Dementia, Mild Cognitive Impairment
Conditions
Keywords
dementia, Mild Cognitive Impairment (MCI), RTMS, CVLT
Brief summary
The purpose is to is to study if repetitive transcranial magnetic stimulation (rTMS) improves cognitive function in patients with neurodegenerative conditions which may manifest as mild to moderate cognitive impairment and, in late phase, dementia. This study also intends to investigate if the responses to rTMS intervention are either positively or negatively correlated with the initial severity of cognitive impairment.
Detailed description
The primary hypothesis is that rTMS applied to the dorsolateral prefrontal cortex will lead to improved memory, language and executive function compared to patients who receive a sham, control treatment. The improvement is defined as having higher performance on the California Verbal Learning Test (CVLT-II). Secondary Hypotheses are that: * 1: rTMS- will lead to higher performance on secondary cognitive measures relating to executive function and naming compared to performance by participants in the sham treatment group at the termination of treatment; and that * 2: rTMS-induced memory improvement parallels changes in serum and cerebrospinal fluid (CSF) brain-derived neurotrophic factor (BDNF) levels after treatment.
Interventions
DEVICERTMS
stimulation of the brain with magnetic pulses
DEVICEsham
sham noise to block the sound of stimulation
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
55 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* Veterans aged 55 years or older * Diagnosed with Mild Cognitive Impairment (MCI) or dementia likely due to Alzheimer's disease. * Ability to obtain a Motor Threshold, determined during the screening process. * With an adequately stable condition and living environment to enable attendance at scheduled clinic visits. * If on a prescription medication for cognition that medication dose will be stable for at least 4 weeks prior to randomization into the study and participant will be willing to remain on a stable regimen during the acute treatment phase. * Able to read, verbalize understanding, and voluntarily sign the Informed Consent Form to be signed by the participant, or a designated legal representative when the participant lacks decision making capacity prior to participating in any study- specific procedures or assessments.
Exclusion criteria
* Patients with prior exposure to rTMS or electroconvulsive therapy (ECT). * Unable to safely withdraw, at least two weeks prior to treatment commencement, from medications that substantially increase the risk of having seizures. * Have a cardiac pacemaker or a cochlear implant. * Have an implanted device deep brain stimulation or metal in the brain * Current substance abuse not including caffeine or nicotine as determined by patient report or chart review. * Active current suicidal intent or plan as determined by patient report or chart review. * Current or Prior history of a seizure disorder as determined by patient report or chart review * Traumatic brain injury within the last two months * Participation in another concurrent interventional clinical trial * Known current psychosis as determined by patient report or chart review. * Current or prior history of a mass lesion, cerebral infarct or other non-cognitive, active central nervous system (CNS) disease that would increase the risk for seizure. * Not fluent in English or a hearing impairment severe enough to impair comprehension
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes From Baseline CVLT Scores After Treatment and 4 Month Later | Assessed at baseline, end of treatment, and 4-month post-treatment follow up | Changes of California verbal learning test scores (CVLT) from baseline after treatment and 4 months later. CVLT is 16 points scoring system. (minimum=0, maximum=16, higher the better memory). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Plasma BDNF Levels After Treatment | within a week following the last treatment session and 4 months later | Changes in BDNF plasma levels (pg/ml) from baseline were analyzed after treatment. BDNF is a plasma biomarker, minimum=0, no maximum. Higher number means more BDNF synthesis). |
| Changes in Animal Fluency After Treatment and 4 Months Later | Assessed at baseline, end of treatment, and 4-month post-treatment follow up | Animal Fluency (AF) is a scoring system to assess the ability to generate a list of related words. The score is the number of animals the examinee can name in one minute time. (Minimum = 0, No maximum, higher the better). |
| Changes in Boston Naming After Treatment | Assessed at baseline, end of treatment, and 4-month post-treatment follow up | Changes in Boston Naming Test (BNT) from baseline was analyzed. BNT is a 60 points scoring system. (minimum=0, maximum=60, higher the better). |
| Brief Visual Memory Test (BVMT) | assessed at baseline, end of treatment and 4-month post-treatment follow up | A piece of paper with 6 simple drawings is presented to the subject for 10 seconds. The subject is then asked to draw these drawings from memory. The process is repeated three times to assess visual memory and learning. Each correct drawing scores two pints. Maximum score for three trials is 36. Minimum score is 0. Higher the better. |
| Montreal Cognitive Assessment (MoCA) | Assessed at baseline, end of treatment, and 4-month post-treatment follow up | MoCA is a one page, 30 point cognitive screening test. It test the following cognitive domains: 1. short-term memory (5 points)- two learning trials of five nouns and delayed recall after approximately five minutes. 2. visuospatial abilities - clock-drawing task (3 points) and copy a cube (1 point). 3. executive functions - alternation task abbreviated trail-making B (1 point), and a two-item verbal abstraction task (2 points). 4. attention, concentration, and working memory - a sustained attention task (target detection using tapping; 1 point), a serial subtraction task (3 points), and digits forward and backward (1 point each). 5. language - three-item confrontation naming (3 points), repetition of two sentences (2 points), and verbal fluency (1 point). 6. abstract reasoning - describe the similarity of tasks (2 points). 7. orientation to time and place (6 points). Minimum score: 0. Maximum score: 30. Higher the better. |
| Changes in Trail Making B Test Score After Treatment and 4 Months Later | Assessed at baseline, end of treatment, and 4-month post-treatment follow up | Trail making B is a scoring system for the assessment of the mental flexibility, processing speed and executive function. The score is the time (in seconds) it takes for the examinee to draw line segments connecting sequentially from 1-A-2-B-3....all the way to12-L-13. (The lower score means faster speed and means better performance. The minimum is (hypothetically) zero. There is no maximum. However, in some test centers, the maximum allowed time is 200 seconds. |
Countries
United States
Participant flow
Recruitment details
Two hundred and twenty nine patients were screened. 43 patients signed consent. 32 were enrolled.
