of semantically unrelated - untrained word-lists	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	Each untrained word-list (not practiced during the intervention period) will consist of 12 semantically unrelated words (as in RVLT). Word lists will be constructed using psycholinguistic databases. There will be 5 Trials to learn each list. The investigators will compute the raw score of items correctly recalled by summing all scores from Trial 1 to Trial 5 and transforming to percent correct (range: 0-100%) at each time point of the study. Increase in scores is considered a benefit.
Change in auditory delayed recall accuracy of semantically unrelated - untrained word-lists	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	Each untrained word-list (not practiced during the intervention period) will consist of 12 semantically unrelated words (as in RVLT). Word lists will be constructed using psycholinguistic databases. There will be 5 Trials to recall each list, and then participants will be asked to recall that list 20 minutes later (delayed recall). The investigators will compute the raw score of items correctly recalled (delayed recall) and transform to percent correct (range: 0-100%) at each time point of the study. Increase in scores is considered a benefit.

Secondary Outcome Measures

Name	Time	Method
Change in non-word repetition score	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	TALSA tasks include non-word repetition, with sets of 1-6 non-words. Scoring will be based on percent of non-words correctly repeated. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%), computing change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit.
Change in sentence repetition score	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	Sentence repetition tasks come from the TALSA, with scoring based on percent of words in sentences correctly repeated. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%), computing change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit.
Change in oral naming Boston Naming Test score	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	Accuracy in oral picture naming (30-item Boston Naming Test) will be compared for tDCS and sham conditions. The Boston Naming Test is a widely used picture naming test that detects lexical retrieval deficits in the oral modality. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%), computing change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit.
Change in oral naming Philadelphia Naming Test score	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	Accuracy in oral picture naming (Philadelphia Naming Test) will be compared for tDCS and sham conditions. The Philadelphia Naming Test is an extensive picture naming test that comprises 275 items from a wide range of frequencies and other psycholinguistic characteristics. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%), computing change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit.
Change in written naming as assessed by Boston Naming Test	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	Accuracy in written picture naming (30-item Boston Naming Test) will be compared for tDCS and sham conditions. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%), computing change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit.
Change in word repetition score	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	Temple Assessment of Language and Short-Term Memory in Aphasia (TALSA) tasks include word repetition, with sets of 1-6 words. Scoring will be based on percent of words correctly repeated. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%), computing change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit.
Change in oral naming of action as assessed by Hopkins Assessment of Naming Actions (HANA)	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	Accuracy in oral naming of actions will be compared for tDCS and sham conditions. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%), computing change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit.
Change in Rey Auditory-Verbal Learning Test (RAVLT) score	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	RAVLT is a well-established verbal memory test. RAVLT includes a 5-trial presentation of a 15-word list (List A), a single presentation of an interference list (List B)(Trial 6), two post-interference recall trials (one immediate - Trial 7, one delayed - Trial 8) and recognition of the target words in the orthographic modality with distractors (Trial 9). Scoring includes the percent score of Trial 1, Trial 5, Trial 8 and Trial 9 as well as the sum of Trial 1 through 5, and the difference between Trial 5 and Trial 1 computed as the percent difference between the scores before intervention and each time point after. Increase in score is considered a benefit.
Change in Mini Mental State Examination (MMSE)	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	MMSE is a well-established cognitive assessment test. It examines functions including registration (repeating named prompts), attention and calculation, recall, language, ability to follow simple commands and orientation. The total raw score is out of 30 points. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%), computing change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit.
Change in Mnemonic Similarity Task (MST) score	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	MST is a well-established test in order to assess high interference memory and general recognition memory via pattern separation. It involves differentiating between previously learned images and novel images. For the MST tasks, the Pattern Separation (PS) score will be calculated using two measures: a) the rate of similar items correctly identified minus the rate of similar items misidentified as new (S\|S-S\|N); b) the rate of similar items correctly identified minus the rate of similar items misidentified as old (S\|S-O\|S). The number of correct responses for each category of items (i.e., old, similar, new) and the type of errors (i.e., identifications of new items as similar; identification of similar items as old) will also be tracked. Change in outcome in percent difference will be computed between the scores before intervention and each time point after. Increase in scores is considered a benefit.
