Successful Aging and Enrichment (SAGE): Effects of Environmental Stimulation on Cognitive Health and Neuroplasticity
Phase: NA
Conditions: Cognitive Health, Healthy Aging
Sponsor: Brigham and Women's Hospital

 
 
 
 
 
 
Title: Successful Aging and Enrichment (SAGE): Effects of Environmental Stimulation 
on Cognitive Health and Neural Plasticity 
 
Last Updated: 06/04/2014 
NCT: Not available 

1 
Detailed Protocol: SAGE 
 
Version Date: 06/04/2014 
Detailed Protocol 
 
Successful Aging and Enrichment (SAGE): Effects of Environmental Stimulation  
on Cognitive Health and Neural Plasticity 
 
 
Background and Significance   
 
Increasing numbers of individuals are living into old age [1-3]. According to a recent UN report (2007), 
individuals over the age of 60 are the fastest growing age group on earth. They currently account for 700 
million people around the world. By 2050, the numbers are expected to grow to 2 billion. The number of 
individuals projected to become demented is proportional to the growth in the aging population. Today 
around 25 million people suffer from dementia, a disease that is relatively rare before the age of 65. 
After 65, the proportion of demented persons in the population doubles every five years until 90+, when 
approximately half of that population suffers from this syndrome. The global cost of dementia care in 
2009 has been estimated to $421.6 billion [4]. If nothing can be done to prevent, cure, or at least delay 
the incidence of dementia, the resources to take care of all demented individuals will constitute an 
enormous burden for many countries. Advancing our knowledge about factors that contribute to 
cognitive health among the elderly is thus both an important and urgent task. Models developed by 
Brookmeyer and colleagues [5] suggest that an intervention that could delay the mean onset of 
Alzheimer’s Disease (AD) by ~5 years would lead to a 50% reduction in incident rates. Even a 1 year 
delay would be associated with a 10% reduction in incidence. 
 
A large number of epidemiological studies have found that an active lifestyle contributes to cognitive 
health across the lifespan [6]. The protective factors reported include intellectual and physical 
enrichment activities; social activities and networks; awareness and concentration (mindfulness) 
practices; and cognitive activity. Some studies have indicated that these types of activities may also have 
a positive effect when performed late in life. Critics, however, claim that associations from 
epidemiological studies do not constitute a sound basis for conclusions about causality.  
 
In 2010, a systematic review of potential factors that might prevent cognitive decline indicated that the 
quality of evidence was low for all reported factors, except for cognitive training, the main reason being 
lack of experimental validation in human studies [7]. More recently, one experimental study in humans 
found that physical exercise had positive effects on BDNF, an important marker of neural plasticity and 
cognitive health [8].  
 
 A common model to explain the possible effect of environmental stimulation on cognitive health 
involves its impact on reserve capacity [6, 9]. The basic idea is that a brain that has received more 
stimulation will have richer neural networks and greater capacity to develop new neural connections 
with learning (i.e., the stimulated brain will be more plastic). Another implication is that loss of function 
of part of a brain (e.g., due to underlying neurodegenerative disease, stroke, or trauma) can more easily 
be compensated for. On a cognitive level, reserve could also facilitate the development of alternative 
processing strategies or behaviors to compensate for difficulties in a particular area. 
 
The evidence that physical stimulation, mental stimulation, and awareness (mindfulness) training may 
have beneficial effects on the brain and cognition is reviewed below. 
 

2 
Detailed Protocol: SAGE 
 
Version Date: 06/04/2014 
Physical Activity 
 
Studies of animals have indicated that exercise promotes neurogenesis and synaptogenesis. Exercise up-
regulates the production of brain derived neurotrophic factor (BDNF) [10, 11]. BDNF is believed to help 
induce neurogenesis and promote survival and/or neuronal differentiation. It has also been linked to 
long-term potentiation necessary for memory formation. A Cochrane Database System Review [12] 
noted that 8 out of 11 randomized controlled exercise intervention studies reported that structured 
aerobic exercise interventions resulted in increased cardiorespiratory fitness of the intervention group, 
with an average improvement of approximately 14%. This improvement was associated with better 
performance on cognitive functions, including auditory attention (effect size 0.52), speed of information 
processing (effect size 0.26), and visual attention (effect size 0.26).  
 
Physical activity and exercise has been associated with the enhancement of cognitive and brain function, 
and with a reduced risk for clinical dementia [13-22]. A recent review article published in Nature 
Reviews: Neuroscience [23] concluded that physical activity improved cognition in both normal older 
adults and patients with early AD. Although benefits were seen for a range of cognitive functions, there 
appeared to be disproportionate improvement in executive control (including planning, working 
memory, and multi-tasking). Particularly intriguing are the exercise intervention studies that have 
looked at effects on not only cognition but also underlying brain structure and activity. For instance, in a 
study reported by Colcombe and colleagues [24], older individuals who participated in an aerobic 
training group exhibited significant increases in the size of components of the prefrontal cortex and 
superior temporal lobes. In another study by the same researchers [25], more physically fit older 
subjects as well as those randomly assigned to participate in the aerobic fitness training group 
performed better on an attention task (more efficient response to conflicting cues on a flanker task). 
Moreover, functional magnetic resonance imaging (fMRI) revealed that older subjects exhibited greater 
neural activity in regions associated with attentional control (middle and superior frontal gyrus, superior 
parietal lobule) and less activity in the anterior cingulate cortex. 
 
Cognitive Stimulation 
 
There have been numerous studies comparing animals placed in “enriched” versus standard 
environments. An enriched environment often means a cage filled with potentially interesting objects 
and structures to explore. The opportunity for aging animals to interact with a more complex 
environment appears to influence neurogenesis , dendritic complexity, the capacity to compensate for 
injury, and and promotes cognitive abilities and the capacity to compensate for injury [26-30].  
 
Morphometric MRI studies of the human brain have provided evidence that cognitive activity or training 
alters brain morphology of relevant structures, leading to an increase in cortical thickness. For example, 
comparisons of the MRIs of individuals learning to juggle versus those of control subjects reveal an 
increased size of bilateral mid-temporal grey matter and left posterior intra-parietal sulcus, structures 
associated with the visual processing of movement [31]. Similarly, comparisons of the MRIs of licensed 
London taxi drivers versus control subjects reveal increased volume of the posterior hippocampus 
believed to help mediate spatial memory  [32]. fMRI has been used to examine the impact of cognitive 
training on older adults. For example, Erickson and colleagues [33] conducted a randomized, 
longitudinal dual-task training study in older subjects. They found that training improved task 
performance and was associated with an increase in asymmetric hemispheric activation (increase in left 
and decrease in right hemisphere activity within the ventral lateral prefrontal cortex (PFC), and a 

3 
Detailed Protocol: SAGE 
 
Version Date: 06/04/2014 
decrease in age-related differences in the pattern of prefrontal activation). Logan and colleagues [34] 
found that training that emphasized semantic elaboration during a memory encoding task led to 
improved performance of older subjects. This was associated with increased activity of the PFC 
(especially the left ventral region), which, compared to young subjects, had been under-recruited at 
baseline, prior to training. Both studies suggest that the aging brain can exhibit plasticity that may be 
influenced by training and intervention programs. 
 
Formal cognitive training has been shown to improve measures of intellectual performance. For 
example, in a study by Ball and colleagues [35], older individuals (65-94 years old) were randomly 
assigned to one of three training groups for memory (verbal episodic memory), reasoning (problem-
solving that follows a serial pattern), or speed of processing (visual search and identification), or to a 
control group. The initial intervention improved performance relative to baseline; however the 
improvement was limited to the cognitive realm that had been targeted. Improvements lasted through 
the 2 years of follow-up. Other studies also have supported the potential benefit of cognitive training in 
older adults  [22, 36, 37]. Recently, there has been some evidence of transfer of improvement beyond 
the specific cognitive activity that was trained, especially when the training was directed at working 
memory and executive control [38-40]. 
 
Mindfulness Meditation 
 
The literature indicates that there are two types of mindfulness. Each is comprised of pragmatic 
practices and psychological orientations. In relation to both types of mindfulness, Jon Kabat-Zinn refers 
to the pragmatic aspects of mindfulness as a “scaffolding” used to support the psychological 
orientations of mindfulness [41]. 
 
The first type of mindfulness is derived from ancient contemplative traditions (e.g., Buddhist meditation 
practices) [42]. Pragmatically, this first type can include the practice of taking a seated posture with the 
eyes closed or partially open, the practice of walking, or another pedestrian task, while silently focusing 
on observing somatic sensation, sensory stimuli (sound, smell), breath, mental activity, or emotional 
activity [43, 44]. The psychological orientation during this pragmatic practice is described by Kabat-Zinn 
as “paying attention in a particular way: on purpose, in the present moment, and non-judgmentally to 
the unfolding of experience moment to moment” [45].  There is no attempt to alter perception, just to 
direct attention . 
 
The second type of mindfulness has been pioneered by Ellen Langer and is concerned with shifting 
perspective, or “reperceiving” [46]. The pragmatic practice for this type of mindfulness is outward 
focused: one observes a person, thing, or idea. Psychologically, one is still oriented to non-judgment and 
moment-to-moment awareness, but, in addition, one is oriented to experience the person, place, or 
idea in novel ways [47]. 
 
There are several other integral components of psychological orientation in both forms of mindfulness. 
One is non-striving: instead of choosing a goal-oriented or competitive mindset, one cultivates an 
attitude of patience, compassion, and acceptance for what is happening in the present moment. Also, 
instead of a discriminating mindset, one chooses a mindset of inclusive curiosity [46].  Instead of seeking 
to avoid unpleasant experience or retain pleasant experiences, all experiences are seen as equally 
valuable [48]. We aim to include aspects of all of these components and practices in our mindfulness 
intervention.  

4 
Detailed Protocol: SAGE 
 
Version Date: 06/04/2014 
There is evidence of the impact of mindfulness practice on attentional control and mental efficiency [49-
54]. Both intervention and comparison studies of long-term meditators vs. non-meditators suggest that 
mindful meditation may alter brain structure and physiology [49-51, 55-61]. The literature also supports 
the feasibility of mindfulness training in older adults [62, 63]. 
 
To the best of our knowledge, the proposed study would be the first to experimentally compare the 
impact of different types of structured training programs on markers of cognitive and brain health in 
older adults. 
 
Relevant Previous Research by the Project’s Investigators 
 
The proposed research is a collaborative effort between Linnaeus University, Vaxjo, Sweden and the 
Brigham and Women’s Hospital, Boston MA. It brings together researchers who have been investigating 
different aspects of cognitive aging. 
 
