Mild Cognitive Impairment
Conditions
Keywords
Mild Cognitive Impairment, Vagal Nerve Stimulation, tVNS, Alzheimer's disease
Brief summary
Patients with amnestic mild cognitive impairment (MCI) often have compromised quality of life (QOL). Cognitive impairment is a major contributor to decrements in QOL and progression of MCI often leads to loss of independence and withdrawal from social participation. MCI, in many patients, is an early expression of neurodegenerative disease. Patients with MCI frequently convert to Alzheimer's disease (AD) (12-16 percent by some estimates per year). Treatments for MCI are of limited scope and availability and of limited effectiveness. Thus, there is great need for treatments that can improve cognition and extend QOL in patients with MCI. The investigators propose to investigate the effect of a non-invasive and safe intervention that should have direct influence on brain systems underlying AD, transcutaneous vagal nerve stimulation (tVNS).
Detailed description
Patients with amnestic mild cognitive impairment (MCI) often have compromised quality of life (QOL). Cognitive impairment is a major contributor to decrements in QOL and progression of MCI often leads to loss of independence and withdrawal from social participation. MCI, in many patients, is an early expression of neurodegenerative disease. Patients with MCI frequently convert to Alzheimer's disease (AD) (12-16 percent by some estimates per year). Treatments for MCI are of limited scope and availability and of limited effectiveness. Thus, there is great need for treatments that can improve cognition and extend QOL in patients with MCI. The investigators propose to investigate the effect of a non-invasive and safe intervention that should have direct influence on brain systems underlying AD, transcutaneous vagal nerve stimulation (tVNS). Transcutaneous vagal nerve stimulation (tVNS) may ameliorate symptoms of MCI. The investigators have demonstrated, in patients with epilepsy, that VNS improves memory; however, tVNS has not been used to treat patients with MCI. tVNS can now be performed without surgery by transcutaneous stimulation of the auricular branch with electrodes on the external ear. tVNS has the potential to improve cognition and may even alter the course of decline in patients with MCI. The investigators will employ a multimodal MRI-based neuroimaging approach combined with comprehensive and targeted cognitive testing to assess changes with tVNS in cognition in patients with MCI. The investigators will evaluate the effects of tVNS on patients who have been diagnosed with MCI as well as healthy older controls. Very little in the way of mechanistic data or understanding of individual differences in response to tVNS in MCI/AD has been published. Thus, this is a necessary study to evaluate the potential utility of tVNS to enhance cognitive performance in patients with MCI. These data may serve as a platform for supporting the development of a clinical treatment trial with this technology.
Interventions
Non-invasive stimulation provided by transcutaneous electrical nerve stimulation device at 20Hz, 100 μs pulse width
DEVICESham stimulation
Sham stimulation will be performed using electrodes placed on earlobe
Sponsors
Department of Health and Human Services
National Institute on Aging (NIA)
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Masking description
The sham stimulation experience is very similar to the tVNS stimulation experience. The electrodes are placed in a proximal location. Thus, without knowledge of the anatomy, the participants will be unable to determine which stimulation session is the tVNS one.
Intervention model description
All participants will be assigned to either transcutaneous vagal nerve stimulation or sham for the first session, then switch to the other condition for their second session after a 1 week washout period.
Eligibility
Sex/Gender
ALL
Age
60 Years to 89 Years
Healthy volunteers
Yes
Inclusion criteria
* Diagnosed with amnestic mild cognitive impairment/mild Alzheimer's disease * Preservation of independence in functional abilities * Healthy aged adults without MCI to serve as control group
Exclusion criteria
* Other medical or neurological conditions that may be associated with significant impaired cognition (e..g, moderate to severe traumatic brain injury, epilepsy, etc...) * Vascular dementia or other non-AD spectrum diagnosed neurodegenerative disorders * Significant current depression * Uncorrected vision/hearing loss * Unable to undergo MRI exam
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rey Auditory Verbal Learning Test (Total Delayed Recall) | 30 minutes after administration of 5 list learning trials; 2 minutes to complete delayed recall of word-list | The Rey Auditory Verbal Learning Test (RAVLT) is a verbal learning and memory task with a 15-item word list learned over 5 trials. The total delayed recall score is the number of total correct words recalled (ranging from 0 to 15) after a 30 minute delay. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Initial Sham This group will receive sham stimulation, initially. Participants will be randomized between the two arms of the crossover sessions (initial tVNS vs. initial Sham). Behavioral portions of the testing will then be carried out twice, with at least 72 hours between sessions (to avoid carryover effects).