Change in written naming as assessed by Philadelphia Naming Test	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	Accuracy in written picture naming (Philadelphia Naming Test) will be compared for tDCS and sham conditions. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%), computing change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit.
Change in syntactic comprehension as assessed by Subject-relative, Object-relative, Active, Passive (S.O.A.P.) Syntactic Battery	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	The 40-item Subject-relative, Object-relative, Active, Passive (S.O.A.P.) Syntactic Battery of various sub-tests will be used to assess argument structure comprehension and production. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%), computing change in outcome in percent difference between baseline and each time point. Increase in score is considered benefit.
Change in verbal fluency task score	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	Verbal fluency tasks (semantic and letter fluency) involve generating as many words as possible in one minute. Scoring will be based on number of words generated per minute. The investigators will compute the raw score of items correct and compute change in outcome between baseline and each time point. Increase in score is considered benefit.
Change in spelling as assessed by the Johns Hopkins Dysgraphia battery	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	Accuracy in spelling using the Johns Hopkins Dysgraphia battery will be compared for tDCS and sham conditions. The investigators will compute the raw score of items correct using a spelling scoring system accounting for additions, substitutions, and deletions, and transform to percent correct (range: 0-100%), computing change in outcome in percent difference before intervention and each time point after. Increase in score is considered a benefit.
Change in digit span forward score	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	Digit span forward involves the recall of a series of single digits (sets of 1-8 digits) in the same order the digits were presented. Scoring will be based on the number of consecutive digits correctly recalled. The investigators will compute the change in outcome between the time point before intervention and each time point after. Increase in score is considered a benefit.
Change in digit span backward score	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	Digit span backward involves the recall of a series of single digits (sets of 1-8 digits) in the reverse order than the digits were presented. Scoring will be based on the number of consecutive digits correctly recalled. The investigators will compute the change in outcome between the time point before intervention and each time point after. Increase in score is considered a benefit.
Change in spatial span forward score	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	Spatial span forward involves the recall of a series of positions on a board (sets of 1-9) in the same order the digits were presented. Scoring will be based on the number of consecutive positions correctly recalled. The investigators will compute the change in outcome between the time point before intervention and each time point after. Increase in score is considered a benefit.
Change in spatial span backward score	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	Spatial span backward involves the recall of a series of positions (sets of 1-8) in the reverse order than the digits were presented. Scoring will be based on the number of consecutive positions correctly recalled. The investigators will compute the change in outcome between the time point before intervention and each time point after. Increase in score is considered a benefit.
Change in semantic content of connected speech	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	Using the Cookie Theft image from the Boston Diagnostic Aphasia Examination (BDAE) and the Circus image from the Apraxia Battery for Adults (ABA) investigators will obtain representative language samples as participants describe the images. The investigators will compute the raw score of items (semantics) correct and transform to percent correct (range: 0-100%), computing change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit.
Change in attention and manipulation of information scores	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	Using the Trail Making Test (TMT) parts A and B, which include the sequential connection of letters/numbers in order to complete a trail, the investigators will obtain the time required by the participants to finish the tasks. Decrease in the time is considered a benefit.
Change in volumetric measurements of select brain regions	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	Using Magnetization-Prepared Rapid Gradient-Echo (MPRAGE) Magnetic Resonance Imaging (MRI) investigators will perform volumetric measurements of select brain regions. Measurements will be collected in millimeters cubed (mm\^3).
Change in Gamma-Aminobutyric Acid (GABA) concentration	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	Using Magnetic Resonance Spectroscopy (MRS) investigators will measure metabolite (GABA) concentrations from select brain regions in international units (IU).
Change in functional connectivity of select brain regions (z-correlations)	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	Using resting stage functional MRI (rs-fMRI) investigators will detect activity of various brain regions under a resting/task-negative condition, which will help evaluate functional regional interactions as indicated by the z-correlations between the selected brain area.
Change in location of white matter tracts of select brain regions	Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks	Using Diffusion Tensor Imaging (DTI) investigators will estimate the location of the brain's white matter tracts on the regions of concern.
Change in anisotropy of white matter tracts of select brain regions	Before intervention, immediately after intervention and 3 months post intervention, up to 31 weeks	Using Diffusion Tensor Imaging (DTI) investigators will estimate the anisotropy of the brain's white matter tracts on the brain regions of concern.

Trial Locations

Locations (1)

Johns Hopkins Hospital; 🇺🇸 Baltimore, Maryland, United States