Protocol
1. Project Title : Platform for Multi-Modal Cognitive Enhancement in the Elderly
2. Investigator(s):
Dawn Bowers, Ph.D., Professor, Clinical and Health Psychology (Primary Investigator) Michael Marsiske, Ph.D., Assoc. Professor, Clinical and Health Psychology (Co-PI) Bruce Crosson, Ph.D., Professor, Clinical & Health Psychology Chris Hass, Ph.D., Dept of Applied Kinesiology and Physiology Michael Okun, M.D., Associate Professor, Neurology William Perlstein, Ph.D., Associate Professor, Clinical & Health Psychology Brent A. Reynolds, Ph.D., Professor, Neurosurgery David Weiner, M.D., Professor, Medicine and Physiology, Chief Nephrology & Hypertension Division Vonetta Dotson, Ph.D., Assist. Professor, Clinical and Health Psychology (Co-PI) Robert Slaton, M.D., Internist (Unaffiliated Investigator) Dennis Steindler, Ph.D., Medical Director MBI (Steering Committee, Project Champion)
3. Abstract:
Cognitive decline is an acknowledged consequence of aging and is a precursor to dementia. There are an estimated 27 million individuals affected by dementia worldwide, with the cost of care in many developed countries beginning to surpass those associated with cardiovascular disease and cancer combined.1 Due to the shift in the age profile of our population it is estimated that by 2030 there will be over 7.7 million individuals in the US with dementia, hence, there is an urgent need to develop strategies to prevent or hinder the escalation in the presentation of severe cognitive dysfunction. To this point, a delay of symptom onset may be a reasonable short-term tangible goal, as delay of dementia presentation by five years would effectively halve the burden of disease.2
In this proposal, we intend to pilot the combined use of two of the most powerful behavioral interventions: cognitive training and physical exercise. Individually, these two interventions have a wealth of pre-clinical and clinical data supporting their effectiveness as interventions to increase brain plasticity and enhance cognition. What is unknown, at present, is whether there is synergistic benefit that derives from combining these interventions, and if so the extent of this benefit.
Thus, the overall aim of the present study is to determine how cognitive training and physical exercise interact to improve cognitive status of non-demented healthy elders. We specifically want to learn whether pre-dosing with physical exercise “primes” or augments the positive effects of cognitive training and whether this benefit occurs relatively quickly or more gradually over time. We will also examine whether the expected 06.28.10 IRB # 179-2010 1 | P a g e
cognitive benefits are associated with biological markers such as BDNF(Brain Derived Neurotrophic Factor) changes in overall physical fitness, mood, or other factors (i.e., self- efficacy). Finally, we want to learn whether the popular Wii-Fit exercise program exerts similar benefits on cognitive training as more traditional physical exercise. To address these aims, we plan to conduct a randomized, parallel-group study of cognitive training (Posit Science Insight Program) combined with either a standard physical exercise or a video-based exercise program (Nintendo Wii Fit Plus). Participants will include at least 60 community residing normal elders who will participate in 16 weeks of training. Response to these interventions will be examined with respect to cognitive, mood, biological markers, and quality of life indices. If successful, the obtained findings will provide initial evidence-based information regarding the effectiveness of exercise pre- dosing on cognitive training that can be easily implemented in home settings using commercially available computer and television-guided modules. This is particularly important given the rapidly expanding aging community and the relatively simple, low cost, and potentially clinically effective benefits that may derive from non-pharmacologic behavioral approaches to health.
4. Background:
A. Neurogenesis and Cerebral Cortical Plasticity
This study will address potential enhancement of brain function for the elderly, exploiting a combination of learning and exercise regimens. Even though such an approach has been investigated by many others, it has not been analyzed under the conditions laid-out in this proposal within a large, controlled, and highly-accessible study group.
The investigators on this grant have expertise in neurogenesis and cerebral cortical plasticity, cognitive intervention, as well as clinical trial presentation for mild cognitive impairment that together with the novel learning and assessment approaches, make such a study feasible. Since it is generally accepted that the brain like all tissues and organs, undergoes changes during a lifetime that can lead to cognitive decline as a result of so- called normal aging3 our approaches and expertise offer a reasonable platform for analyzing both the behavioral and biological underpinnings of lifelong learning and exercise for maintaining and even enhancing cognitive neural function.
