Impact of Combined Behavioral Interventions on Cognitive Outcomes in MCI
Phase: NA
Conditions: Mild Cognitive Impairment
Sponsor: University of California, San Diego

Study Protocol and Statistical Analysis Plan 
Document Date: May 4, 2018 
 
 
ID: NPSASA-14-321959 
NCT: 02864069 
    Impact of Combined Behavioral Interventions on Cognitive 
Outcomes in MCI 

SPECIFIC AIMS/HYPOTHESES:  Primary Aim: Compare the efficacy of participating in 
singular [(walking or computer training (CT)] vs. combined (walking and CT) behavioral 
interventions in maintaining/ improving cognitive functioning, quality of life (QOL), and daily 
functioning, in 60 adults with mild cognitive impairment (MCI) or cognitive complaints, ages 
55-80. Primary hypotheses: 1: The combined group will show greater cognitive benefits 
(objective neuropsychological and ecological measures of cognition) 0- and 3-months post-
intervention than either singular intervention group. 2: The combined group will have greater 
QOL benefits (patient and informant self-report) and maintenance of independent functioning 
(Independent Living Scales; ILS, CDR) 0- and 3-months post-intervention than either singular 
intervention group.  Secondary Aim:  Compare any differential cognitive benefits of physical vs. 
cognitive interventions.  Secondary hypothesis:  Walking will result in greatest benefits to 
executive functioning while CT will result in greatest benefits to memory.     
 
EXPERIMENTAL DESIGN AND METHODS:  Participants. We will recruit 60 largely 
sedentary (< 1 hour/week of purposeful aerobic exercise for the past 6 months), though otherwise 
medically healthy, participants with MCI or cognitive complaints, ages 55-80.  Participants will 
be randomized to the walking intervention (n=20), a CT program (n=20), or a combined walking 
and CT intervention (n=20).  Participants will be recruited from the Memory and Aging 
Resilience Center (MARC), the Alzheimer’s Disease Research Center (ADRC) and multiple 
existing studies of aging at the University of California, San Diego (UCSD) who consented to be 
contacted about other studies. We will over-recruit by 10% to account for subject attrition and to 
ensure a final sample size of 60.  These sources should allow for realistic attainment of the 
desired sample size and recruiting from these extant sources is optimal given that many have 
already been screened for general health and gross cognitive status.  Should these recruitment 
avenues be insufficient, however, additional community participants will be recruited. All 
participants will be screened and excluded if they have a history of significant head trauma, other 
neurologic or major psychiatric disorders, known dementia, current substance dependence, or 
any contraindication to increased physical activity.  Participants must also be fluent in English, 
willing to commit to the time requirements of their assigned intervention, and be free of sensory 
or mobility deficits that would interfere with the interventions. Participants not showing 
sufficient adherence to their intervention protocol will be discontinued from the study. If not 
administered by the recruitment source in the last 6-weeks, the Montreal Cognitive Assessment 
(MoCA) and the Clinical Dementia Rating Scale (CDR) will be included in the screening; 
MoCA must be 18-30 and CDR of 0 or 0.5 at entry into the study. Participants cannot be 
engaged in another cognitive training or exercise trial during participation during this 
investigation.  Individuals over age 80 will not be included due to increased risk of mobility 
difficulties and safety concerns in the oldest-old with the walking protocol.  
Procedures: Appropriate individuals who agree to participate will provide informed consent.  
Although participants will be screened for inclusion/exclusion criteria prior to study entry, if 
during the course of any of the following assessments exclusionary information becomes 
available, that participant’s data will not be analyzed.  Dementia is exclusionary at baseline, 
however, if future assessments reveal that a participant has transitioned to dementia, their data 
will be utilized.  We will reduce participant burden and practice effects and maximize use of data 
already available from our recruitment avenues; if participants have undergone 
neuropsychological testing within six weeks of their scheduled baseline assessment, we will 
request their prior test results to use as part of their baseline evaluation and only administer tests 

