Dementia of Alzheimer Type, Mild Cognitive Impairment
Conditions
Keywords
Dementia, Memory, Cognitive Rehabilitation, PET scan, fMRI, Brain Stimulation
Brief summary
This study will test the effects of different doses of a form of non-invasive brain stimulation for the treatment of individuals with mild cognitive impairment (MCI) and dementia of the Alzheimer's Type (DAT).
Detailed description
This research study is being done to learn important information about the effects of weak electrical stimulation on brain functioning in those with mild cognitive impairment (MCI) and dementia of the Alzheimer's type (DAT). The findings will help determine "how much" stimulation is needed to enhance memory and thinking abilities, how it affects brain functioning, and who is most likely to benefit. Ultimately, this information may guide treatment efforts for those at various stages of Alzheimer's disease. The study will use brain imaging to see whether these treatments change how participants learn and remember information. Functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) scans will be used. The study will also use cognitive tests and questionnaires to examine whether participants' memory (and related abilities) change because of treatment. The study will enroll participants with a diagnosis of MCI or DAT. It is expected but not required that participants will be co-enrolled in the University of Michigan Memory and Aging Project (UM-MAP; HUM00000382).
Interventions
DEVICE1 mA HD-tDCS
Participants will receive HD-tDCS at 1 mA for 30 minutes, for between 5-30 sessions.
DEVICE2 mA HD-tDCS
Participants will receive HD-tDCS at 2 mA for 30 minutes, for between 5-30 sessions.
DEVICE3 mA HD-tDCS
Participants will receive HD-tDCS at 3 mA for 30 minutes, for between 5-30 sessions.
DEVICESham
Participants will receive sham (placebo) HD-tDCS for 30 minutes, for between 5-30 sessions.
Sponsors
University of Michigan
National Institute on Aging (NIA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Intervention model description
Eligible participants will be randomized 1:1:1:1 to receive either sham, 1mA, 2mA, or 3mA HD-tDCS for at least 5 sessions and up to 30 sessions using a blocked randomization design.
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of Mild Cognitive Impairment (MCI) or dementia of the Alzheimer's type (DAT) 2. Must be MRI compatible, criteria that also apply for High Definition transcranial direct current stimulation (HD-tDCS; e.g., absence of metallic or electronic implants in the upper body or head) 3. Stable on relevant medications for at least 4 weeks prior to study enrollment
Exclusion criteria
1. Certain neurological diseases 2. Certain psychiatric conditions 3. Severe sensory impairment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Lateral Temporal Cortex Connectivity | Change from Baseline to Post-Intervention (after tDCS Session 5 - day 5 of treatment) and from Baseline to Post-Expansion (after the participant's final tDCS session beyond Session 5, up to 43 weeks). | Primary outcome focuses on default mode network (DMN) between-network functional connectivity because the lateral temporal cortex is a core component of the DMN. Between-network functional connectivity is estimated from fMRI data as strength of temporal coupling between the DMN and other high-level (association) brain networks. For each participant and time point, correlation-based connectivity (Pearson r; Fisher r-to-z transformed; arbitrary units) computed between DMN regions and other regions of the association cortex defined using standard functional atlas. Higher values reflect stronger functional connectivity between DMN and other regions. A Z-score's range is infinite. Expected value is between -3 to 3. Analyses conducted separately for amyloid negative (A-) and amyloid positive (A+) participants. Post Intervention data collection was on day 5 of treatment. Post-Expansion (PE) appointments were not consecutive. Mean time between enrollment and PE was 10 wks, longest was 43 wks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Self-Report of Contentment With Memory | Change from Baseline to Post-Intervention (after tDCS Session 5 - day 5 of treatment) and from Baseline to Post-Expansion (after the participant's final tDCS session beyond Session 5, up to 43 weeks). | The Multifactorial Memory Questionnaire (MMQ) consists of three scales measuring separate aspects of metamemory. Items are rated on a 5-point Likert scale (0-4) based on the test taker's experiences over the previous two weeks. MMQ-Satisfaction (formerly called MMQ-Contentment) scale measures satisfaction, concern, and overall appraisal of one's own memory. Each of 18 statements is rated based on degree of agreement. The score range is 0 to 72, with higher scores indicating a higher degree of satisfaction. Post Intervention data collection was on day 5 of treatment. Post-Expansion (PE) appointments were not consecutive. Mean time between enrollment and PE was 10 wks, longest was 43 wks. |