The serious aging process probably begins as early as the age of 30 and, generally, worsens slowly but steadily thereafter4. Most if not all older adults will eventually experience loss in the ability to process information rapidly 5. Certain cognitive abilities, including visuospatial skill, executive functions, and speech comprehension have been found to generally deteriorate with age 6 ,7. There is a vast lexicon to describe normal age- related cognitive decline, including age-associated memory impairment, age-consistent memory impairment, age-related memory loss, benign senescent forgetfulness, late-life forgetfulness, and aging-associated cognitive decline 8, 9. During normal aging, the extent of cognitive decline gradually increases with age even though there is considerable 06.28.10 IRB # 179-2010 2 | P a g e
variation within a group of individuals as to the nature, degree, and timing of cognitive loss 10. Normal cognitive decline is an inevitable outcome of age despite such variability. There is no question that most individuals living beyond the fifth decade will suffer some degree of cognitive loss.
So-called normal cognitive decline is not the same as pathological cognitive loss, i.e. that involves a sizeable proportion of the elderly and ultimately can lead to dementia. Cognitive decline that has a pathological basis, including potentially loss of neurons, synapses, and neuropoietic stem/progenitor cells 11 may appear to be a healthy, normal aging process in the early stages, and evolve to a significant attenuation of standard operating brain function, particularly that associated with memory functions. Mild cognitive impairment (MCI) occurs in nearly twenty five percent of aging adults, characterized by impaired function in a specific cognitive domain (e.g., memory) with other activities of daily living generally remain unaffected 12. Such individuals with MCI exhibit extreme losses in neuromodulatory activity crucial for sustaining learning operations and vivifying memory (see AsDEaRC, 2001–2002, 2002).
Over three quarters of individuals diagnosed with MCI progress to dementia within 5–8 years following this diagnosis making MCI at least transitional or even high-risk for more serious memory issues including dementia or Alzheimer‟s Disease (AD). That said, only 1-2 % of adults with “normal” age-related cognitive decline develop dementia each year. It is therefore argued that if adults were to live long enough, the progressive physical deterioration of the brain would eventually cause dementia in most if not all cases 13. It is also suggested that some of the dementias, and perhaps MCI cases, represent specific pathological conditions that are not the expected end states of healthy aging 8 and there are findings that support both theories regarding the inevitability of dementia. The elderly become more vulnerable to developing dementia with increasing age, such that almost half of the adults over the age of 85 have AD 14 yet many remain cognitively able even into very old age, experiencing only minor changes in the speed of information processing of especially the most attention-demanding tasks 8. Thus it is clear that normal cognitive decline is a general phenomenon with a clinically significant amount of cognitive decline being increasingly common with advancing age.
B. Relevant Research
There have been countless studies documenting physical, anatomical, physiological, and chemical changes that occur in the aging brain 15, and in all, an extensive research literature has established five basic principles:
(1) Neurons and the strengths and richness of their interconnections progressively atrophy with age; (2) Declining brain machinery includes the cerebral cortex and subcortical structures that are involved in sensation, cognition, memory, motor control, and affect;
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(3) Metabolic decline and the down-regulation of important cellular functions within vital neuronal groups generally occur prior to cell loss; (4) Most aspects of physical and chemical deterioration and resultant neuropathology are in line with behavioral losses; (5) Even though there is substantial variation in the time of onset, course, and magnitude of functional and physical deterioration, these changes are a virtually universal outcome of the later years of an extended human life.
The findings described above lead to a viewpoint referred to as the „„wear and tear‟‟ hypothesis of cognitive decline in aging i.e. brain circuitries just wear down over time with observed anatomical changes (including cell death, metabolic status, connectivity) and consequent functional changes (e.g., memory deficits, reduced processing speed, impaired spatial abilities) are the consequences of any biological or mechanical machine that has been in operation for multiple decades. It is thus clear that cognitive decline is inevitable. There is no question then that the physical aging of the brain underlies many aspects of age-related cognitive decline, yet it is increasingly clear that the inevitable physical deterioration of the aging brain cannot completely account for many of the changes in functioning observed in older adults. There is a growing literature on brain plasticity and the perceptual psychophysics of aging that strongly suggests brain plasticity with negative consequences is an important contributor to age-related cognitive decline. With advancing age, a person‟s schedules and strengths of brain engagement substantially change, and at the same time there is a robust deterioration of brain function. Thus age-related cognitive decline can be a result of changes in brain use and engagement.