The proposed studies parallel on-going research at Sweden’s Karolinska Institutet Alzheimer’s Disease 
Research Center (KI-ADRC), headed by Bengt Winblad. Ann-Charlotte Granholm and Abdul Mohammed  
have previously cooperated on studies concerning the role of BDNF on cognitive function in older 
animals. Their previous findings from experimental studies on rats showed that environmental stimuli 
can have a positive impact on brain anatomy, behavior, and learning ability [64-66]. Environmental 
stimulation increased levels of BDNF [65, 67] in the hippocampus and cortex, two brain regions critically 
involved in cognitive functioning.  Environmentally induced elevation of BDNF levels in experimental 
animals was related to enhanced spatial learning [66, 68]. It is unclear whether environmental 
stimulation in humans modifies neurotrophin levels or cognitive functioning.  In humans, various types 
of stimulation are being considered as prime candidates (e.g., physical exercise and [69] cognitive 
stimulation [70]). However, which type of stimulation is most effective and whether the effects can be 
observed in elderly persons is unknown. 
 
Bengt Winblad has reported that people with higher education are less likely to suffer from dementia 
[71], which has been interpreted as resulting from long-term intellectual stimulation. Moreover, such 
findings are consistent with the model of “cognitive reserve”, which holds that capacities, in particular 
brain-involved capacities, that developed over time serve to mitigate negative effects of age- and 
disease-related changes in the brain. It was also found that individuals who had been living with another 
person as part of a relationship had lower risk of dementia in later life [72], which can be interpreted as 
a result of social and perhaps even intellectual stimulation. However, since both of these results come 
from epidemiological studies, we cannot ascertain a causal link with cognitive health. Even less can be 
said about possible functional factors behind this association. For example, is the cognitive health 
benefit associated with a long-term relationship due to the intellectual challenges of taking into account 
the views and needs of a partner? Or is the cognitive benefit due to the social/emotional consequences 
of living with someone? 
 
The Laboratory of Healthy Cognitive Aging at BWH under the direction of Kirk Daffner has investigated 
curiosity (attention to the novel aspects of one's environment) and cognitive reserve in normal aging 
and neurological disease [73-82].  His lab has demonstrated that successful cognitive aging is strongly 
associated with increased engagement by novel stimuli, as measured by electrophysiological (event-
related potentials) and behavioral markers [74]. The difference between high and average cognitive 
performers in attention to novelty increases with age [74]. However, even among cognitively successful 

5 
Detailed Protocol: SAGE 
 
Version Date: 06/04/2014 
older adults (individuals in their upper 80s and 90s), cognitive resources may be insufficient to 
compensate for age-associated neural changes [81]. Greenwood and Parasuraman have argued that 
exposure to novelty, requiring the brain to adapt to changing demands, serves as a key factor in 
promoting brain plasticity and cognitive integrity [83]. 
 
If interest in novelty is both a marker and promoter of cognitive health, it is critical to determine if this 
process can be influenced through structured interventions involving cognitively stimulating activities, 
physical exercise, or mindfulness training. To our knowledge, the proposed study would be the first to 
systematically test this possibility. 
 
Finally, work at BWH by Farzaneh Sorond has utilized transcranial doppler (TCD) studies to examine 
cerebral blood flow responses in healthy older adults [84-86]. TCD can determine the extent to which 
subjects are capable of enhancing cerebral blood flow in response to cognitive demands and whether 
these responses can be altered by experimental interventions. Neurovascular coupling reflects the link 
between regional synaptic activity and regional cerebral blood flow. Under normal conditions, cerebral 
blood flow and cerebral metabolic rate are coupled, with an increase in metabolic demand leading to an 
increase in blood flow. Dr. Sorond’s lab has shown that compared to fast walking elders, those who are 
slow walkers exhbit impaired neurovasuclar coupling [84]. Another study demonatrated that the pattern 
of blood flow velocities in anterior and posterior circulations differ between healthy old and young 
subjects [85]. A recently published report indicated a strong link between neurovascular coupling and 
cogntive performance in older adults. In individuals with baseline impairments, there was improvementt 
in neurovascular coupling and cognitive funtion with regular cocoa consumption, which may be due to 
its antioxidant, anti-inflammatory, or cholinergic properties [86]. 
 
In summary, the current project engages experts from major research institutions that represent 
different perspectives (biological, pharmacological, psychological, clinical and epidemiological) and who 
bring experience using different methodological approaches,. The composition of this research team 
should facilitate an interdisciplinary approach to study factors of importance for maintaining brain 
health in later life. Together, we have published over 1,000 articles in the field. 
 
Specific Aims 
 
The overarching goal of the current study is to identify factors that promote neural plasticity and 
cognitive health in elderly persons.  
 
The specific aims address the impact of different types of structured mental or physical stimulation over 
a 5 week training period on the following:  
 
1. Biological markers of brain plasticity (e.g., BDNF) 
2. Electrophysiologic markers (event-related potentials) of neural efficiency and capacity 
3. Neuropsychological markers of cognitive performance 
4. Vascular markers of cerebral health (e.g., neurovascular coupling using transcranial doppler) 
 
Subject Selection 
 
We aim to have 200 subjects complete the study. There are two sites: one at BWH and one at Linnaeus 
University, Vaxjo, Sweden, with 100 subjects participating at each site.  

6 
Detailed Protocol: SAGE 
 
Version Date: 06/04/2014 
 
Subjects will be recruited at the two sites with the aim of obtaining a representative sample of healthy, 
elderly participants 65 and older in each country. At BWH, subjects will be recruited through several 
channels, including announcements in local newspapers and other available media; outreach to 
independent living communities; senior activity centers and organizations; and through existing 
databases for studies of healthy aging that exist at BWH.  
 
To be included in the study, participants must: 
 
1. Be 65 or older 
2. Have ≥ 8 years of education 
3. Be sufficiently fluent in the English language to understand instructions and perform the 
neuropsychological tests (as the purpose of the project is to study healthy aging)  
4. Score above levels indicating possible cognitive impairment on the Mini Mental State Exam (MMSE) 
(≥ 26) [87] 
5. Have an estimated intelligence quotient (IQ) score ≥ 90 based on the American National Reading 
Test (AmNART) [88] 
6. Have a score within 2 SD of the age-appropriate mean on the short form of the Boston Naming Test 
[89, 90] 
7. Have a score within 2 SD of the age-appropriate mean on the Logical Memory Subtest of the 
Wechsler Memory Scale—Third Edition [91] 
 
Subjects will be excluded for any of the following reasons:  
 
1. History of CNS diseases or major psychiatric disorders based on DSM-IV criteria [92]  
2. Score of > 10 on the Geriatric Depression Scale [93]  
3. Corrected visual acuity worse than 20-50 as tested by a Snellen wall chart  
4. Severe hearing disability that would interfere with their ability to participate in the experiments 
(e.g., to hear instructions and participate in cognitive testing)  
5. Medical conditions (e.g., heart or pulmonary disease) that would prevent them from 
participating in the physical exercise training program  
6. Evidence of substantial functional decline based on interview questions and completion of a 
questionnaire based on the Clinical Dementia Rating Scale [94] by an informant who knows the 
subject well 
 
Permission will be obtained from subjects to contact their primary care physicians (PCPs). PCPs will be 
asked to confirm that if their patient were assigned to the physical training condition, he/she could 
safely participate. Subjects will be excluded if their PCP does not confirm that they can safely 
participate. 
 
All subjects meeting the inclusion/exclusion criteria will be entered in the study, regardless of race, 
ethnic background, or gender. Every effort will be made to actively recruit minorities and women to 
reflect the racial and gender composition of the age group studied.  
 
We anticipate that subjects will reflect the current demographic composition of the Boston area, with 
approximately 12% from minority groups. In our prior studies on cognitive aging, ~17% of subjects were 
from minority populations (~10% of which were African American). Approximately 58% of our subjects 

7 
Detailed Protocol: SAGE 
 
Version Date: 06/04/2014 
have been women (which reflect the demographics of a population of older subjects). We anticipate 
having a similar mixture of subjects in the proposed study.  
 
Subject Enrollment 
 
Phone Screen 
 
Information about the study: 
Potential subjects will be briefly informed about the study. We will explain that the purpose of the 
research is to identify factors that can help to promote cognitive and brain health in older adults. This 
will be accomplished through examining the impact of different training programs involving physical or 
cognitive exercises and activities. Potential subjects will be told that there are 4 different training 
programs: two programs involve cognitive training, one involves training in mindfulness (awareness), 
and one involves physical training. We will make it clear that participants do not get to choose the 
program, but will be assigned by chance (randomized) to one of these training interventions. All 
participants will come to Brigham and Women’s hospital for a baseline assessment and for a post-
intervention assessment, which will be the same regardless of the training program in which a subject 
participates. These assessments will include cognitive, brain wave, and biological measures of brain 
function and adaptation. Training will take place in the participant’s own home over a 5 week period. 
They will be paid for their time and the cost of parking at BWH will be covered.  
 
Information about the potential subject: 
All potential subjects will be screened by phone, using a standardized telephone interview that reviews 
neurological, medical, and psychiatric conditions, and conducts a brief cognitive test.  
 
Eligible subjects interested in participating will be asked to assent to being randomized to one of the 
four training programs, which will be recorded on the phone screen in-take form. 
 
Permission to Contact a Potential Subject’s PCP 
Eligible subjects will be informed that one of the interventions is a physical exercise training program 
that involves a mild to moderate degree of exertion. All subjects will need “permission” from their PCPs 
indicating they can safely participate in physical exercise.  
 
Potential subjects who remain eligible and interested after the phone screen will be mailed a form to 
sign that will be sent to their PCP authorizing them to complete it. The form will include a brief 
description of the physical exercise program and ask the PCP to state whether or not it is medically safe 
for the person to participate in such a training program, if he/she were assigned to it. We will include a 
stamped, addressed envelope for subjects to mail the form back to us in.  
 
After we receive written authorization from the potential subject, we will contact the PCP’s office, fax 
the form, and provide our secure fax number where the completed form should be sent back. After 
receiving the completed form from the PCP, we will contact the potential subject to let her/him know if 
she/he is eligible to participate. If eligible, we will schedule the pre-intervention assessment, where 
informed consent will be obtained and additional screening procedures and baseline testing will take 
place (see below). 
 
