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.
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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
90
Stimulation will be delivered by a battery-driven constant current stimulator. The electrical current will be administered to a pre-specified region of the brain (angular gyrus). The stimulation will be delivered at an intensity of 2 milliamperes (mA) (estimated current density 0.04 mA/cm2; estimated total charge 0.048 Coulombs/cm2) in a ramp-like fashion for a maximum of 20 minutes. In the active, in-person HD-tDCS the current is delivered in a ring configuration. In the active remote tDCS current is delivered in one electrode patch.
Current will be administered in a ramp-like fashion but after the ramping the intensity will drop to 0 mA. Current under the Sham condition will last for a maximum of 30 seconds.
Participants will receive a word list learning intervention (WordLLI) of semantically related and unrelated word lists. Word lists are presented across 10 trials, with an additional trial after a 10-minute delay to assess delayed recall. Immediately following verbal presentation of word lists during each trial, participants will be instructed to recall as many of the words from the list as possible. Participants may use the written modality as a strategy during recall. Word lists include 12 words matched based on psycholinguistics attributes (e.g., imageability, frequency). This task is designed to help participants improve memory via enhancing list learning capabilities.
Johns Hopkins Hospital
Baltimore, Maryland, United States
RECRUITINGChange in auditory recall accuracy based on the sum of words recalled in Trials 1-5 of semantically related - trained word-lists
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.
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in auditory delayed recall accuracy of semantically related - trained word-lists
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.
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in auditory recall accuracy based on the sum of words recalled in Trials 1-5 of semantically unrelated - trained word-lists
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.
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in auditory delayed recall accuracy of semantically unrelated - trained word-lists
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.
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in auditory recall accuracy based the sum of words recalled in Trials 1-5 of semantically related - untrained word-lists
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.
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in auditory delayed recall accuracy of semantically related - untrained word-lists
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.
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in auditory recall accuracy based on the sum of words recalled in Trials 1-5 of semantically unrelated - untrained word-lists
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.
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in auditory delayed recall accuracy of semantically unrelated - untrained word-lists
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.
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in Rey Auditory-Verbal Learning Test (RAVLT) score
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.
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in Mini Mental State Examination (MMSE)
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.
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in Mnemonic Similarity Task (MST) score
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.
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Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in word repetition score
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.
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in non-word repetition score
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.
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in sentence repetition score
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.
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in oral naming Boston Naming Test score
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.
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in oral naming Philadelphia Naming Test score
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.
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in written naming as assessed by Boston Naming Test
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.
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in written naming as assessed by Philadelphia Naming Test
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.
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in oral naming of action as assessed by Hopkins Assessment of Naming Actions (HANA)
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.
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in syntactic comprehension as assessed by Subject-relative, Object-relative, Active, Passive (S.O.A.P.) Syntactic Battery
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.
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in verbal fluency task score
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.
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in spelling as assessed by the Johns Hopkins Dysgraphia battery
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.
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in digit span forward score
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.
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in digit span backward score
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.
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in spatial span forward score
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.
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in spatial span backward score
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.
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in semantic content of connected speech
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.
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in attention and manipulation of information scores
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.
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in volumetric measurements of select brain regions
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).
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in functional connectivity of select brain regions (z-correlations)
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.
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in Gamma-Aminobutyric Acid (GABA) concentration
Using Magnetic Resonance Spectroscopy (MRS) investigators will measure metabolite (GABA) concentrations from select brain regions in international units (IU).
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in location of white matter tracts of select brain regions
Using Diffusion Tensor Imaging (DTI) investigators will estimate the location of the brain's white matter tracts on the regions of concern.
Time frame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Change in anisotropy of white matter tracts of select brain regions
Using Diffusion Tensor Imaging (DTI) investigators will estimate the anisotropy of the brain's white matter tracts on the brain regions of concern.
Time frame: Before intervention, immediately after intervention and 3 months post intervention, up to 31 weeks