| Self-Report of Memory Mistakes | Change from Baseline to Post-Intervention (after tDCS Session 5 - day 5 of treatment) and from Baseline to Post-Expansion (after the participant's final tDCS session beyond Session 5, up to 43 weeks). | Multifactorial Memory Questionnaire (MMQ) Ability Score - This scale measures self-perception of everyday memory ability. Respondents rate how often they experienced each of 20 common memory mistakes over the previous two weeks. The score range is 0 to 80, with higher scores indicating better self-reported memory ability. Post Intervention data collection was on day 5 of treatment. Post-Expansion (PE) appointments were not consecutive. Mean time between enrollment and PE was 10 wks, longest was 43 wks. |
| Self-Report of Memory Strategies Used | Change from Baseline to Post-Intervention (after tDCS Session 5 - day 5 of treatment) and from Baseline to Post-Expansion (after the participant's final tDCS session beyond Session 5, up to 43 weeks). | Multifactorial Memory Questionnaire (MMQ) Strategies Score - This scale measures the use of practical memory strategies and aids in day-to-day life. Respondents rate how often they used each of 19 memory strategies over the previous two weeks. The score range is 0 to 76, with higher scores indicating greater use of memory strategies. Post Intervention data collection was on day 5 of treatment. Post-Expansion (PE) appointments were not consecutive. Mean time between enrollment and PE was 10 wks, longest was 43 wks. |
| Change in Memory Functioning | Change from Baseline to Post-Intervention (after tDCS Session 5 - day 5 of treatment) and from Baseline to Post-Expansion (after the participant's final tDCS session beyond Session 5, up to 43 weeks). | The Repeatable Battery of the Assessment of Neuropsychological Status (RBANS) is a comprehensive neuropsychological battery for the evaluation of global cognition. The delayed memory section is a measure of delayed recall and recognition for verbal and visual information. It includes the subtests List Recall, List Recognition, Story Memory, and Figure Recall. Low scores on this index indicate difficulties with recognition and retrieval of information from long-term memory stores This index is composed of both auditory and visual measures; therefore, a severe deficit in language, auditory processing, or visual functioning may impact one of the measures more than the other. Analysis included the sum of the raw scores for each of the delayed memory subtests, with possible scores ranging from 0 to 62. Post Intervention data collection was on day 5 of treatment. Post-Expansion (PE) appointments were not consecutive. Mean time between enrollment and PE was 10 wks, longest was 43 wks. |
| Change in Overall Fluid Cognitive Abilities | Change from Baseline to Post-Intervention (after tDCS Session 5 - day 5 of treatment) and from Baseline to Post-Expansion (after the participant's final tDCS session beyond Session 5, up to 43 weeks). | Cognitive function was determined using the NIH Toolbox-Cognition Battery computerized tests, specifically the Fluid composite score. It is derived by averaging the subtests in the Fluid domain to achieve an overall standard score. Fully Corrected T-scores are adjusted for for age, gender, race/ethnicity, and educational attainment. The score compares the score of the participant to those in the NIH Toolbox nationally representative normative sampling. The T-score has a mean of 50 in the general population and a SD of 10. Scores higher than the mean indicate better performance. Post Intervention data collection was on day 5 of treatment. Post-Expansion (PE) appointments were not consecutive. Mean time between enrollment and PE was 10 wks, longest was 43 wks. |
| Cumulative Working Memory Effects of HD-tDCS Across Treatment Sessions | Change from Baseline to Post-Intervention (after tDCS Session 5 - day 5 of treatment) and from Baseline to Post-Expansion (after the participant's final tDCS session beyond Session 5, up to 43 weeks). | The n-back test is a working memory task where participants identify stimulus that matches stimulus experienced "n" steps back. Participants performed a 2-back test, in which they were asked to remember and press a button when shown a stimulus that appeared 2 steps before the current one (e.g. square, circle, square). The number of correct and incorrect identifications are normalized (z-score). Total score is the z-score of correct button presses minus the z-score of incorrect button presses. A higher score (d') reflects better working memory performance. Possible scores range from -4.85 to 4.85. Positive change (increase) in 2-back score across treatment sessions indicates improvement in working memory performance. Data is shown as the mean slope calculation of participants across first 5 days of treatment and across all treatments, x=days of treatment, y=n-back score. Post-Expansion (PE) appointments were not consecutive. Mean time between enrollment and PE was 10 wks. |