Randomization 

8 
Detailed Protocol: SAGE 
 
Version Date: 06/04/2014 
Subjects will be randomly assigned to one of 4 conditions (3 experimental, 1 active control), which will 
be determined prior to the first visit so that the appropriate informed consent form can be completed: 
 
1. Cognitive training using Cogmed (Pearson ®) 
  
2. Awareness (“mindfulness”) training 
 
3. Physical exercise training using an interactive video platform 
 
4. Active control condition using the non-adaptive Cogmed program   
 
We plan to continue to recruit subjects until all 4 arms of the protocol are filled. 
Study Procedures 
 
Pre-Intervention Assessment 
The initial screening evaluation will take place over two half-day sessions, each lasting 3 to 3.5 hours in a 
designated room in the Laboratory of Healthy Cognitive Aging, Center for Brain/Mind Medicine, BWH, 
221 Longwood Avenue, Boston, MA.  
 
The sessions can be completed over one or two days, depending on the subject’s preference. 
 
Pre-Intervention Assessment Session 1  
The first session will include completion of informed consent, a medical history, demographic 
information, including socioeconomic status (SES), survey questionnaires, and tests of visual acuity. 
 
Screening Evaluation (for inclusion/exclusion) 
 
Cognitive Screen 
 
• 
The Mini-Mental State Examination (MMSE), a broad cognitive test on memory, spatial ability, 
memory and orientation, commonly used to screen for cognitive impairment [87] 
• 
American National Adult Reading Test (AmNART), a test of word pronunciation that provides an 
estimated IQ [88] 
• 
Logical Memory I and II, Wechsler Memory Scale—Third Edition, a test of verbal memory [91] 
• 
Boston Naming Test (Short-form, 15-items), a test of confrontation naming [89, 90]. 
 
Depression Screen 
Geriatric Depression Scale [93] 
 
Neurological/Physical Evaluation 
Subjects will undergo a structured neurological examination. Height and weight will be obtained to 
calculate BMI. Visual acuity will be measured (Snellen wall chart). 
 
Gait  
Gait will be assessed through a procedure in which subjects walk 10 meters under two conditions:  
 

9 
Detailed Protocol: SAGE 
 
Version Date: 06/04/2014 
1. Single task (walking at a comfortable pace)  
2. Dual task (walking at a comfortable pace while simultaneously counting backwards by 3’s, 
beginning with a 3 digit number told to the subject) 
 
Every trial involving serial 3’s will start from a different three digit number to reduce learning effects.  
Subjects will be given an opportunity to carry out an untimed practice trial. Under the dual task 
condition, subjects will be instructed to perform as well as they can on both tasks (i.e., no specified 
prioritization). Each condition will be done 2 times, with the order counterbalanced across subjects. The 
first and last meter (gait start up and slow down) will not be counted in the measurements.  
Time to walk 8 meters and number of steps taken will be measured. Under the dual task, we will also 
track how many numbers are generated while carrying out the serial 3’s task (both correct and incorrect 
responses). In addition, the single task of counting backwards by 3’s for 20 seconds will be tested twice 
in a seated position (once prior to and once after the gait testing). 
 
Informant Questionnaire 
Subjects will select someone who knows them well (family member or friend) to complete a set of 
questionnaires. One questionnaire will provide information about a person’s level of functioning (based 
on the Clinical Dementia Rating Scale [94]), and another will inquire about a person’s level of 
engagement (Apathy Scale [95]). The questionnaires will be enclosed with a letter explaining how to 
complete the forms. We will provide a stamped, addressed envelope to return the quesionnaires to us. 
A backup plan will be to mail these materials directly to the informant selected. This would occur if the 
materials were misplaced or if the subject requests us to do so. Informants will be compensated for 
their time by a $10 check that will be mailed to them. 
 
Outcome Measures (Dependent variables measured at baseline and after the 5 week intervention) 
• 
Cambridge Neuropsychological Test Automated Battery (CANTAB), a computerized assessment 
of cognitive functions:  
• 
CANTAB Paired Associate Learning (PAL) – assesses visual memory and new learning 
• 
CANTAB Attention Switching Task (AST) – measures cued attentional set-shifting  
• 
CANTAB Reaction Time (RTI) – measures speed of response to visual target when the 
stimulus is either predictable (simple RT) or unpredictable (choice RT)  
• 
CANTAB Spatial Span (SSP) – assesses working memory  
• 
CANTAB One Touch Stockings of Cambridge (OTS) – a test of non-verbal reasoning 
• 
Trail Making Test, Parts A and B, tests of visual attention and task switching [96] 
• 
Digit Symbol Coding, WAIS-IV, a test of processing speed [96] 
• 
Controlled Oral Word Association Test (COWAT), a test of verbal retrieval and word generation 
[97] 
• 
Categorical Fluency (a test of rapid retrieval of semantic knowledge) [97] 
 
Subject Questionnaires 
Self-report about race and ethnicity  
Self-report of socioeconomic status 
International Physical Activity Questionnaire (IPAQ) (www.ipaq.ki.se) [98] 
Handedness questionnaire [99] 
Apathy Screen [95] 
Need for Cognition Scale [100] 
Mindful Attention Awareness Scale [101] 

10 
Detailed Protocol: SAGE 
 
Version Date: 06/04/2014 
Quality of Life Scale (QOL) [102] 
Pittsburgh Sleep Quality Index [103] 
SF-36(tm) Health Survey [104, 105] 
 
Pre-Intervention Assessment: Session 2 
Session 2 will start in the ERP laboratory at 221 Longwood Avenue. 
 
Blood Samples 
Subjects will be escorted to the phlebotomy lab at the BWH Center for Clinical Investigation, 221 
Longwood Avenue, which is in the same building as where our offices are located. They will be given the 
opportunity to sit quietly in the waiting area for ~10 minutes before being escorted to a phlebotomy 
room. Blood samples will be taken via a cannula inserted into a vein by a BWH phlebotomist. 
Approximately 35 ml of blood will be collected. 
 
Approximately 10 ml of blood will be prepared according to the method recommended by the Granholm 
Laboratory, Medical University of South Carolina.  
In brief, one vacutainer tube with ~10 ml of whole blood is collected. This collection of blood will yield 
eight Eppendorf  tubes with about 0.5 ml of serum in each.  Another Eppendorf tube will contain the 
buffy coat (if available), and the vacutainer tube will contain the blood clot.  
 
In the event that the BWH Center for Clinical Investigation is unavailable for blood processing and 
packaging, the sample will be taken to the Clinical Trial Center at BWH, where processing and packaging 
will be completed. 
 
After freezing / storage, four of the Eppendorf  tubes of serum, as well as one Eppendorf  tube 
containing buffy coat, and the vacutainer  tube containing the clot will be sent on dry ice by overnight 
mail to the Lotta Granholm Laboratory, Basic Science Building 410, 173 Ashley Avenue, Medical 
University of South Carolina, Charleston, South Carolina 29407. 
 
The remaining four Eppendorf tubes of serum will continue to be stored at BWH until the Granholm Lab 
confirms receipt of the specimens. If the Granholm lab does not require these tubes, they will be 
transported to the De Jager Lab at Brigham and Women’s Hospital and stored at BWH/Harvard-Partners 
Center for Genetics and Genomics, New Research Building, Rm 164 (see below). 
 
To prepare the serum, the blood first stays for 30 minutes at room temperature and is then centrifuged 
(at 4° C) for 10 minutes. The serum is then collected in a separate polypropylene container, mixed by 
inverting several times, and finally distributed into eight Eppendorf tubes, with 0.5 ml of serum in each. 
These will be kept frozen in Ziplock bags at -70° to -80°. The clot and the buffy coat (if available) will also 
be frozen and sent to the Granholm Lab.  
 
Additional blood will be collected and stored for future analyses, if/when additional funding becomes 
available. Approximately 5 ml will be collected (EDTA tube) for potential genetic analysis (identifying genetic 
variants that may impact age-related cognitive decline), and 20 ml will be collected (Lithium heparin tube) 
for purification and cryopreservation of peripheral blood mononuclear cells (PBMCs) from which epigenetic 
factors and markers of immune function can be derived. Preparation of blood products will be done by the 

11 
Detailed Protocol: SAGE 
 
Version Date: 06/04/2014 
De Jager Lab at Brigham and Women’s Hospital, and stored at BWH/Harvard-Partners Center for Genetics 
and Genomics, New Research Building, Rm 164. In the future, stored blood products may be sent for 
analysis at the Broad Institute at MIT or similar facilities that collaborate with BWH researchers. The 
informed consent forms will seek permission to store blood samples indefinitely for future study. 
 
ERPs 
Subjects will then participate in ERP experiments while data on brain waves are being collected. An 
ActiveTwo electrode cap (Behavioral Brain Sciences Center, Birmingham, UK) will be used to hold to the 
scalp a full array of 128 Ag-AgCl BioSemi (Amsterdam, The Netherlands) “active” electrodes whose 
locations are based on a pre-configured montage. Electrodes are arranged in equidistant concentric 
circles from the 10-20 system position Cz. In addition to the 128 electrodes on the scalp, 6 mini bio-
potential electrodes will be placed over the left and right mastoid, beneath each eye, and next to the 
outer canthi of the eyes to check for eye blinks and vertical and horizontal eye movements. EEG activity 
will be digitized at a sampling rate of 512 Hz. 
 
During the experimental protocols, visual or auditory stimuli will be presented. Participants will be asked 
to respond to designated stimuli by button press or foot pedal. Visual stimuli will include simple 
geometric shapes, letters, and complex figures that are presented on a high resolution monitor. 
Auditory stimuli will be presented binaurally at between 75dB SPL and 90dB SPL through high quality 
headphones.  
 
The protocols will assess electrophysiological responses to novelty processing (subject-controlled 
novelty oddball task), working memory/attention (n-back task), and visual and auditory perception 
(visual and auditory evoked potential studies). Before beginning any new experimental condition, 
subjects will be given step-by-step explanations of what to do. Subjects will participate in practice trials. 
A brief break will occur between each block, and longer breaks will take place between each 
experimental condition. 
 