Transcutaneous vagal nerve stimulation: Non-invasive stimulation provided by transcutaneous electrical nerve stimulation device at 20Hz, 100 μs pulse width
Sham stimulation: Sham stimulation will be performed using electrodes placed on earlobe | 41 |
| Initial tVNS This group will receive transcutaneous vagal nerve stimulation, initially. Participants will be randomized between the two arms of the crossover sessions (initial tVNS vs. initial Sham). Behavioral portions of the testing will then be carried out twice, with at least 72 hours between sessions (to avoid carryover effects).
Transcutaneous vagal nerve stimulation: Non-invasive stimulation provided by transcutaneous electrical nerve stimulation device at 20Hz, 100 μs pulse width
Sham stimulation: Sham stimulation will be performed using electrodes placed on earlobe | 18 |
| Total | 59 |
Baseline characteristics
| Characteristic | Initial Sham | Total | Initial tVNS |
|---|---|---|---|
| Age, Continuous | 75.56 years STANDARD_DEVIATION 7.36 | 75.81 years STANDARD_DEVIATION 7.18 | 75.94 years STANDARD_DEVIATION 6.96 |
| Beck Depression Inventory-2 | 8.32 units on a scale STANDARD_DEVIATION 6.99 | 8.24 units on a scale STANDARD_DEVIATION 6.73 | 8.06 units on a scale STANDARD_DEVIATION 6.32 |
| Clinical Dementia Rating Scale (sum of boxes) | 0.66 units on a scale STANDARD_DEVIATION 1.18 | 0.59 units on a scale STANDARD_DEVIATION 0.99 | 0.44 units on a scale STANDARD_DEVIATION 0.16 |
| Functional Activities Questionnaire | 3.27 units on a scale STANDARD_DEVIATION 3 | 3.15 units on a scale STANDARD_DEVIATION 2.91 | 2.89 units on a scale STANDARD_DEVIATION 2.74 |
| Hopkins Verbal Learning Test (recognition) | 7.37 units on a scale STANDARD_DEVIATION 2.67 | 7.36 units on a scale STANDARD_DEVIATION 2.88 | 7.35 units on a scale STANDARD_DEVIATION 3.41 |
| Hopkins Verbal Learning Test (total delayed recall) | 1.71 units on a scale STANDARD_DEVIATION 2.44 | 1.78 units on a scale STANDARD_DEVIATION 2.58 | 1.94 units on a scale STANDARD_DEVIATION 2.97 |
| Hopkins Verbal Learning Test (total immediate recall) | 17.46 units on a scale STANDARD_DEVIATION 4.61 | 16.88 units on a scale STANDARD_DEVIATION 4.48 | 15.47 units on a scale STANDARD_DEVIATION 3.94 |
| Hopkins Verbal Learning Test (total retention) | 22.62 units on a scale STANDARD_DEVIATION 30.03 | 23.81 units on a scale STANDARD_DEVIATION 33.1 | 26.67 units on a scale STANDARD_DEVIATION 40.44 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 39 Participants | 56 Participants | 17 Participants |
| Sex: Female, Male Female | 21 Participants | 35 Participants | 14 Participants |
| Sex: Female, Male Male | 20 Participants | 24 Participants | 4 Participants |
| Wechsler Test of Adult Reading (standard score) | 112.35 units on a scale STANDARD_DEVIATION 12.11 | 111.9 units on a scale STANDARD_DEVIATION 12.01 | 110.89 units on a scale STANDARD_DEVIATION 12.07 |
| Years of Education | 15.93 years STANDARD_DEVIATION 2.78 | 16.08 years STANDARD_DEVIATION 2.77 | 16.44 years STANDARD_DEVIATION 2.78 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 59 | 0 / 59 |
| other Total, other adverse events | 0 / 59 | 0 / 59 |
| serious Total, serious adverse events | 0 / 59 | 0 / 59 |
Outcome results
Primary
Rey Auditory Verbal Learning Test (Total Delayed Recall)
The Rey Auditory Verbal Learning Test (RAVLT) is a verbal learning and memory task with a 15-item word list learned over 5 trials. The total delayed recall score is the number of total correct words recalled (ranging from 0 to 15) after a 30 minute delay.
Time frame: 30 minutes after administration of 5 list learning trials; 2 minutes to complete delayed recall of word-list
Population: As a crossover design, each participant operated as their own control. Therefore results of data analysis are presented per intervention (i.e., tVNS vs. Sham) rather than per arm (i.e., first tVNS, then Sham, etc.).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sham | Rey Auditory Verbal Learning Test (Total Delayed Recall) | 6.43 score on a scale |
| tVNS | Rey Auditory Verbal Learning Test (Total Delayed Recall) | 7.83 score on a scale |
Comparison: A linear mixed effects model was conducted to account for carryover and order effects in this crossover trial.~Assuming α = 0.05, two-sided test, and 60 participants in total. If the carryover effect is negligible, we will have 90% power to detect an effect size of 0.604 for memory improvementp-value: 0.11Mixed Models Analysis