C. The Brain is Receptive to Learning-Induced “Plasticity” Through Life
It is generally accepted that brain plasticity refers to the brain‟s lifelong capacity for physical and functional change, and this competence explains how experience can induce learning throughout one‟s life. Critical period-associated plasticity, as explored by one of the investigators on this grant 16 in looking at how the cerebral cortex is built during development, has generally been dissociated from the types of plasticity that must occur during adulthood and aging because no new neurons are supposed to be generated and circuitry reorganization is supposed to be a undertaking reserved for only the young. Thus historically, brain plasticity has been more often discussed in the contexts of early child development, stroke recovery, and perceptual learning than in regard to aging. We now know that neurogenesis does occur over a life time even in the human 11 and even though we are not yet certain as to the role of stem and progenitor cell neuropoiesis in memory and learning thoughout life, there is no question that new neurons and glia are added to areas of the brain where such functions are at least postulated to occur 17.
We now believe that circuitry reorganization and enhancing neural function through behavioral or pharmacological interventions is possible regardless of age; thus the concept of lifelong brain plasticity not being possible because the human brain is hard- wired in early life is no longer tenable. There are “critical periods” during childhood
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development whereby the brain develops its physical structures and long-range interconnections that determine neurological functioning during this early time in neurohistogenesis, but many of the same attributes of developmental plasticity are retained in the adult brain, including a responsiveness to “peripheral” stimuli (including environmental, as in the case of whisker function, shaping activity-driven neural representations, again see Cooper and Steindler, 1989 as an example) 16 that we have grown to appreciate through developmental neurobiology shape the structure and function of neurons, glia, and synaptic circuitries involved in behaviors including not only somatosensory recognition but also higher forebrain cognition. As even the state and activity of glia were implicated in such developmental critical periods 18, these cells have re-emerged as key players in adult cerebral cortical functioning by being shown to be key elements involved in fMRI signals 19. It has been established that during developmental critical periods, the brain is capable of substantial remodeling in response to alterations in input; but after the critical period closed, again, it was generally reported that the brain was not capable of further significant remodeling, elaboration, or growth.
Such a notion of the brain‟s development being incontrovertible, with long range interconnections established in early life contributing to the belief that age-related cognitive decline was inevitable and irreversible has now been replaced, due to multi- disciplinary research advances, with a very different view about the origin and maintenance of human capabilities.
The new view suggests that the brain is always plastic; i.e., the brain is capable of reorganization, including developing new short-range interconnections, at any age throughout adult life. Brain plasticity experiments have documented a number of important ways in which progressive learning changes brain machinery, including perhaps neurogenic elements that even without the possibility that the production of new neurons is directly involved in memory or other functions, their presence changes the cellular and molecular milieu of the brain in ways we just do not yet understand despite studies that show both correlative and non-correlative associations with the learning and memory structures and functions in the brain 17, 20,21. In all, such new research demonstrates that the adult brain continuously adapts to disproportionately relevant sensory stimuli and behavioral outputs within well-coordinated populations of neurons, and this is achieved by engaging competitive processes in brain networks that refine the selective representations of sensory inputs or motor actions, typically resulting in increased strengths of cortical resources devoted to, and enhanced representational fidelity (or „„precision‟‟) of, the learned stimulus or behavior. Exploiting these now generally accepted plasticity components and outcomes is the focus of the present proposal.
D. Previous Human and Animal Research Studies
Studies in humans have documented that cognitive activity thwarts future decline with aging, perhaps by building what is referred to as a „„cognitive reserve,‟‟ - a euphemism for strengthened brain processing machinery 22. In recent years, various well-designed, prospective studies have shown that participation in cognitively stimulating activities 23 ,24,
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intellectually complex work 25 as well as leisure activities 26 ,27 during adulthood reduces the risk of loss of cognitive prowess in later life. Involvement in cognitive activity would potentially counter each of the four conditions believed to contribute to functional decline in the elderly: cognitive activity is the opposite of brain disuse; it would strengthen the brain processing machinery to ensure less noisy, distracting processing; it is likely to be done within behavioral contexts (e.g., attention, reward, novelty) that strengthen neuromodulatory control; and it disrupts the downwards spiral of negative learning. Human behavioral studies have shown that losses in sensory, cognitive and motor processing are reversible. Specific training regimens are known to refine degraded representations in the sensory and motor cortices 28, improve signal-to-noise conditions for neuronal representations and distributed neuronal response coherence, can restore the effectiveness of long-range feed-forward connections 29, 30, 31 and neglected cognitive skills can be strengthened and refined by utilization 32.