Subject-controlled Novelty Oddball Task: The experimental procedures for the Novelty Processing Task 
are analogous to the ones described in published reports [74, 75]. Two hundred and fifty line drawings, 
white on black background, will be presented in 5 blocks of 50, each at the center of a high-resolution 
computer monitor.  All stimuli will subtend a visual angle of approximately 2.75° along their longest 
dimension.  There will be three categories of visual stimuli:  1) a repetitive Standard Stimulus (a 
triangle)--70% frequency, 2) a Target Stimulus (upside down triangle)--approximately 15% frequency, 
and 3) Novel Stimuli, randomly drawn from a set of unusual/unfamiliar line drawings (e.g., impossible or 
fragmented objects) shown only one time each--approximately 15% frequency, many of which come 
from the collection of drawings that have been used by Kroll and Potter (1984) [106] and Kosslyn et al. 
(1994) [107]. Stimuli will appear within a fixation box, subtending a visual angle of approximately 3.5° x 
3.5°, that remains on the screen at all times. Participants will be told that the study is investigating how 
people look at different kinds of line drawings.  They will be viewing a set of drawings and can look at 
each picture for however long or short they like.  They control the viewing duration by pressing a button 
(with their dominant hand) that leads to the erasure of the current stimulus and the onset of a blank 
screen, followed by the presentation of the next stimulus.  Participants will be told that they will not be 
asked questions about the drawings at the end of the experiment.  Also, participants will be told to 
respond to the designated target stimulus by pressing a foot pedal (ipsilateral to the button 
press).  Instructions will indicate that accuracy is more important than speed.   
 

12 
Detailed Protocol: SAGE 
 
Version Date: 06/04/2014 
N-Back Task: The experimental procedures for the N-Back Task are analogous to the ones described in a 
previous report [108]. Subjects will perform a verbal n-back paradigm in the visual modality with three 
levels of difficulty (0-back, 1-back, 2-back).  Stimuli will consist of letters of the alphabet, white on a 
black background, presented at the center of a high-resolution computer monitor for 200 ms, in pseudo-
random order.  Under each n-back condition, subjects were shown a series of 300 letters, divided into 
three blocks.  For each level of n-back, 75% of trials will be non-matches and 25% of trials will be 
matches.  Subjects will be instructed to respond only to match letters (button press on a game 
controller).  Subjects will be told to respond as quickly as possible without sacrificing accuracy.  The 
interval between the onset of consecutive visual stimuli will be fixed at 2200 ms. The hand used for 
button press and the order of n-back level will be counterbalanced across subjects.  
 
Evoked Potentials: 
Visual evoked potentials: Subjects will be view a series of checkerboard stimuli (4° visual angle) flashed 
to the right or left visual field (presented at 1-9 Hz) while they fixate on a dot at the center of the screen.  
 
[74]ERP Recordings 
ERP data collection and analysis will follow published reports by Daffner et al. (2012) [109]. An 
ActiveTwo electrode cap (Behavioral Brain Sciences Center, Birmingham, UK) will be used to hold 128 
electrodes to the scalp. EEG activity will be digitized at a sampling rate of 512 Hz. 
 
ERP Data analysis 
EEG data will be analyzed using ERPLAB and EEGLAB [110] toolboxes that operate within the MATLAB 
framework. EEG epochs for different stimulus types will be averaged separately. Although many event-
related potentials (ERPs) will be measured, the focus of analysis will be on the P3b component, which 
reflects categorization/memory updating and the P3a component, which reflects orienting/executive 
control. The size of these components serves as an index of the amount of resources allocated to 
perform the task, and the latency of the component serves as an index of processing speed. 
 
Transcranial Doppler (TCD)  
Information about blood flow using transcranial doppler (TCD), a non-invasive technique, also will be 
collected during an n-back task and in response to flashing checkerboard stimuli. TCD recordings will be 
done either before or after the ERP experiments. 
 
Neurovascular coupling reflects the link between regional synaptic activity and regional cerebral blood 
flow. Under normal conditions, cerebral blood flow and cerebral metabolic rate are coupled, with an 
increase in metabolic demand leading to an increase in blood flow. Neurovascular coupling will be 
indexed by changes in bilateral middle cerebral artery blood flow velocities during the n-back task. 
A 2-MHz, pulsed flat transcranial Doppler probe (MultiDop, DWL) will be placed over each temporal 
bone. The signal on both probes will be range gated to a depth of 45 mm to 60 mm, to insure insonation 
of the M1 segment of the middle cerebral artery. Once the signals are maximized, the probe will be fixed 
in place for the duration of the test using a Velcro headband that will be placed over the ERP electrode 
cap. Localization and determination of the proper artery and position will be performed according to 
standard techniques. Normally, in about 1 out of 5 older people, these blood vessels cannot be tested.  
 
Baseline physical activity monitoring (accelerometry) 
For the week between Session 2 at BWH and the start of the structured intervention in the homes of 
subjects, they will be asked to wear an accelerometer that is fitted snuggly around the waist using the 

13 
Detailed Protocol: SAGE 
 
Version Date: 06/04/2014 
elastic waistband and is placed over the right hip. Subjects will be asked to wear the accelerometer 
while awake during 7 consecutive days, except during water based activities since the accelerometer is 
not waterproof. This will provide baseline data on the level of physical activity/movement in which 
subjects are engaged. 
 
Accelerometry provides a physiometric measure of motor activity. The accelerometer is a lightweight, 
small (matchbox sized) non obtrusive device that measures and records accelerations. The 
accelerometer output is digitized by a twelve-bit Analog to Digital Convertor (ADC) at a rate of 30 Hz. 
Once digitized the signal passes through a digital filter that band-limits the accelerometer to the 
frequency range of 0.25-2.5 Hz. The frequency range detects normal human motion and rejects 
changing accelerations within the passband. 
 
Interventions – General Features and Overview 
All of the interventions will include the following features: the duration will be ~35 minutes per day, 5 
days/week, over a 5 week period. A member of the research team will visit the subject's home to 
introduce the training program, and carefully review how to use the appropriate software on a 
computer, which will be loaned to subjects while they participate in the project. If the subject’s home 
does not have internet access, the tablet provided will include prepaid wireless internet access. The 
team member will be present during a practice run to facilitate the process and address any concerns. 
 
Subjects will be instructed to carry out the training sessions during the same part of the day (e.g., early 
morning), and to set up a routine in which they will not be disturbed by phone calls or visitors. 
Individuals will be told not train more than once a day. They will be encouraged to maintain their other 
activities and not substitute the training stimulation for another activity in which they have been 
routinely engaged.  
 
For both cognitive and physical training, subjects will begin with a level they can easily manage. The 
difficulty will be slowly increased as their performance improves (due to training effects), with the aim 
of keeping the subjective effort approximately constant and moderately challenging through the 5 
weeks. Similarly, for the mindfulness training, the meditations and tasks will become more self-directed 
and challenging during the 5 week course. 
 
A member of the research team will communicate with each subject on a weekly basis (via phone call or 
email, whichever mode of communication is more convenient for the subject) to provide feedback and 
address any questions or concerns. Subjects will also be encouraged to contact the research team at any 
time they have questions or concerns. Data will be monitored for potential breaks, interruptions, and 
unusual performance ﬂuctuations.  
 
1. Cognitive training using Cogmed (Pearson ®) 
During the initial session, a member of the research team will visit the subject's home and introduce the 
subject to the Cogmed training program (www.cogmed.com). Individuals will start at the same low 
difficulty level. As training proceeds, task difficulty will be individually adjusted based on performance by 
increasing/decreasing the number of items individuals have to remember, such that a participant 
reaches approximately 60% correct per day for each task. Each training session will start at the task 
difficulty level where the participant ended in the previous session. Performance and reaction time data 
will be continuously recorded while subjects are doing the task, and these data will be sent via the 
internet to the research team after each session. A member of the research team will communicate with 

14 
Detailed Protocol: SAGE 
 
Version Date: 06/04/2014 
each subject on a weekly basis (via phone call or email) to provide feedback and address any questions 
or concerns.  
 
2. Awareness (mindfulness) training 
During the initial session, a member of the research team will visit the subject's home and introduce the 
subject to mindfulness techniques. For this training, subjects will participate in a series of mindfulness 
exercises.  Before the start of each session, subjects will log-on to a secure password-required website. 
Each session will consist one fifteen minute guided mindfulness meditation that we will label 
“Mindfulness Meditation Session”, and 3 six minute guided Mindfulness-in-Action tasks such as “mindful 
listening”, “mindful observing”, and “mindful walking,” which we will label “Mindfulness Task 1”, 
“Mindfulness Task 2”, etc. The meditation and tasks will become increasingly more self-directed over 
the 5 weeks; the degree of guidance will decrease to keep the subjective effort approximately constant 
and moderately challenging through the 5 weeks.  
The mindfulness meditations will be narrated by one guide and the tasks will be narrated by a different 
guide. We will have 7 mindfulness tasks in total, whose order of presentation will be counterbalanced 
across sessions: 1. mindful observing of place, 2. mindful eating, 3. mindful observing of object, 4. 
mindful observing of person, 5. mindful walking, 6. mindful listening, and 7. mindful writing with the 
non-dominant  and dominant hand.  
At the end of each session, participants will write brief reflections stored via the website (e.g., an 
estimate of the amount of time subjects experienced their thoughts as wandering) both as an integral 
part of the mindfulness process and as a means of increasing the likelihood that subjects fully 
participate in each session. Each session will be structured as follows: Login, Mindfulness Meditation 
Session, Mindfulness Task 1, Mindfulness Task 2, Mindfulness Task 3, Write Log Reflection, Logout.  
Login and logout times will be recorded to keep track of a subject’s participation. A member of the 
research team will communicate with each subject on a weekly basis (via phone call or email) to provide 
feedback and address any questions or concerns. 
 
3. Physical exercise training using an interactive video platform 
Subjects will participate in a structured physical exercise training program that aims to progressively 
increase their level of activity over the 5 week training period. During the initial session, a member of 
the research team will visit the subject's home and introduce the subject to the different aspects of the 
training program (e.g., interactive video, accelerometer). An interactive video will be used to present a 
structured exercise program. This interactive video is being created with exercise physiology specialists 
in Sweden. It will run using an application on the computer (connected to a monitor or TV screen if 
possible).  
 
Each training session will begin with warm up/stretching exercises, followed by a series of aerobic 
exercises, with breaks every few minutes. The aerobic exercises will be followed by a cool 
down/stretching period.  
 

15 
Detailed Protocol: SAGE 
 
Version Date: 06/04/2014 
Aerobic exercises will include relatively low impact activities like walking, jogging, or running in place, 
which will aim to put limited demands on balance. Each exercise will be explained and demonstrated in 
the video. All exercises can be done standing, sitting, or next to a chair that provides balance support as 
demonstrated in the videos. After the first session, for each subsequent session the difficulty level will 
start at one level below the previous session’s average difficulty level (e.g. if they exercise at the most 
difficult level for most of the time during one session, the next session will start at the medium difficulty 
level). Each exercise will be explained and demonstrated in the video.   
 
