Mild Cognitive Impairment (MCI), Mild Neurocognitive Disorder, Neurocognitive Disorders, Cognitive Dysfunction, Cognition Disorders
Conditions
Keywords
Aging, Alzheimers, Memory Loss, Mild Cognitive Impairment, Transcranial Magnetic Stimulation, cognitive training
Brief summary
This is a randomized clinical trial of a treatment that combines non-invasive brain stimulation with computerized cognitive training (CCT) for people with mild cognitive impairment (MCI). The form of brain stimulation used in this study is accelerated intermittent theta burst stimulation (iTBS). All participants receive the same amount of iTBS and are randomly assigned to engage in one of two types of CCT. The goals of the study are to see if this combined treatment is feasible and acceptable to people with MCI and whether combined iTBS and CCT improves memory, thinking skills, mood, and daily function.
Detailed description
This is a randomized, sham-controlled trial of combined intermittent theta burst stimulation (iTBS) and computerized cognitive training (CCT) for people with mild cognitive impairment (MCI). The primary objectives of this study are to determine the feasibility, acceptability, and preliminary effect sizes of 3-day combined iTBS+CCT for improving neurocognitive and psychosocial function in MCI.
Interventions
DEVICEAccelerated iTBS
A MagVenture MagPro Transcranial Magnetic Stimulation (TMS) System with Brainsight neuronavigation will be used. All participants will receive active treatment: 12 sessions (3 min each) of iTBS on each of 3 treatment days within an 8-day span. A single session = 600 pulses of 50 Hz iTBS triplets delivered every 200ms in 2s trains repeated every 10s (8s inter-train interval) for 190s. Stimulation intensity is 120% resting motor threshold (rMT) delivered at the left dorsolateral prefrontal cortex. Total pulses = 21,600. Inter-session intervals will be approx. 15 min.
DEVICEComputerized Cognitive Training
CCT will be delivered through the online BrainHQ platform. Participants will engage in adaptive visual speed of processing training during the 15-min breaks between iTBS sessions (11 sessions on each treatment day, total CCT time = 495 min).
DEVICESham Computerized Cognitive Training
Sham CCT will be delivered through the online BrainHQ platform. Participants will engage in non-adaptive control games during the 15-min breaks between iTBS sessions (11 sessions on each treatment day, total sham CCT time = 495 min).
Sponsors
Medical University of South Carolina
National Institutes of Health (NIH)
National Institute on Aging (NIA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Intervention model description
Each participant will be randomized after W0 (pre-treatment assessments) to either active or sham CCT. A random permuted block design (block sizes of 2 and 4) will be used to ensure equal sample sizes of the two groups, with an allocation ratio of 1:1 and stratification by monoclonal antibody (mAB) treatment (i.e., naïve vs. treated, where "treated" refers to either prior or current treatment) to ensure balance across groups in this covariate. All participants will receive the same number of CCT and iTBS sessions per day irrespective of group they are assigned.
Eligibility
Sex/Gender
ALL
Age
60 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Age 60-85 (inclusive). 2. English as a first/primary language. 3. Adequate sensorimotor function and verbal expressive abilities to complete all assessments. 4. Must have a co-participant (e.g. spouse, adult child or relative, sibling, cohabitator, friend, caregiver) who has at least weekly in-person contact with the participant and is willing to participate in the study as a collateral informant. 5. Meets the following requirements for current and prior medications and treatments: 1. Is on fixed pharmacotherapy (i.e. stable dose of medication/s) for ≥ 4 weeks before enrollment. This includes, but is not limited to, cholinesterase inhibitors, NMDA receptor antagonists, and antidepressants. 2. Anti-amyloid monoclonal antibody therapy for AD/MCI: * Prior treatment is permitted if last infusion occurred ≥ 8 weeks before enrollment. * Current treatment is permitted if the dose has been stable for ≥ 12 weeks before enrollment, with no planned dose change during study participation. 3. Prior TMS treatment is permitted if the last stimulation session was ≥ 24 weeks before enrollment. 6. Documented diagnosis of MCI per NIA-AA criteria or Mild Neurocognitive Disorder per DSM-5 criteria by a healthcare provider within the past year, with a presumed etiology of possible or probable AD 7. Met actuarial neuropsychological criteria for MCI43 within the past year (i.e. ≥2 impaired scores within one cognitive domain, or ≥1 impaired scores in ≥3 domains, where an impaired score is defined as ≤16th percentile using appropriate demographically-corrected norms).