There is also a growing literature from animal studies that support the notion that behavioral interventions, such as an enriched environment designed to stimulate cognition, promotes positive plastic changes in the brain and can even reverse the negative physical, sensory, and cognitive aspects of advancing age 33,34, 35. Again, these studies also have shown that neurogenesis, new neuron production, can be increased in areas where cell division and proliferation are possible (e.g., the hippocampus) 36 and apoptotic cell death can be reduced 37. Most notably, gray matter can be thickened, most likely a result of elaboration of dendrites, spines, and synapses in the cortical neurophil 38 ,39, 40,15 but new glia may also be involved in synaptic and circuitry resculpturing 41. Myelination, which had previously been thought to be irrecoverable in the adult brain, can even be restored 42, 43. There are neuromodulatory control systems that are weakened during aging and that can be strengthened by behavioral training, and such training can enhance metabolic states and the production and release of key neurotransmitters of limbic system and basal ganglia44. Such an effective and intense reactivation of cortical and subcortical modulatory control can enhance function of higher cognitive structures and functions45. Thus under optimal environmental conditions, it is possible that most physical aspects of the brain can recover from age-related losses. Likewise, loss of vascular dynamics that are attributed to ACh control of nitric-oxide-related enzymes is also believed to foreshadow AD pathology, and this may be at least partially overcome46. It has also been demonstrated that even certain pathological hallmarks of AD, such as amyloid burden, could be ameliorated by exposure to an enriched environment47.
Numerous studies now have shown that behavioral training or exposure to a novel environment can further shape representations in the somatosensory and motor cortices of animals48; exposure to an enriched environment also can improve memory and learning in older animals49) and animals that are cognitively impaired50,51. This is most likely attributable to augmenting synaptic arrangements that enhance memory and learning36, 50. It is now considered reasonable to postulate that the negative effects of earlier exposure to an impoverished environment can be at least partially reversed by exposure to an enriched environment later in life52.
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Such an extensive list of studies, plus many more not able to be adequately reviewed here, hopefully clearly shows that substantial reorganization and recovery is possible even in the aged brain. Physical losses appear to be reversible, and many aspects of sensory, motor, neuromodulatory, and cognitive structures and circuitries can be potentially restored to near-optimal levels of functioning. Studies proposed here will more clearly define the extent of positive plastic changes that may be achieved, and the conditions under which these changes can be maintained over time.
E. Preliminary Results
Evidence from animal models demonstrates several possible mechanisms that may underlie the ameliorative effects of aerobic exercise on cortical structure in aging. For example, in rats exercise has been shown to increase brain neurotrophins such as brain- derived neurotrophic factor, 53,54 and nerve growth factor55,53. Also, physical activity has been shown to have neuroprotective effects on the brain, leading to neurogenesis in the hippocampus, new cell growth 56 and protection from ischemic damage within the hippocampal formation 57. Additionally, chronic exercise is associated with growth of blood vessels (angiogenesis) and synaptogenesis in cortex 58,59,60. Collectively, these transformations result in a brain that is more efficient and neuroplastic resulting in increased performance and learning in the animal56.
Primary work from Kramer and colleagues has led to the seminal observation that aerobic exercise and/or cardiovascular fitness may retard or reverse age-related cognitive decline. Colcombe and colleagues61,62,63 demonstrated that older adults with greater levels of cardiovascular fitness had significantly less atrophy of gray matter in the frontal cortex as well as significantly less loss of tissues in both the anterior and posterior white matter tracts. Several more recent randomized-controlled trials also report that aerobic exercise has its greatest effects on frontal lobe. For example, older adults who participated in a 6-month aerobic fitness training had significantly increased brain volume in both gray and white matter compared to controls64. This finding is meaningful because frontal areas typically demonstrate the greatest age-related decline65. Studies in healthy older adults have also shown that cognitive improvements due to exercise may be observable even 18 months after the intervention 66 and that cognitive effects do not necessarily have to be mediated by improvements in fitness 67. Not surprisingly, the combinations of aerobic and mental training have been shown to have a greater effect on cognitive function than either training modality on its own68,696 However, despite these fairly impressive results, few studies have investigated this approach. The investigators of this proposal have individually and/or as a group, a solid track record of investigating cognition, and motor function and extensive experience in exercise and interventional trials as well as with other populations.