There will be a water break every 8-10 minutes and an Exertion Check-In Break every 3-4 minutes.  At 
each Exertion Check-In break, subjects will push one of 3 buttons to rate their perceived level of 
exertion (“Too Easy”, “Somewhat Hard”, “Too Hard”). If they choose “Too Easy”, the next set of 
exercises will be a bit faster. If they choose “Too Hard”, the next set of exercises will be a bit slower. If 
they choose “Somewhat Hard”, the next set of exercises will stay at the same level. Subjects are told 
that the goal is to work at a level that requires a modest degree of effort, where they feel stimulated 
and like they are working hard, but not so hard that they feel dizzy or short of breath.  
 
If they want to make the exercise easier or harder anytime, they can press the “Pause” button on the 
computer screen and choose “Too Easy” or “Too Hard”.  
If they would like a short break, they can also press the “Pause” button on the computer screen. When 
they are ready to start again, they can press the “Resume” button.  
 
If they need to stop the exercise completely they can press the “Pause” button and then press “Start 
Over Later". 
 
 If, for some reason, they feel unable to carry out a particular exercise (e.g., inability to bend a knee 
because of arthritis), they will be able to press the “Pause” button and then the “Skip Exercise” button 
on the computer that will trigger the display and demonstration of an alternative exercise (e.g. Step 
Touch instead of Skipping). 
For the five weeks of the exercise training, during all waking hours –except during water- based 
activities- subjects will wear an accelerometer, as described earlier. The accelerometer will provide 
measurements of the intensity of physical activity during the exercise training and allow us to chart the 
degree to which it increases over the 5 week program. At least once a week subjects will connect the 
accelerometer to an adapter attached to the computer. This will allow the accelerometer to be 
recharged and allow research staff to upload the, the activity data via the internet to our laboratory at 
BWH. Subjects will be given feedback about the amount of “activity units” that they have accrued during 
the training sessions, which will be automatically added to a log for their review that is stored on the 
computer. This will provide additional feedback to subjects about their progress and can serve to 
encourage them to increase the number of activity units per session over the course of their 5 weeks of 
training. A member of the research team will communicate with each subject on a weekly basis (via 
phone call or email) to provide feedback and address any questions or concerns. 

16 
Detailed Protocol: SAGE 
 
Version Date: 06/04/2014 
 
4. Low level of cognitive training using the Cogmed program (which will serve as an active control 
condition) 
 
Individuals in the control group will participate in the same computerized Cogmed training program as 
described above. The main difference is that for the control group task difficulty will remain at the same 
low starting level, rather than increasing over time. The instructions given to subjects will be identical to 
the ones used in the cognitive training intervention. During the initial session, a member of the research 
team will visit the subject's home and introduce the subject to the Cogmed training program 
(www.cogmed.com). As with the active training group, performance and reaction time data will be 
continuously recorded while subjects are doing the task and these data will be sent automatically to the 
research team after each session. A member of the research team will communicate with each subject 
on a weekly basis (via phone call or email) to provide feedback and address any questions or concerns. 
 
Post-Intervention Assessment 
Shortly after completing their 5 week intervention program, subjects will return to our BWH Lab at, 221 
Longwood Avenue, Boston, MA for 2 half-day sessions. Every effort will be made to have the subjects 
return to the Lab within 2 days of completing the training program.  
 
During these sessions, we will repeat the following measurements, as described in the section on pre-
intervention assessment: 
 
Collection of blood 
Cognitive Testing (CANTAB subtests, Trail Making Test, Parts A and B, Digit Symbol Coding, WAIS-IV, 
Controlled Oral Word Association Test (COWAT)) [96, 97] 
Completion of questionnaires 
Neurologic/gait assessment 
ERP studies 
Transcranial doppler studies 
 
Subjects will be paid for their time, as follows:  
 
Pre-intervention evaluation session 1 $60 
Pre-intervention evaluation session 2 $60 
    Structured intervention 
$30/week for 5 weeks 
  Post-intervention evaluation session 1 $60 
Post-intervention evaluation session 2 $60 
Completion of all study components $60 
 
Subjects who choose to discontinue participation will be paid for their time in a prorated manner. Check 
request forms will be sent to BWH (accounts payable) and a check will be mailed to the address 
designated by the subject. During the evaluation session, the cost of parking will be covered by a 
voucher applicable to any BWH parking facility.  
 
Biostatistical Analysis 
 

17 
Detailed Protocol: SAGE 
 
Version Date: 06/04/2014 
We will mainly use MANCOVA methods to compare the different conditions while controlling for various 
background factors, such as age and baseline cognitive performance. Cognitive change scores will be the 
main outcome variables. In addition, we will analyze changes from baseline in BDNF levels, gait score 
neural activity, as measured by ERPs, and degree of vascular coupling, as measured by TCDs.  
 
In separate analyses, we will investigate whether various cognitive domains (e.g., executive functions, 
memory) are differentially affected by different types of stimulation. We will also perform separate 
analyses for closer investigation of how age, education, intelligence and mood may modify the 
experimental effects.  
 
Risks and Discomforts 
 
During the Intervention Programs only subjects whose primary care doctor indicate are safe to engage in 
in the physical exercise training program will be able to participate in the study (even if they are 
randomly assigned to one of the non-physical exercise intervention programs). In the physical exercise 
training program, perceived level of effort will be carefully monitored and subjects who report their 
perceived exertion to be hard will be instructed to decrease their level of effort. During the initial visit to 
the subject’s home, the study staff will prepare a card that includes the name and phone number of the 
subject’s PCP, in case medical issues arise.  
 
During all of the structured intervention phases, study staff will be regularly communicating with 
participants to answer questions, address concerns, and try to augment a subject’s level of comfort with 
the training activity. 
 
Physical fitness training for 35 minutes, titrated to a moderate level of effort, is generally safe and often 
recommended for healthy adults. During exercise, there is a risk of fatigue, dyspnea, palpatations, and 
muscle cramps or aches. Following exercise, there is a risk of muscle, joint, or back discomfort. While 
exercising, individuals with heart disease are at risk for chest discomfort/angina.  
 
Subjects will be told that if they experience symptoms, they should stop exercising. If they experience 
chest discomfort, they should contact their primary care physician. If the chest discomfort is severe, 911 
emergency medical services should be called and the subject should be taken to a hospital emergency 
room for evaluation. For other symptoms, they should page the research team. 
The PI, a physician, will review the symptoms with the subject and help determine whether further 
medical assessment is appropriate. As a safety measure, subjects can only participate in this study if 
approved by their primary care physician.  
 
Cognitive training poses no serious clinical risks for participants. The cognitive exercises may cause some 
degree of frustration or fatigue. The subject may stop the testing at any time or decline to answer any 
question.  
 
Awareness training poses no serious clinical risks for participants. It may make some individuals feel 
fatigued or frustrated.  
 
During the interview, neuropsychological testing, and ERP paradigms, subjects may become anxious, 
frustrated, or fatigued. The study staff consists of trained individuals who will attempt to make subjects 
as comfortable as possible. Although it is hoped that subjects will answer all of the questions, they may 

18 
Detailed Protocol: SAGE 
 
Version Date: 06/04/2014 
skip over any questions that they choose not to answer. A subject may experience some tiredness or 
restlessness during the experimental tasks. If so, the subject can take a break or discontinue the testing.  
 
Obtaining a blood sample by inserting a cannula into a vessel is a routine and safe procedure. However, 
complications can occur, such as bleeding, bruising, and feeling dizzy/lightheaded. There is a small risk of 
infection, and of fainting. Bloods will be drawn by experienced phlebotomists. 
 
There are no serious risks associated with the collection of electrophysiological (ERP) data. The cap with 
electrodes fits snugly and may cause minor discomfort. If so, the investigator will try to adjust the fit. 
Different sized caps will be available to facilitate a comfortable fit. There is a small risk of minor skin 
sensitivity, chapping, or drying associated with the conductive gel. Also, there is a slight risk for infection 
at an electrode site, if the skin is injured during the procedure. The electrode gel itself may leave the 
hair untidy. However, it is water-soluble and will wash out easily. Electrodes around the eyes and behind 
the ears are attached with stickers and may cause slight discomfort upon removal. 
 
There are no known serious risks associated with measuring blood flow using Transcranial Doppler (TCD) 
Ultrasound. The headband that holds the ultrasound camera may cause minor discomfort. The 
technician carrying out this study will be experienced and try to adjust the fit to make it as comfortable 
as possible. During the n-back task, a subject may experience some fatigue or restlessness. If so, the 
subject can take a break or discontinue the testing. 
 
There are no known serious risks associated with measuring movements using accelerometry. The band 
around the waist that holds the device fits snugly and may be experienced by some as uncomfortable. If 
so, the band can be adjusted to make it more comfortable.  
 
There are no known serious risks associated with measuring heart rate using the using the Polar device. 
The band around the chest that holds the device fits needs to fit snugly may be experienced by some as 
uncomfortable. If so, the band can be adjusted to make it more comfortable.  
 
Potential Benefits 
 
Evidence to date would suggest that participating in cognitively or physically stimulating activities may 
promote brain health. However, there are no proven benefits to subjects who participate in this study. 
The results may benefit others by elucidating mechanisms that contribute to successful cognitive aging. 
These results may be useful in developing rational interventions aimed at preserving cognitive and 
functional status in older individuals 
 
Monitoring and Quality Assurance 
 
The Principal Investigator and Co-Investigators will report any and all serious and non-serious adverse 
events to the IRB within a timely manner. 
 
Study personnel must immediately report to the PI any adverse events from this study. All adverse 
events will be reviewed by the PI and reported to the Partners Human Research Committee (HRC) in 
accordance with ICH Guidelines.  
 

19 
Detailed Protocol: SAGE 
 
Version Date: 06/04/2014 
The PI will be responsible for monitoring and assuring the validity and integrity of all of the data, for 
monitoring the day-to-day activities of all study procedures, and for the adherence to the IRB-approved 
protocol. The PI will maintain a tracking log to reflect all adverse events regardless of relationship or 
expectedness and submit the updated log each year during the IRB renewal process. 
 