Pre-assignment details
Thirty two patients were enrolled.
Participants by arm
| Arm | Count |
|---|---|
| RTMS repetitive transcranial magnetic stimulation
RTMS: stimulation of the brain with magnetic pulses | 14 |
| Sham sham noise to block the sound of treatment
sham: sham noise to block the sound of stimulation | 18 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | RTMS | Sham | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 12 Participants | 13 Participants | 25 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 5 Participants | 7 Participants |
| Age, Continuous | 71.4 years STANDARD_DEVIATION 7.4 | 70.4 years STANDARD_DEVIATION 7.7 | 70.8 years STANDARD_DEVIATION 7.5 |
| neuropsychological testing | 14 Participants | 18 Participants | 32 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 12 Participants | 22 Participants |
| Region of Enrollment United States | 14 Participants | 18 Participants | 32 Participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 14 Participants | 17 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 18 |
| other Total, other adverse events | 0 / 14 | 0 / 18 |
| serious Total, serious adverse events | 1 / 14 | 2 / 18 |
Outcome results
Primary
Changes From Baseline CVLT Scores After Treatment and 4 Month Later
Changes of California verbal learning test scores (CVLT) from baseline after treatment and 4 months later. CVLT is 16 points scoring system. (minimum=0, maximum=16, higher the better memory).
Time frame: Assessed at baseline, end of treatment, and 4-month post-treatment follow up
Population: Sham arm: 18 started, 2 withdrew, 3 did not test properly at baseline, 1 did not show for follow up.~13 sets of data were available at baseline, 13 sets were available at end of treatment, 12 sets were available at follow up. Active arm: 14 started, one withdrew, one did not show for follow up. 13 sets of data were available at baseline, 13 sets were available at end of treatment, 12 sets were available at follow up.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RTMS | Changes From Baseline CVLT Scores After Treatment and 4 Month Later | Baseline | 8.5 score on a scale | Standard Deviation 4.6 |
| RTMS | Changes From Baseline CVLT Scores After Treatment and 4 Month Later | End of treatment | 8.6 score on a scale | Standard Deviation 4.3 |
| RTMS | Changes From Baseline CVLT Scores After Treatment and 4 Month Later | 4 month follow up | 10.1 score on a scale | Standard Deviation 4.1 |
| Sham | Changes From Baseline CVLT Scores After Treatment and 4 Month Later | Baseline | 9.4 score on a scale | Standard Deviation 3.8 |
| Sham | Changes From Baseline CVLT Scores After Treatment and 4 Month Later | End of treatment | 8.3 score on a scale | Standard Deviation 3.7 |
| Sham | Changes From Baseline CVLT Scores After Treatment and 4 Month Later | 4 month follow up | 9.2 score on a scale | Standard Deviation 4.2 |
Secondary
Brief Visual Memory Test (BVMT)
A piece of paper with 6 simple drawings is presented to the subject for 10 seconds. The subject is then asked to draw these drawings from memory. The process is repeated three times to assess visual memory and learning. Each correct drawing scores two pints. Maximum score for three trials is 36. Minimum score is 0. Higher the better.