| Cumulative Memory Accuracy Effects of HD-tDCS Across Treatment Sessions | Change from Baseline to Post-Intervention (after tDCS Session 5 - day 5 of treatment) and from Baseline to Post-Expansion (after the participant's final tDCS session beyond Session 5, up to 43 weeks). | Paired Associates task is a verbal memory task that asks participants to learn a list of word pairs. After a delay, participants are shown correct and mismatched word pairs one at a time and asked to identify if the displayed word pair was from the list they were asked to learn or not. Total accuracy is a proportion (total correct responses divided by total trials completed) ranging from 0 to 1 that measures the accuracy of a participant's responses to both correct and mismatched word pairs. Higher scores indicate better verbal memory performance, and positive changes over time indicate an improvement in verbal memory performance, measured after baseline (Session 1) and every intervention session (Sessions 2-5) Data is shown as the mean slope calculation of participants across first 5 days of treatment and across all treatments, x=days of treatment, y= total accuracy. Post-Expansion (PE) appointments were not consecutive. Mean time between enrollment and PE was 10 wks. |
| Cumulative Memory Sensitivity Effects of HD-tDCS Across Daily Sessions | Baseline | Verbal memory performance for computerized Paired Associates task, summarized with a computational model (linear ballistic accumulator decision model). The model uses each participant's accuracy and reaction times across trials to estimate how efficiently they accumulate information to distinguish previously studied (target) word pairs from new (lure) pairs. Reported outcome is the average memory sensitivity score at baseline, expressed as unitless model values (scores on a scale) where higher scores indicate better discrimination, scores near zero indicate chance-level performance, and negative scores (if present) indicate performance worse than chance. |
| Tolerability of HD-tDCS | Assessed immediately after each HD-tDCS session (participants received up to 30 sessions over approximately 1-12 weeks); values represent mean symptom burden averaged across all post-stimulation assessments | Tolerability was assessed using the HD-tDCS Safety Questionnaire, an 11-item symptom checklist. The questionnaire assesses the presence (yes/no) of 10 specific self-reported symptoms (Itching, Burning, Tingling, Scalp Pain, Trouble Concentrating, Sleep problems, Headache, Mood Change, Neck Pain, and Other symptoms) and 1 oberserved symptom, Skin Redness. Skin Redness was excluded from this analysis as it is not related to the participant's perception of tolerability. The total score (symptom burden) was calculated by summing the number of symptoms present across the 10 items for each session. Score range: 0 to 10 symptoms, where 0 = no symptoms present and 10 = all symptoms present. Higher scores indicate worse tolerability (more symptoms experienced). Values represent the mean number of symptoms per session, calculated by averaging symptom burden scores across all post-stimulation assessments within each treatment group. |
| Effectiveness of Blinding of HD-tDCS | Assessed immediately after each HD-tDCS session (participants received up to 30 sessions over approximately 1-12 weeks) | Participant's perception of treatment assignment assessed after each stimulation session using a 3-category ordinal scale. Participants guessed whether they received: (0) Sham stimulation, (1) Don't Know, or (2) Active stimulation. The scale is ordinal with Sham \< Don't Know \< Active. Effective blinding is indicated by no significant difference in the distribution of perceived assignment between active and sham groups (i.e., participants in active groups cannot reliably distinguish their treatment from sham). Higher proportional odds ratios would indicate active group participants were more likely to guess "active"; lower ratios would indicate sham participants were more likely to guess "active" (paradoxical pattern suggesting convincing sham condition). |
| Change in Default Mode Network Connectivity | Change from Baseline to Post-Intervention (after tDCS Session 5 - day 5 of treatment) and from Baseline to Post-Expansion (after the participant's final tDCS session beyond Session 5, up to 43 weeks). | The outcome focuses on default mode network (DMN) within-network functional connectivity. Within-network functional connectivity is estimated from fMRI data as strength of temporal coupling within DMN regions (nodes). For each participant and time point, correlation-based connectivity (Pearson r; Fisher r-to-z transformed; arbitrary units) was computed between DMN regions defined using a standard functional atlas. Higher values reflect stronger functional connectivity within DMN. A Z-score's range is infinite. Expected value is around -3 to 3. Analyses are conducted separately for amyloid negative (A-) and amyloid positive (A+) participants. Post Intervention data collection was on day 5 of treatment. Post-Expansion (PE) appointments were not consecutive. Mean time between enrollment and PE was 10 wks, longest was 43 wks. |
| Cumulative Cognitive Change Across Daily Consecutive Sessions | Change from Baseline to Post-Intervention (after tDCS Session 5 - day 5 of treatment) and from Baseline to Post-Expansion (after the participant's final tDCS session beyond Session 5, up to 43 weeks). | Measured through change in Cogstate or other comparable computerized cognitive testing scores across consecutive daily sessions. |