 
REFERENCES 
 
[1] 
Baltes, P. B., & Smith, J. (2003). New frontiers in the future of aging: From successful aging of the 
young old to the dilemmas of the fourth age. Gerontology, 49(2), 123-135.  
[2] 
Centers for Disease Control and Prevention Prevention. (2011). The CDC healthy brain initiative: 
Progress 2006-2011.    
[3] 
Hagberg, B., Bauer Alfredson, B., Poon, L. W., & Homma, A. (2001). Cognitive functioning in 
centenarians: A coordinated analysis of results from three countries. Journals of Gerontology. 
Series B: Psychological Sciences and Social Sciences, 56(3), P141-151.  
[4] 
Wimo, A., Winblad, B., & Jonsson, L. (2010). The worldwide societal costs of dementia: 
Estimates for 2009. Alzheimers Dement, 6(2), 98-103. doi: 10.1016/j.jalz.2010.01.010 
[5] 
Brookmeyer, R., Evans, D. A., Hebert, L., Langa, K. M., Heeringa, S. G., Plassman, B. L., & Kukull, 
W. A. (2011). National estimates of the prevalence of alzheimer's disease in the United States. 
Alzheimer's and Dementia, 7(1), 61-73. doi: 10.1016/j.jalz.2010.11.007 
[6] 
Daffner, K. R. (2010). Promoting successful cognitive aging: A comprehensive review. J 
Alzheimers.Dis., 19, 1101-1122.  
[7] 
Plassman, B. L., Williams, J. W., Jr., Burke, J. R., Holsinger, T., & Benjamin, S. (2010). Systematic 
review: Factors associated with risk for and possible prevention of cognitive decline in later life. 
Annals of Internal Medicine, 153(3), 182-193. doi: 10.7326/0003-4819-153-3-201008030-00258 
[8] 
Coelho, F. M., Pereira, D. S., Lustosa, L. P., Silva, J. P., Dias, J. M., Dias, R. C., . . . Pereira, L. S. 
(2012). Physical therapy intervention (PTI) increases plasma brain-derived neurotrophic factor 
(BDNF) levels in non-frail and pre-frail elderly women. Archives of Gerontology and Geriatrics, 
54(3), 415-420. doi: 10.1016/j.archger.2011.05.014 
[9] 
Stern, Y. (2009). Cognitive reserve. Neuropsychologia, 47(10), 2015-2028. doi: 
10.1016/j.neuropsychologia.2009.03.004 
[10] 
Churchill, J. D., Galvez, R., Colcombe, S., Swain, R. A., Kramer, A. F., & Greenough, W. T. (2002). 
Exercise, experience and the aging brain. Neurobiology of Aging, 23(5), 941-955.  
[11] 
Neeper, S. A., Gomez-Pinilla, F., Choi, J., & Cotman, C. W. (1996). Physical activity increases mrna 
for brain-derived neurotrophic factor and nerve growth factor in rat brain. Brain Research, 
726(1-2), 49-56.  
[12] 
Angevaren, M., Aufdemkampe, G., Verhaar, H. J., Aleman, A., & Vanhees, L. (2008). Physical 
activity and enhanced fitness to improve cognitive function in older people without known 
cognitive impairment. Cochrane Database Systematic Reviews, (3). doi: 
10.1002/14651858.CD005381.pub2 
[13] 
Kramer, A. F., & Erickson, K. I. (2007). Capitalizing on cortical plasticity: Influence of physical 
activity on cognition and brain function. Trends in Cognitive Sciences, 11(8), 342-348. doi: 
10.1016/j.tics.2007.06.009 
[14] 
Erickson, K. I., Voss, M. W., Prakash, R. S., Basak, C., Szabo, A., Chaddock, L., . . . Kramer, A. F. 
(2011). Exercise training increases size of hippocampus and improves memory. Proceedings of 

20 
Detailed Protocol: SAGE 
 
Version Date: 06/04/2014 
the National Academy of Sciences of the United States of America, 108(7), 3017-3022. doi: 
10.1073/pnas.1015950108 
[15] 
Baker, L. D., Frank, L. L., Foster-Schubert, K., Green, P. S., Wilkinson, C. W., McTiernan, A., . . . 
Craft, S. (2010). Effects of aerobic exercise on mild cognitive impairment: A controlled trial. 
Archives of Neurology, 67(1), 71-79. doi: 10.1001/archneurol.2009.307 
[16] 
Kramer, A. F., Colcombe, S. J., McAuley, E., Scalf, P. E., & Erickson, K. I. (2005). Fitness, aging and 
neurocognitive function. Neurobiology of Aging, 26 Suppl 1, 124-127. doi: 
10.1016/j.neurobiolaging.2005.09.009 
[17] 
Ruscheweyh, R., Willemer, C., Kruger, K., Duning, T., Warnecke, T., Sommer, J., . . . Floel, A. 
(2011). Physical activity and memory functions: An interventional study. Neurobiology of Aging, 
32(7), 1304-1319. doi: 10.1016/j.neurobiolaging.2009.08.001 
[18] 
Larson, E. B., Wang, L., Bowen, J. D., McCormick, W. C., Teri, L., Crane, P., & Kukull, W. (2006). 
Exercise is associated with reduced risk for incident dementia among persons 65 years of age 
and older. Annals of Internal Medicine, 144(2), 73-81.  
[19] 
Laurin, D., Verreault, R., Lindsay, J., MacPherson, K., & Rockwood, K. (2001). Physical activity and 
risk of cognitive impairment and dementia in elderly persons. Archives of Neurology, 58(3), 498-
504.  
[20] 
Pereira, A. C., Huddleston, D. E., Brickman, A. M., Sosunov, A. A., Hen, R., McKhann, G. M., . . . 
Small, S. A. (2007). An in vivo correlate of exercise-induced neurogenesis in the adult dentate 
gyrus. Proceedings of the National Academy of Sciences of the United States of America, 104(13), 
5638-5643. doi: 10.1073/pnas.0611721104 
[21] 
Abbott, R. D., White, L. R., Ross, G. W., Masaki, K. H., Curb, J. D., & Petrovitch, H. (2004). Walking 
and dementia in physically capable elderly men. JAMA, 292(12), 1447-1453. doi: 
10.1001/jama.292.12.1447 
[22] 
Hindin, S. B., & Zelinski, E. M. (2012). Extended practice and aerobic exercise interventions 
benefit untrained cognitive outcomes in older adults: A meta-analysis. Journal of the American 
Geriatrics Society, 60(1), 136-141. doi: 10.1111/j.1532-5415.2011.03761.x 
[23] 
Hillman, C. H., Erickson, K. I., & Kramer, A. F. (2008). Be smart, exercise your heart: Exercise 
effects on brain and cognition. Nature Reviews: Neuroscience, 9(1), 58-65.  
[24] 
Colcombe, S. J., Erickson, K. I., Scalf, P. E., Kim, J. S., Prakash, R., McAuley, E., . . . Kramer, A. F. 
(2006). Aerobic exercise training increases brain volume in aging humans. Journals of 
Gerontology. Series A: Biological Sciences and Medical Sciences, 61(11), 1166-1170.  
[25] 
Colcombe, S. J., Kramer, A. F., Erickson, K. I., Scalf, P., McAuley, E., Cohen, N. J., . . . Elavsky, S. 
(2004). Cardiovascular fitness, cortical plasticity, and aging. Proceedings of the National 
Academy of Sciences of the United States of America, 101(9), 3316-3321. doi: 
10.1073/pnas.0400266101 
[26] 
Fan, Y., Liu, Z., Weinstein, P. R., Fike, J. R., & Liu, J. (2007). Environmental enrichment enhances 
neurogenesis and improves functional outcome after cranial irradiation. European Journal of 
Neuroscience, 25(1), 38-46. doi: 10.1111/j.1460-9568.2006.05269.x 
[27] 
Albert, M. S. (2007). Changing the trajectory of cognitive decline? New England Journal of 
Medicine, 357(5), 502-503. doi: 10.1056/NEJMcibr073273 
[28] 
Connor, J. R., Melone, J. H., Yuen, A. R., & Diamond, M. C. (1981). Dendritic length in aged rats' 
occipital cortex: An environmentally induced response. Experimental Neurology, 73(3), 827-830.  
[29] 
Kempermann, G., Kuhn, H. G., & Gage, F. H. (1997). More hippocampus neurons in adult mice 
living in an enriched environment. Nature, 386, 493-495.  
[30] 
van Praag, H., Kempermann, G., & Gage, F. H. (2000). Neural consequences of environmental 
enrichment. Nature Reviews: Neuroscience, 1(3), 191-198. doi: 10.1038/35044558 