Exclusion criteria
1. Telephone Interview for Cognitive Status (TICS) score of ≤ 22 suggestive of dementia. 2. Prior diagnosis of Dementia (NIA-AA) or Major Neurocognitive Disorder (DSM-5). 3. Daily/weekly anticholinergic or sedative use. Stimulants may be allowed pending investigator review. 4. History of significant or unstable condition/s or treatments for these condition/s that may impact cognition (as determined by the study investigators) such as significant cardiac (e.g. heart failure), infectious (e.g. HIV, urinary tract infection), or metabolic disease (e.g. labile diabetes), cancer (e.g. brain cancer, chemotherapy-induced cognitive impairment), severe mental illness (e.g., bipolar disorder, psychoses), alcohol or substance use disorder, developmental disorder (e.g. autism spectrum disorder, intellectual disability), or other neurologic disease (e.g. movement disorder, multiple sclerosis, moderate to severe brain injury, seizures). 5. Plan to initiate treatment for AD/MCI with monoclonal antibody therapy during study participation. 6. For those currently receiving monoclonal antibody therapy, documented history of clinically significant amyloid-related imaging abnormalities (ARIA) in their medical record. 7. Current use of any implanted brain stimulation device. 8. Enrolled in a clinical trial or has received an investigational medication or device in the last 30 days that may impact cognition or mood. 9. MRI contraindications (e.g., ferromagnetic implants, claustrophobia). 10. Unable or unwilling to engage in BrainHQ activities. 11. TMS contraindications (e.g., ferromagnetic implants, conditions or treatments that lower seizure threshold, taking medications that have short half-lives) or no identifiable motor threshold.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Retention | From enrollment to the end of study at week 6 (1-month post-treatment assessment). | Percent of participants who completed all study procedures(i.e., Week 0 pre-treatment assessments, all treatment sessions, and Week 2 and Week 6 follow-up assessments). This will be calculated as a binary count (1=yes, 0=no) of completers divided by the total number of participants. |
| Adherence | On each of the 3 treatment days during Week 1 | Percent of treatment sessions completed. This will be calculated as the number of full iTBS and CCT sessions completed by each participant divided by the prescribed number of sessions. |
| Acceptability | Week 0 (1 week pre-treatment), Week 2 (1 week post-treatment) | Ratings of treatment acceptability on the Theoretical Framework of Acceptability (TFA) Questionnaire. The TFA is a self-report measure on which participants rate their perceptions of treatment acceptability via 5-point Likert-scale ratings on 8 items regarding the following: affective attitude, burden, perceived effectiveness, intervention coherence, self-efficacy, opportunity costs, ethicality, and general acceptability. Item scores will be averaged (ranging from 0-5), with higher scores indicating greater intervention acceptability. |
| Change in NIH Toolbox-Cognition Battery (NIHTB-CB) Fluid Composite | Week 0 (1 week pre-treatment), Week 2 (1 week post-treatment), and Week 6 (4 weeks post-treatment) | The NIHTB-CB is a performance-based, iPad-administered \~30-minute suite of 7 tests that ascertain abilities in different cognitive domains (e.g. executive function, episodic memory, working memory, processing speed, language). It was developed using advanced psychometric techniques to minimize measurement error and produces normed subtest and composite scores. We will use the fully-corrected T-score (range T=0-100; Mean T=50, SD=10; higher scores indicate better cognition) of the Fluid Cognition Composite (normed for age and years of education). |
| Change in Preclinical Alzheimer's Cognitive Composite (Mayo-PACC) Z-score | Week 0 (1 week pre-treatment), Week 2 (1 week post-treatment), and Week 6 (4 weeks post-treatment) | The Mayo-PACC is a composite derived from a brief battery of three neuropsychological tests of verbal episodic memory, processing speed, and semantic fluency. Z-scores will be computed for each test using a cognitively unimpaired normative reference; these will be averaged to create a single composite Z-score (Mean Z=0, SD=1; higher scores indicate better cognition). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Quick Dementia Rating System (QDRS) Total Score | Week 0 (1 week pre-treatment), Week 2 (1 week post-treatment), and Week 6 (4 weeks post-treatment) | The QDRS is an informant-rated measure used to evaluate changes in participants' memory, orientation, and functional abilities on a 5-point scale (0, 0.5, 1, 2, 3). Item scores are summed, and higher scores suggest greater impairment. |
| Change in Informant-rated Everyday Cognition (ECog-II) Scale Total Score | Week 0 (1 week pre-treatment), Week 2 (1 week post-treatment), and Week 6 (4 weeks post-treatment) | The ECog-II scale is an informant-rated questionnaire of change in participants' everyday cognitive and functional abilities in six domains: memory, language, visuospatial function, and executive function. Each item is scored on a 4-point scale (0-"Better or no change", 1-"Questionable/occasionally worse", 2-"Consistently a little worse", 3-"Consistently much worse"). Each item also has an "I don't know" response option, which does not contribute to their score. Item scores will be averaged (range: 0-3), with higher scores indicating greater impairment. |
Countries
United States
Contacts
CONTACTKaitlin Cox
PRINCIPAL_INVESTIGATORStephanie Aghamoosa
Medical University of South Carolina
Outcome results
None listed