| Change in Global Cognition | Change from Baseline to Post-Intervention (after tDCS Session 5 - day 5 of treatment) and from Baseline to Post-Expansion (after the participant's final tDCS session beyond Session 5, up to 43 weeks). | The Repeatable Battery of the Assessment of Neuropsychological Status (RBANS) is a comprehensive neuropsychological battery for the evaluation of global cognition and has been validated in subjects with mild cognitive impairment, moderate to severe traumatic brain injuries, vascular dementias, and Alzheimer's disease. Data was analyzed using the sum of the subtest raw scores, which is an indicator of the general cognitive functioning of the examinee. Low scores suggest general cognitive impairment even when some individual subtest scores may be within normal limits. Individuals with low scores on this measure exhibit problems with attention, memory, language, and construction skills. Possible scores range from 0 to 321. Post Intervention data collection was on day 5 of treatment. Post-Expansion (PE) appointments were not consecutive. Mean time between enrollment and PE was 10 wks, longest was 43 wks. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORBenjamin Hampstead, PhD
Associate Professor
Participant flow
Pre-assignment details
Number enrolled reflects the number of people who consented and were determined to be eligible for participation.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 72.6 years STANDARD_DEVIATION 7.2 |
| Baseline RBANS total Amyloid Negative participants | 179.5 Score on a scale STANDARD_DEVIATION 27.45 |
| Baseline RBANS total Amyloid Positive participants | 152.15 Score on a scale STANDARD_DEVIATION 37.58 |
| Default Mode Network Connectivity Amyloid Negative Participants | 0.388 Fisher z-transformed Pearson correlation STANDARD_DEVIATION 0.085 |
| Default Mode Network Connectivity Amyloid Positive Participants | 0.367 Fisher z-transformed Pearson correlation STANDARD_DEVIATION 0.091 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 231 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Lateral Temporal Cortex Connectivity Amyloid Negative Participants | 0.159 Fisher z-transformed Pearson correlation STANDARD_DEVIATION 0.074 |
| Lateral Temporal Cortex Connectivity Amyloid Positive Participants | 0.154 Fisher z-transformed Pearson correlation STANDARD_DEVIATION 0.063 |
| Multifactorial Memory Questionnaire (MMQ) Subsections Ability - Amyloid Negative participants | 45.2 score on a scale STANDARD_DEVIATION 15.92 |
| Multifactorial Memory Questionnaire (MMQ) Subsections Ability- Amyloid Positive participants | 44.26 score on a scale STANDARD_DEVIATION 11.25 |
| Multifactorial Memory Questionnaire (MMQ) Subsections Contentment - Amyloid Negative participants | 35.6 score on a scale STANDARD_DEVIATION 7.73 |
| Multifactorial Memory Questionnaire (MMQ) Subsections Contentment - Amyloid Positive participants | 29.93 score on a scale STANDARD_DEVIATION 11.09 |
| Multifactorial Memory Questionnaire (MMQ) Subsections Strategies- Amyloid Negative participants | 38.69 score on a scale STANDARD_DEVIATION 11.53 |
| Multifactorial Memory Questionnaire (MMQ) Subsections Strategies- Amyloid Positive participants | 36.16 score on a scale STANDARD_DEVIATION 12.08 |
| NIH Toolbox Cognition Fluid Composite Score Amyloid Negative participants | 90.8 score on a scale STANDARD_DEVIATION 12.62 |
| NIH Toolbox Cognition Fluid Composite Score Amyloid Positive participants | 76.88 score on a scale STANDARD_DEVIATION 13.44 |
| Paired Associates Task Amyloid Negative Participants | 0.599 Proportion of correct responses STANDARD_DEVIATION 0.051 |
| Paired Associates Task Amyloid Positive Participants | 0.567 Proportion of correct responses STANDARD_DEVIATION 0.057 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 26 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 49 Participants |
| RBANS delayed recall subscale Amyloid Negative participants | 19.67 Score on a scale STANDARD_DEVIATION 8.24 |
| RBANS delayed recall subscale Amyloid Positive participants | 8.95 Score on a scale STANDARD_DEVIATION 7.69 |
| Region of Enrollment United States | 58 participants |
| Sex: Female, Male Female | 31 Participants |
| Sex: Female, Male Male | 28 Participants |
| Working Memory (0-back) Amyloid Negative Participants | 4.46 d' (dimensionless) STANDARD_DEVIATION 0.752 |
| Working Memory (0-back) Amyloid Positive Participants | 4.40 d' (dimensionless) STANDARD_DEVIATION 0.779 |
| Working Memory (2-back) Amyloid Negative Participants | 2.05 d' (dimensionless) STANDARD_DEVIATION 0.968 |
| Working Memory (2-back) Amyloid Positive Participants | 2.21 d' (dimensionless) STANDARD_DEVIATION 1.06 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 59 | 0 / 59 | 0 / 58 | 0 / 57 |
| other Total, other adverse events | 58 / 59 | 56 / 59 | 55 / 58 | 56 / 57 |
| serious Total, serious adverse events | 0 / 59 | 1 / 59 | 1 / 58 | 0 / 57 |
Outcome results
None listed