21 
Detailed Protocol: SAGE 
 
Version Date: 06/04/2014 
[31] 
Draganski, B., Gaser, C., Busch, V., Schuierer, G., Bogdahn, U., & May, A. (2004). Neuroplasticity: 
Changes in grey matter induced by training. Nature, 427(6972), 311-312. doi: 10.1038/427311a 
[32] 
Maguire, E. A., Gadian, D. G., Johnsrude, I. S., Good, C. D., Ashburner, J., Frackowiak, R. S., & 
Frith, C. D. (2000). Navigation-related structural change in the hippocampi of taxi drivers. 
Proceedings of the National Academy of Sciences of the United States of America, 97(8), 4398-
4403. doi: 10.1073/pnas.070039597 
[33] 
Erickson, K. I., Colcombe, S. J., Wadhwa, R., Bherer, L., Peterson, M. S., Scalf, P. E., . . . Kramer, A. 
F. (2007). Training-induced plasticity in older adults: Effects of training on hemispheric 
asymmetry. Neurobiology of Aging, 28(2), 272-283. doi: 10.1016/j.neurobiolaging.2005.12.012 
[34] 
Logan, J. M., Sanders, A. L., Snyder, A. Z., Morris, J. C., & Buckner, R. L. (2002). Under-
recruitment and nonselective recruitment: Dissociable neural mechanisms associated with 
aging. Neuron, 33(5), 827-840.  
[35] 
Ball, K., Berch, D. B., Helmers, K. F., Jobe, J. B., Leveck, M. D., Marsiske, M., . . . Vital Elderly 
Study, G. (2002). Effects of cognitive training interventions with older adults: A randomized 
controlled trial. JAMA, 288(18), 2271-2281.  
[36] 
Buschkuehl, M., Jaeggi, S. M., Hutchison, S., Perrig-Chiello, P., Dapp, C., Muller, M., . . . Perrig, W. 
J. (2008). Impact of working memory training on memory performance in old-old adults. 
Psychology and Aging, 23(4), 743-753. doi: 10.1037/a0014342 
[37] 
Smith, G. E., Housen, P., Yaffe, K., Ruff, R., Kennison, R. F., Mahncke, H. W., & Zelinski, E. M. 
(2009). A cognitive training program based on principles of brain plasticity: Results from the 
improvement in memory with plasticity-based adaptive cognitive training (IMPACT) study. 
Journal of the American Geriatrics Society, 57(4), 594-603. doi: 10.1111/j.1532-
5415.2008.02167.x 
[38] 
Jaeggi, S. M., Buschkuehl, M., Jonides, J., & Perrig, W. J. (2008). Improving fluid intelligence with 
training on working memory. Proceedings of the National Academy of Sciences of the United 
States of America, 105(19), 6829-6833. doi: 10.1073/pnas.0801268105 
[39] 
Anguera, J. A., Boccanfuso, J., Rintoul, J. L., Al-Hashimi, O., Faraji, F., Janowich, J., . . . Gazzaley, A. 
(2013). Video game training enhances cognitive control in older adults. Nature, 501(7465), 97-
101. doi: 10.1038/nature12486 
[40] 
Persson, J., & Reuter-Lorenz, P. A. (2008). Gaining control: Training executive function and far 
transfer of the ability to resolve interference. Psychological Science, 19(9), 881-888. doi: 
10.1111/j.1467-9280.2008.02172.x 
[41] 
Kabat-Zinn, J. (2005). Coming to our senses. London: Piatkus Books. 
[42] 
Chiesa, A., & Malinowski, P. (2011). Mindfulness-based approaches: Are they all the same? 
Journal of Clinical Psychology, 67(4), 404-424. doi: 10.1002/jclp.20776 
[43] 
Kabat-Zinn, J. (1990). Full catastrophe living: Using the wisdom of your body and mind to face 
stress, pain, and illness. New York: Delacorte Press. 
[44] 
Baer, R. A. (2006). Mindfulness-based treatment approaches: Clinician's guide to evidence based 
treatment approaches. Amsterdam; Boston: Elsevier Academic Press. 
[45] 
Kabat-Zinn, J. (2005). Wherever you go, there you are: Mindfulness meditation in everday life (10 
ed.). New York: Hyperion. 
[46] 
Bishop, S. R., Lau, M., Shapiro, S., Carlson, L., Anderson, N. D., & Carmody, J. (2004). 
Mindfulness: A proposed operational definition. Clinical Psychology: Science and Practice, 11(3), 
230-241.  
[47] 
Langer, E. (2000). Mindful learning. Current Directions in Psychological Science, 9(6), 220-223.  
[48] 
Shapiro, S. L., Carlson, L. E., Astin, J. A., & Freedman, B. (2006). Mechanisms of mindfulness. 
Journal of Clinical Psychology, 62(3), 373-386. doi: 10.1002/jclp.20237 

22 
Detailed Protocol: SAGE 
 
Version Date: 06/04/2014 
[49] 
Allen, M., Dietz, M., Blair, K. S., van Beek, M., Rees, G., Vestergaard-Poulsen, P., . . . Roepstorff, 
A. (2012). Cognitive-affective neural plasticity following active-controlled mindfulness 
intervention. Journal of Neuroscience, 32(44), 15601-15610. doi: 10.1523/JNEUROSCI.2957-
12.2012 
[50] 
Slagter, H. A., Lutz, A., Greischar, L. L., Francis, A. D., Nieuwenhuis, S., Davis, J. M., & Davidson, R. 
J. (2007). Mental training affects distribution of limited brain resources. PLoS Biology, 5(6), e138. 
doi: 10.1371/journal.pbio.0050138 
[51] 
Kozasa, E. H., Sato, J. R., Lacerda, S. S., Barreiros, M. A., Radvany, J., Russell, T. A., . . . Amaro, E., 
Jr. (2012). Meditation training increases brain efficiency in an attention task. Neuroimage, 59(1), 
745-749. doi: 10.1016/j.neuroimage.2011.06.088 
[52] 
Zeidan, F., Johnson, S. K., Diamond, B. J., David, Z., & Goolkasian, P. (2010). Mindfulness 
meditation improves cognition: Evidence of brief mental training. Consciousness and Cognition, 
19(2), 597-605. doi: 10.1016/j.concog.2010.03.014 
[53] 
Chiesa, A., Calati, R., & Serretti, A. (2011). Does mindfulness training improve cognitive abilities? 
A systematic review of neuropsychological findings. Clinical Psychology Review, 31(3), 449-464. 
doi: 10.1016/j.cpr.2010.11.003 
[54] 
Zanesco, A. P., King, B. G., Maclean, K. A., & Saron, C. D. (2013). Executive control and felt 
concentrative engagement following intensive meditation training. Frontiers in Human 
Neuroscience, 7, 566. doi: 10.3389/fnhum.2013.00566 
[55] 
Chiesa, A., & Serretti, A. (2010). A systematic review of neurobiological and clinical features of 
mindfulness meditations. Psychological Medicine, 40(8), 1239-1252. doi: 
10.1017/S0033291709991747 
[56] 
Luders, E., Clark, K., Narr, K. L., & Toga, A. W. (2011). Enhanced brain connectivity in long-term 
meditation practitioners. Neuroimage, 57(4), 1308-1316. doi: 
10.1016/j.neuroimage.2011.05.075 
[57] 
Holzel, B. K., Carmody, J., Vangel, M., Congleton, C., Yerramsetti, S. M., Gard, T., & Lazar, S. W. 
(2011). Mindfulness practice leads to increases in regional brain gray matter density. Psychiatry 
Research, 191(1), 36-43. doi: 10.1016/j.pscychresns.2010.08.006 
[58] 
Kang, D. H., Jo, H. J., Jung, W. H., Kim, S. H., Jung, Y. H., Choi, C. H., . . . Kwon, J. S. (2013). The 
effect of meditation on brain structure: Cortical thickness mapping and diffusion tensor imaging. 
Social Cognitive and Affective Neuroscience, 8(1), 27-33. doi: 10.1093/scan/nss056 
[59] 
Pagnoni, G., & Cekic, M. (2007). Age effects on gray matter volume and attentional performance 
in zen meditation. Neurobiology of Aging, 28(10), 1623-1627. doi: 
10.1016/j.neurobiolaging.2007.06.008 
[60] 
Taylor, V. A., Daneault, V., Grant, J., Scavone, G., Breton, E., Roffe-Vidal, S., . . . Beauregard, M. 
(2013). Impact of meditation training on the default mode network during a restful state. Social 
Cognitive and Affective Neuroscience, 8(1), 4-14. doi: 10.1093/scan/nsr087 
[61] 
Luders, E., Toga, A. W., Lepore, N., & Gaser, C. (2009). The underlying anatomical correlates of 
long-term meditation: Larger hippocampal and frontal volumes of gray matter. Neuroimage, 
45(3), 672-678.  
[62] 
Palta, P., Page, G., Piferi, R. L., Gill, J. M., Hayat, M. J., Connolly, A. B., & Szanton, S. L. (2012). 
Evaluation of a mindfulness-based intervention program to decrease blood pressure in low-
income African-american older adults. Journal of Urban Health, 89(2), 308-316. doi: 
10.1007/s11524-011-9654-6 
[63] 
Alexander, C. N., Langer, E. J., Newman, R. I., Chandler, H. M., & Davies, J. L. (1989). 
Transcendental meditation, mindfulness, and longevity: An experimental study with the elderly. 
Journal of Personality and Social Psychology, 57(6), 950-964.  

23 
Detailed Protocol: SAGE 
 
Version Date: 06/04/2014 
[64] 
Henriksson, B. G., Mohammed, A. H., & Winblad, B. (1994). [early stimulation--good memory in 
old age?]. Nordisk Medicin, 109(2), 64-65.  
[65] 
Pham, T. M., Winblad, B., Granholm, A. C., & Mohammed, A. H. (2002). Environmental 
influences on brain neurotrophins in rats. Pharmacology, Biochemistry and Behavior, 73(1), 167-
175.  
[66] 
Mohammed, A. H., Zhu, S. W., Darmopil, S., Hjerling-Leffler, J., Ernfors, P., Winblad, B., . . . 
Bogdanovic, N. (2002). Environmental enrichment and the brain. Progress in Brain Research, 
138, 109-133. doi: 10.1016/S0079-6123(02)38074-9 
[67] 
Mohammed, A. K., Winblad, B., Ebendal, T., & Larkfors, L. (1990). Environmental influence on 
behaviour and nerve growth factor in the brain. Brain Research, 528(1), 62-72.  
[68] 
Fahnestock, M., Garzon, D., Holsinger, R. M., & Michalski, B. (2002). Neurotrophic factors and 
alzheimer's disease: Are we focusing on the wrong molecule? Journal of Neural Transmission. 
Supplementum, (62), 241-252.  
[69] 
Zoladz, J. A., & Pilc, A. (2010). The effect of physical activity on the brain derived neurotrophic 
factor: From animal to human studies. Journal of Physiology and Pharmacology, 61(5), 533-541.  
[70] 
Brehmer, Y., Rieckmann, A., Bellander, M., Westerberg, H., Fischer, H., & Backman, L. (2011). 
Neural correlates of training-related working-memory gains in old age. Neuroimage, 58(4), 
1110-1120. doi: 10.1016/j.neuroimage.2011.06.079 
[71] 
Ngandu, T., von Strauss, E., Helkala, E. L., Winblad, B., Nissinen, A., Tuomilehto, J., . . . Kivipelto, 
M. (2007). Education and dementia: What lies behind the association? Neurology, 69(14), 1442-
1450.  
[72] 
Hakansson, K., Rovio, S., Helkala, E. L., Vilska, A. R., Winblad, B., Soininen, H., . . . Kivipelto, M. 
(2009). Association between mid-life marital status and cognitive function in later life: 
Population based cohort study. BMJ, 339, b2462. doi: 10.1136/bmj.b2462 
[73] 
Daffner, K. R., Ryan, K. K., Williams, D. M., Budson, A. E., Rentz, D. M., Wolk, D. A., & Holcomb, P. 
J. (2006). Increased responsiveness to novelty is associated with successful cognitive aging. 
Journal of Cognitive Neuroscience, 18(10), 1759-1773.  
[74] 
Riis, J. L., Chong, H., Ryan, K. K., Wolk, D. A., Rentz, D. M., Holcomb, P. J., & Daffner, K. R. (2008). 
Compensatory neural activity distinguishes different patterns of normal cognitive aging. 
Neuroimage, 39(1), 441-454. doi: 10.1016/j.neuroimage.2007.08.034 
[75] 
Daffner, K. R., Mesulam, M. M., Scinto, L. F., Acar, D., Calvo, V., Faust, R., . . . Holcomb, P. (2000). 
The central role of the prefrontal cortex in directing attention to novel events. Brain, 123(5), 
927-939.  
[76] 
Daffner, K. R., Rentz, D. M., Scinto, L. F. M., Faust, R., Budson, A. E., & Holcomb, P. J. (2001). 
Pathophysiology underlying diminished attention to novel events in patients with early AD. 
Neurology, 56, 1377-1383.  
[77] 
Daffner, K. R., Scinto, L. F., Weitzman, A. M., Faust, R., Rentz, D. M., Budson, A. E., & Holcomb, P. 
J. (2003). Frontal and parietal components of a cerebral network mediating voluntary attention 
to novel events. Journal of Cognitive Neuroscience, 15(2), 294-313.  
[78] 
Daffner, K. R., Ryan, K. K., Williams, D. M., Budson, A. E., Rentz, D. M., Scinto, L. F. M., & 
Holcomb, P. J. (2005). Age-related differences in novelty and target processing among 
cognitively high performing adults. Neurobiology of Aging, 26, 1123-1295.  
[79] 
Riis, J. L., Chong, H., McGinnnis, S., Tarbi, E., Sun, X., Holcomb, P. J., . . . Daffner, K. R. (2009). 
Age-related changes in early novelty processing as measured by ERPs. Biological Psychology, 
82(1), 33-44.  
[80] 
Chong, H., Riis, J. L., McGinnis, S. M., Williams, D. M., Holcomb, P. J., & Daffner, K. R. (2008). To 
ignore or explore: Top-down modulation of novelty processing. J.Cogn Neurosci., 20(1), 120-134.  

