Transcranial Direct Current Stimulation in Typical and Atypical Alzheimer's Disease
Overview
- Phase
- Not Applicable
- Intervention
- Not specified
- Conditions
- Alzheimer Disease, Early Onset
- Sponsor
- Johns Hopkins University
- Enrollment
- 90
- Locations
- 1
- Primary Endpoint
- Change in auditory recall accuracy based on the sum of words recalled in Trials 1-5 of semantically related - trained word-lists
- Status
- Recruiting
- Last Updated
- 7 months ago
Overview
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.
Investigators
Eligibility Criteria
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.
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.
Outcomes
Primary Outcomes
Change in auditory recall accuracy based on the sum of words recalled in Trials 1-5 of semantically related - trained word-lists
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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 Outcomes
- Change in non-word repetition score(Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks)
- Change in sentence repetition score(Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks)
- Change in oral naming Boston Naming Test score(Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks)
- Change in oral naming Philadelphia Naming Test score(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(Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks)
- Change in word repetition score(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)(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(Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks)
- Change in Mini Mental State Examination (MMSE)(Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks)
- Change in Mnemonic Similarity Task (MST) score(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(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(Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks)
- Change in verbal fluency task score(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(Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks)
- Change in digit span forward score(Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks)
- Change in digit span backward score(Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks)
- Change in spatial span forward score(Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks)
- Change in spatial span backward score(Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks)
- Change in semantic content of connected speech(Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks)
- Change in attention and manipulation of information scores(Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks)
- Change in volumetric measurements of select brain regions(Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks)
- Change in Gamma-Aminobutyric Acid (GABA) concentration(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)(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(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(Before intervention, immediately after intervention and 3 months post intervention, up to 31 weeks)