Time frame: assessed at baseline, end of treatment and 4-month post-treatment follow up
Population: Sham arm: 18 started, 2 withdrew, 3 did not test properly at baseline, 1 did not show for follow up.~13 sets of data were available at baseline, 13 sets were available at end of treatment, 12 sets were available at follow up. Active arm: 14 started, one withdrew, one did not show for follow up. 13 sets of data were available at baseline, 13 sets were available at end of treatment, 12 sets were available at follow up.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RTMS | Brief Visual Memory Test (BVMT) | Baseline | 18.9 score on a scale | Standard Deviation 9 |
| RTMS | Brief Visual Memory Test (BVMT) | End of treatment | 19.4 score on a scale | Standard Deviation 8.7 |
| RTMS | Brief Visual Memory Test (BVMT) | 4 month follow up | 18.8 score on a scale | Standard Deviation 7.5 |
| Sham | Brief Visual Memory Test (BVMT) | Baseline | 17.4 score on a scale | Standard Deviation 6.4 |
| Sham | Brief Visual Memory Test (BVMT) | End of treatment | 17.2 score on a scale | Standard Deviation 7.3 |
| Sham | Brief Visual Memory Test (BVMT) | 4 month follow up | 16.6 score on a scale | Standard Deviation 7 |
Secondary
Changes in Animal Fluency After Treatment and 4 Months Later
Animal Fluency (AF) is a scoring system to assess the ability to generate a list of related words. The score is the number of animals the examinee can name in one minute time. (Minimum = 0, No maximum, higher the better).
Time frame: Assessed at baseline, end of treatment, and 4-month post-treatment follow up
Population: Sham arm: 18 started, 2 withdrew, 3 did not test properly at baseline, 1 did not show for follow up.~13 sets of data were available at baseline, 13 sets were available at end of treatment, 12 sets were available at follow up. Active arm: 14 started, one withdrew, one did not test properly at end of treatment, one did not show for follow up.~13 sets of data were available at baseline, 12 sets were available at end of treatment, 12 sets were available at follow up.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RTMS | Changes in Animal Fluency After Treatment and 4 Months Later | baseline | 17.8 units on a scale | Standard Deviation 6.6 |
| RTMS | Changes in Animal Fluency After Treatment and 4 Months Later | end of treatment | 15.6 units on a scale | Standard Deviation 4.9 |
| RTMS | Changes in Animal Fluency After Treatment and 4 Months Later | 4 month followup | 15.8 units on a scale | Standard Deviation 5.4 |
| Sham | Changes in Animal Fluency After Treatment and 4 Months Later | baseline | 15.8 units on a scale | Standard Deviation 3.4 |
| Sham | Changes in Animal Fluency After Treatment and 4 Months Later | end of treatment | 16.8 units on a scale | Standard Deviation 3 |
| Sham | Changes in Animal Fluency After Treatment and 4 Months Later | 4 month followup | 16.9 units on a scale | Standard Deviation 5.1 |
Secondary
Changes in Boston Naming After Treatment
Changes in Boston Naming Test (BNT) from baseline was analyzed. BNT is a 60 points scoring system. (minimum=0, maximum=60, higher the better).
Time frame: Assessed at baseline, end of treatment, and 4-month post-treatment follow up
Population: Sham arm: 18 started, 2 withdrew, 3 did not test properly at baseline, 1 did not show for follow up.~13 sets of data were available at baseline, 13 sets were available at end of treatment, 12 sets were available at follow up. Active arm: 14 started, one withdrew, one did not show for follow up. 13 sets of data were available at baseline, 13 sets were available at end of treatment, 12 sets were available at follow up.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RTMS | Changes in Boston Naming After Treatment | baseline | 52.7 units on a scale | Standard Deviation 12.4 |
| RTMS | Changes in Boston Naming After Treatment | End of treatment | 52.8 units on a scale | Standard Deviation 13.2 |
| RTMS | Changes in Boston Naming After Treatment | 4 month followup | 54.4 units on a scale | Standard Deviation 13.1 |
| Sham | Changes in Boston Naming After Treatment | baseline | 53.7 units on a scale | Standard Deviation 8.3 |
| Sham | Changes in Boston Naming After Treatment | End of treatment | 56.5 units on a scale | Standard Deviation 3.6 |
| Sham | Changes in Boston Naming After Treatment | 4 month followup | 55.0 units on a scale | Standard Deviation 5.3 |
Secondary
Changes in Plasma BDNF Levels After Treatment
Changes in BDNF plasma levels (pg/ml) from baseline were analyzed after treatment. BDNF is a plasma biomarker, minimum=0, no maximum. Higher number means more BDNF synthesis).