24 
Detailed Protocol: SAGE 
 
Version Date: 06/04/2014 
[81] 
Daffner, K. R., Sun, X., Tarbi, E. C., Rentz, D. M., Holcomb, P. J., & Riis, J. L. (2011). Does 
compensatory neural activity survive old-old age? Neuroimage, 54(1), 427-438. doi: 
10.1016/j.neuroimage.2010.08.006 
[82] 
Haring, A. E., Zhuravleva, T. Y., Alperin, B. R., Rentz, D. M., Holcomb, P. J., & Daffner, K. R. (2013). 
Age-related differences in enhancement and suppression of neural activity underlying selective 
attention in matched young and old adults. Brain Research, 1499, 69-79. doi: 
10.1016/j.brainres.2013.01.003 
[83] 
Greenwood, P. M., & Parasuraman, R. (2010). Neuronal and cognitive plasticity: A 
neurocognitive framework for ameliorating cognitive aging. Frontiers in Aging Neuroscience, 2, 
150. doi: 10.3389/fnagi.2010.00150 
[84] 
Sorond, F. A., Kiely, D. K., Galica, A., Moscufo, N., Serrador, J. M., Iloputaife, I., . . . Lipsitz, L. A. 
(2011). Neurovascular coupling is impaired in slow walkers: The mobilize Boston study. Annals of 
Neurology, 70(2), 213-220. doi: 10.1002/ana.22433 
[85] 
Sorond, F. A., Schnyer, D. M., Serrador, J. M., Milberg, W. P., & Lipsitz, L. A. (2008). Cerebral 
blood flow regulation during cognitive tasks: Effects of healthy aging. Cortex, 44(2), 179-184. 
doi: 10.1016/j.cortex.2006.01.003 
[86] 
Sorond, F. A., Hurwitz, S., Salat, D. H., Greve, D. N., & Fisher, N. D. (2013). Neurovascular 
coupling, cerebral white matter integrity, and response to cocoa in older people. Neurology, 
81(10), 904-909. doi: 10.1212/WNL.0b013e3182a351aa 
[87] 
Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975). "Mini-mental state": A practical method 
for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research, 12(3), 
189-198.  
[88] 
Ryan, J., & Paolo, A. (1992). A screening procedure for estimating premorbid intelligence in the 
elderly. Clinical Neuropsychologist, 6(1), 53-62.  
[89] 
Kaplan, E., Goodglass, H., & Weintraub, S. (1983). Boston naming test. Philadelphia: Lea & 
Febiger. 
[90] 
Lansing, A. E., Ivnik, R. J., Cullum, C. M., & Randolph, C. (1999). An empirically derived short form 
of the Boston naming test. Archives of Clinical Neuropsychology, 14(6), 481-487. doi: 
http://dx.doi.org/10.1016/S0887-6177(98)00022-5 
[91] 
Wechsler, D. (1997). Wechsler Adult Intelligence Scale. WAIS-III. Administration and scoring 
manual (3rd ed.). San Antonio, TX: The Psychological Corporation. 
[92] 
American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders 
(4th ed.). Washington, DC: American Psychological Association. 
[93] 
Yesavage, J. A., Brink, T. L., Rose, T. L., Lum, O., Huang, V., Adey, M., & Leirer, V. O. (1982). 
Development and validation of a geriatric depression screening scale: A preliminary report. 
Journal of Psychiatric Research, 17(1), 37-49.  
[94] 
Morris, J. C. (1993). The Clinical Dementia Rating Scale (CDR): Current version and scoring rules. 
Neurology, 43, 2412-2414.  
[95] 
Marin, R. S., Biedrzycki, R. C., & Firinciogullari, S. (1991). Reliability and validity of the Apathy 
Evaluation Scale. Psychiatry Research, 38(2), 143-162.  
[96] 
Reitan, R., & Wolfson, D. (1985). The Halstead-Reitan neuropsychological test battery: Theory 
and clinical interpretation. Tucson: Neuropsychology Press. 
[97] 
Ivnik, R. J., Malec, J. F., Smith, G. E., Tangalos, E. G., & Petersen, R. C. (1996). Neuropsychological 
tests' norms above age 55: COWAT, BNT, MAE Token, WRAT-R Reading, AMNART, STROOP, 
TMT, and JLO. The Clinical Neuropsychologist, 10(3), 262-278.  
[98] 
Craig, C. L., Marshall, A. L., Sjostrom, M., Bauman, A. E., Booth, M. L., Ainsworth, B. E., . . . Oja, P. 
(2003). International physical activity questionnaire: 12-country reliability and validity. Medicine 

25 
Detailed Protocol: SAGE 
 
Version Date: 06/04/2014 
and Science in Sports and Exercise, 35(8), 1381-1395. doi: 
10.1249/01.MSS.0000078924.61453.FB 
[99] 
Oldfield, R. C. (1971). The assessment and analysis of handedness: The Edinburgh inventory. 
Neuropsychologia, 9(1), 97-113.  
[100] 
Cacioppo, J. T., Petty, R. E., & Kao, C. F. (1984). The efficient assessment of need for cognition. 
Journal of Personality Assessment, 48(3), 306-307. doi: 10.1207/s15327752jpa4803_13 
[101] 
Brown, K. W., & Ryan, R. M. (2003). The benefits of being present: Mindfulness and its role in 
psychological well-being. Journal of Personality and Social Psychology, 84(4), 822-848.  
[102] 
Burckhardt, C. S., Anderson, K. L., Archenholtz, B., & Hagg, O. (2003). The Flanagan Quality of 
Life Scale: Evidence of construct validity. Health and Quality of Life Outcomes, 1, 59. doi: 
10.1186/1477-7525-1-59 
[103] 
Buysse, D. J., Reynolds, C. F., 3rd, Monk, T. H., Berman, S. R., & Kupfer, D. J. (1989). The 
Pittsburgh Sleep Quality Index: A new instrument for psychiatric practice and research. 
Psychiatry Research, 28(2), 193-213.  
[104] 
Hays, R. D., Sherbourne, C. D., & Mazel, R. (1995). User's manual for the medical outcomes study 
(mos) core measures of health-related quality of life. In R. Corporation (Ed.). Santa Monica, CA: 
RAND Corporation. 
[105] 
Stewart, A. L. W. J. E. (1992). Measuring functioning and well-being : The medical outcomes 
study approach. Durham: Duke University Press. 
[106] 
Kroll, J. F., & Potter, M. C. (1984). Recognizing words, pictures, and concepts: A comparison of 
lexical, object and reality decisions. Journal of Verbal Learning and Verbal Behavior, 23(1), 39-66.  
[107] 
Kosslyn, S. M., Alpert, N. M., Thompson, W. L., Chabris, C. F., Rauch, S. L., & Anderson, A. K. 
(1994). Identifying objects seen from different viewpoints: A pet investigation. Brain, 117, 1055-
1071.  
[108] 
Daffner, K. R., Chong, H., Sun, X., Tarbi, E. C., Riis, J. L., McGinnis, S. M., & Holcomb, P. J. (2011). 
Mechanisms underlying age- and performance-related differences in working memory. Journal 
of Cognitive Neuroscience, 23(6), 1298-1314. doi: 10.1162/jocn.2010.21540 
[109] 
Daffner, K. R., Zhuravleva, T. Y., Sun, X., Tarbi, E. C., Haring, A. E., Rentz, D. M., & Holcomb, P. J. 
(2012). Does modulation of selective attention to features reflect enhancement or suppression 
of neural activity? Biological Psychology, 89(2), 398-407.  
[110] 
Delorme, A., & Makeig, S. (2004). EEGLAB: An open source toolbox for analysis of single-trial EEG 
dynamics including independent component analysis. Journal of Neuroscience Methods, 134(1), 
9-21. doi: 10.1016/j.jneumeth.2003.10.009 
[111] 
Borg, G. (1970). Perceived exertion as an indicator of somatic stress. Scandinavian Journal of 
Rehabilitation Medicine, 2(2), 92-98.  
[112] 
Borg, G. A. (1982). Psychophysical bases of perceived exertion. Medicine and Science in Sports 
and Exercise, 14(5), 377-381.  
[113] 
Eston, R. G., & Williams, J. G. (1988). Reliability of ratings of perceived effort regulation of 
exercise intensity. British Journal of Sports Medicine, 22(4), 153-155.  
[114] 
Dunbar, C. C., Robertson, R. J., Baun, R., Blandin, M. F., Metz, K., Burdett, R., & Goss, F. L. (1992). 
The validity of regulating exercise intensity by ratings of perceived exertion. Medicine and 
Science in Sports and Exercise, 24(1), 94-99.  
[115] 
Skinner, J. S., Hutsler, R., Bergsteinova, V., & Buskirk, E. R. (1973). The validity and reliability of a 
rating scale of perceived exertion. Medicine and Science in Sports, 5(2), 94-96.