not previously given. All participants will obtain medical clearance by a physician to participate 
in the protocol and provide basic medical information (including medical history, basic health 
and fitness variables, stroke risk factors, blood pressure, height, weight, and body mass index).  
All participants will undergo neuropsychological assessment on three occasions:  a baseline 
assessment, immediately post-intervention (0-month post), and extended follow-up at 3-months 
post-intervention (3-month post).  Based on prior research, the assessment measures were chosen 
to cover executive functioning and memory, daily functioning, and informant report of 
functioning, in particular.  Ecological measures of cognition are also included to be able to 
determine generalizability and impact on everyday functional skills. The baseline assessment 
will entail a comprehensive neuropsychological exam consisting of measures of global cognitive 
functioning and estimated premorbid intellectual functioning (American National Adult Reading 
Test; ANART) the Wechsler Abbreviated Scale of Intelligence (WASI), language (the Boston 
Naming Test (BNT),  memory (Hopkins Verbal Learning Test (HVLT), executive functioning 
[selected subtests from the Delis Kaplan Executive Functioning System (DKEFS)], 
attention/working memory from WAIS-IV: Symbol Search, and Digit Span, Symbol-Digit 
Modalities Test (SDMT), the CDR, and an ecologically valid assessment of cognitive 
functioning (Rivermead Behavioural Memory Test; RBMT) that will test some skills specifically 
trained in the CT condition (e.g., name learning, and story learning) but also additional untrained 
skills such as prospective memory. We will also administer the ILS, a practical measures of 
functional living skills (Loeb, 1996), the Everyday Cognition Scale (ECog), an informant-based 
questionnaire of everyday cognitive skills with multiple scales covering memory, language, 
visuospatial abilities, executive functioning, and divided attention (Farias et al., 2008), a self-
report measure of mood (the Geriatric Depression Scale), a measure of QOL, the Quality of Life 
Interview-Brief Version [QOLI-Brief (Lehman, Kernan, & Postrado, 1994)], and a self-report 
assessment of current and past physical activity including the Community Health Activities 
Monitoring Program for Seniors (Stewart et al., 2001).   
The walking intervention will begin following baseline assessments and will be continued for 
12 weeks.  The walking group will be given a pedometer (a small, unobtrusive device, clipped to 
a waistband or put in a pocket that saves step data for one week, and should not impede normal 
daily activities) to use daily and log their daily steps, with an identified goal of increasing step 
counts by 3000 steps a day over the course of the intervention.  After obtaining a weeklong 
baseline step count, individuals in the intervention group will be placed on a program to 
progressively increase their step counts by 100 steps daily each week for the first three weeks, by 
200 steps daily for weeks four through six, by 300 steps daily for weeks seven through nine, and 
by 400 steps daily for weeks ten through twelve.  These are cumulative step increases so that 
participants will increase average daily step counts by 3000 steps over the course of the 
intervention. Mean baseline step counts for sedentary older adults in our pilot work were 4150 
per day; therefore, most participants will almost double their daily activity by the end of the 
intervention.  To guide participants and maintain adherence to the study protocol, the study 
coordinator will contact the participants weekly to discuss activity logs and adjust step goals.  
The study coordinator will also be available via phone throughout the study to answer questions 
that may arise.   
In the CT condition, participants will use Brain HQ, a computer cognitive training program 
(Posit Science Corporation,San Francisco, CA), shown to be well tolerated by older adults with 
positive short and long-term cognitive outcomes (Rebok et al., 2014; Smith et al., 2009).   
Participants will complete 6 Brain HQ modules:  ‘To Do List Training,’ dedicated to verbal 

memory, ‘Syllable Stacks,’ a working memory module, ‘Divided Attention,’ ‘Mixed Signals,’ 
targeting inhibition, ‘In the Know,’ for story learning, and ‘Face Facts,’ for name learning.  
Participants will use the program 60 minutes/day, 5 days/week for 12 weeks.  They will receive a 
brief introduction to the program on site at the MARC (log-in, which modules to complete, and 
how long to spend each day on CT).  These instructions will then be repeated via phone once the 
participant is on their home computer and can be supplemented by an in-home visit if significant 
technological difficulties exist.  If participants do not have a home computer/internet access, they 
can complete the modules at another location such as a public library, senior center, or at the 
MARC, but training will still be self-directed.  Brain HQ offers a secure clinician portal that 
allows for monitoring of usage and progress of participants but the study coordinator will still be 
in weekly phone contact with participants to discuss activity logs and answer any questions.   
The combined condition will concurrently follow both the walking and the CT programs as 
described above.    
STATISTICAL ANALYSES:  Assuming a one tailed test, a medium effect size with power of .7 
can be obtained with the sample size of 20 per group.  The groups will be compared on baseline 
characteristics, including program adherence, using t-tests and χ2 and analyses will be adjusted to 
account for any observed group differences. Lifestyle covariates such as health, prior physical 
activity, mood, and education will also be explored and used as appropriate.  We will employ 
reliable change analyses to take into account change in neuropsychological test scores over the 
course of the intervention while also accounting for predicted practice effects.  To address the 
primary hypothesis, group comparisons of changes in neuropsychological test scores and 
measures of daily functioning between the groups will be determined via ANCOVA and 
repeated measures analyses.  For the CT condition in particular, we will examine whether any 
cognitive benefits generalize beyond the trained task.  To address the secondary hypothesis, we 
will use logistic regression to determine the degree to which intervention group predicts 
differential cognitive outcomes. Correlations between neuropsychological test scores and health 
and fitness variables will also be explored.