Time frame: within a week following the last treatment session and 4 months later
Population: Sham arm: 18 started, 13 had baseline BDNF collected, two withdrew. 13 sets of data were available at baseline, 11 sets of data were available at end of treatment. Active arm: 14 started, two did not have BDNF collected. 12 sets of data were available at baseline and at end of treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RTMS | Changes in Plasma BDNF Levels After Treatment | baseline | 5089 pg/ml | Standard Deviation 3508 |
| RTMS | Changes in Plasma BDNF Levels After Treatment | post treatment | 5229 pg/ml | Standard Deviation 3713 |
| Sham | Changes in Plasma BDNF Levels After Treatment | baseline | 5054 pg/ml | Standard Deviation 3440 |
| Sham | Changes in Plasma BDNF Levels After Treatment | post treatment | 5350 pg/ml | Standard Deviation 4981 |
Secondary
Changes in Trail Making B Test Score After Treatment and 4 Months Later
Trail making B is a scoring system for the assessment of the mental flexibility, processing speed and executive function. The score is the time (in seconds) it takes for the examinee to draw line segments connecting sequentially from 1-A-2-B-3....all the way to12-L-13. (The lower score means faster speed and means better performance. The minimum is (hypothetically) zero. There is no maximum. However, in some test centers, the maximum allowed time is 200 seconds.
Time frame: Assessed at baseline, end of treatment, and 4-month post-treatment follow up
Population: Sham arm: 18 started, 2 withdrew, 3 did not test properly at baseline, 1 did not show for follow up.~13 sets of data were available at baseline, 13 sets were available at end of treatment, 12 sets were available at follow up. Active arm: 14 started, one withdrew, one did not show for follow up. 13 sets of data were available at baseline, 13 sets were available at end of treatment, 12 sets were available at follow up.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RTMS | Changes in Trail Making B Test Score After Treatment and 4 Months Later | baseline | 187.5 Seconds | Standard Deviation 222.2 |
| RTMS | Changes in Trail Making B Test Score After Treatment and 4 Months Later | end of treatment | 179.8 Seconds | Standard Deviation 207.7 |
| RTMS | Changes in Trail Making B Test Score After Treatment and 4 Months Later | 4 month followup | 185.8 Seconds | Standard Deviation 237.8 |
| Sham | Changes in Trail Making B Test Score After Treatment and 4 Months Later | baseline | 172.8 Seconds | Standard Deviation 94.8 |
| Sham | Changes in Trail Making B Test Score After Treatment and 4 Months Later | end of treatment | 150.4 Seconds | Standard Deviation 64.9 |
| Sham | Changes in Trail Making B Test Score After Treatment and 4 Months Later | 4 month followup | 197.6 Seconds | Standard Deviation 204.9 |
Secondary
Montreal Cognitive Assessment (MoCA)
MoCA is a one page, 30 point cognitive screening test. It test the following cognitive domains: 1. short-term memory (5 points)- two learning trials of five nouns and delayed recall after approximately five minutes. 2. visuospatial abilities - clock-drawing task (3 points) and copy a cube (1 point). 3. executive functions - alternation task abbreviated trail-making B (1 point), and a two-item verbal abstraction task (2 points). 4. attention, concentration, and working memory - a sustained attention task (target detection using tapping; 1 point), a serial subtraction task (3 points), and digits forward and backward (1 point each). 5. language - three-item confrontation naming (3 points), repetition of two sentences (2 points), and verbal fluency (1 point). 6. abstract reasoning - describe the similarity of tasks (2 points). 7. orientation to time and place (6 points). Minimum score: 0. Maximum score: 30. Higher the better.
Time frame: Assessed at baseline, end of treatment, and 4-month post-treatment follow up
Population: Sham arm: 18 started, 2 withdrew, 3 did not test properly at baseline, 1 did not show for follow up.~13 sets of data were available at baseline, 13 sets were available at end of treatment, 12 sets were available at follow up. Active arm: 14 started, one withdrew, two did not test properly at end of treatment, one did not show for follow up.~13 sets of data were available at baseline, 11 sets were available at end of treatment, 12 sets were available at follow up.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RTMS | Montreal Cognitive Assessment (MoCA) | baseline | 22.4 score on a scale | Standard Deviation 6.1 |
| RTMS | Montreal Cognitive Assessment (MoCA) | end of treatment | 22.0 score on a scale | Standard Deviation 6 |
| RTMS | Montreal Cognitive Assessment (MoCA) | 4 month follow up | 24.8 score on a scale | Standard Deviation 6.2 |
| Sham | Montreal Cognitive Assessment (MoCA) | baseline | 24.3 score on a scale | Standard Deviation 3 |
| Sham | Montreal Cognitive Assessment (MoCA) | end of treatment | 24.1 score on a scale | Standard Deviation 3.9 |
| Sham | Montreal Cognitive Assessment (MoCA) | 4 month follow up | 24.7 score on a scale | Standard Deviation 4.4 |