F. Summary
Overall, the above mentioned large group of studies shows that substantial recovery is possible in the aging brain, physical losses can be reversed, and aspects of sensory,
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motor, and cognitive systems can be restored to more youthful levels of functioning. Two of the strongest effectors have been behavioral interventions (cognitive stimulation and exercise) suggesting that safe and cost effective programs can be implemented to produce a meaningful improvement in cognitive ability that will persist after training and transfer to non-trained domains. This speaks to the core of our proposal, where we intend to pilot the implementation of cognitive training and exercise and measure its effectiveness on a number of outcomes including cognitive ability, transference to everyday tasks, maintenance beyond the training period and conversion to MCI.
5. Specific Aims:
The overall aim of the present study is to determine how cognitive training and physical exercise interact to improve the functional cognitive status of older adults. To address this aim, healthy non-demented elders will participate in a randomized parallel-group study of cognitive training combined with a physical exercise program over a 16 week period. Participants will be randomized to one of three intervention groups: cognitive training alone, cognitive training in conjunction with traditional aerobic exercise (treadmill walking or recumbent biking), or cognitive training in conjunction with the Nintendo Wii-Fit Plus program. Cognitive training will involve approximately 40 hours of training on a well- validated Posit Science brain training program called Insight. Participants will be tested on neurocognitive, mood, memory, physical and other probes prior to, during, and immediately following training and again 3 months later. Our specific aims are as follows:
Specific Aim 1: To determine whether pre-dosing with physical exercise “primes” or augments the effects of a cognitive intervention.. Specifically, does pre-dosing with exercise prime the brain‟s physiologic readiness for subsequent cognitive change? To address this question, participants will engage in 3 weeks of consecutive exercise prior to engaging in a week of cognitive training. This monthly pattern will recur four times during the 16 week program. The primary outcome measure is a functional cognition score derived from an empirically validated measure from the ACTIVE trial (Timed Instrumental Activities of Daily Living). Secondary outcomes include performance on more traditional neurocognitive domains of memory and executive functioning as well as embedded tests within the Insight program itself. Based on preliminary results and that in the literature, we anticipate greater cognitive benefits in the Exercise + Cognitive training groups than the Cognitive Training alone group.
As an exploratory part of this aim, we will also address whether there are differences in short-term maintenance effects as a result of engagement in exercise. To do so, participants will be re-evaluated 3 months after the program has ended. Particular attention will be paid to intervening events (illness, continued exercise, etc.) that might potentially modulate long term training effects during the 3 month post-training interval. We hypothesize that the combination program (cognitive plus exercise) will have stronger maintenance effects than cognitive training alone. 06.28.10 IRB # 179-2010 8 | P a g e
Specific Aim 2: To determine the trajectory of exercise pre-dosing benefits over time. We specifically want to learn whether the benefits on cognitive intervention due to physical exercise occur relatively quickly or whether they gradually develop over the course of the 16 week program. To address this question, we will evaluate participants using select cognitive probes at targeted points in time: immediately following each week of cognitive training (i.e., weeks 4, 8, 12, and 16) and 3 months post training. This will enable us to examine trajectory of benefit/change over time in participants receiving exercise versus those who do not. We suspect that a major benefit of exercise pre- dosing will occur by the 12th week of the program.
Specific Aim 3: To examine the impact of training on everyday functioning, mood, and other non-cognitive aspects of daily living. Across all time points, participants will complete participant-reported outcome (PRO) assessment along with measures of mood, fatigue, and insomnia. As an exploratory aim, we will also examine the relationship among pre-post changes in cognitive status and the following variables: changes in aerobic fitness, changes in certain proteins that are associated with neurogenesis (i.e., BDNF) and possibly red blood cell gas transport (AQP1, AE1, RhAG), and overall activity level.
Specific Aim 4: To determine whether a video-based exercise program, Nintendo Wii-Fit Plus, will exert similar effects on cognitive training as a more traditional exercise program. Although several recent studies have raised questions about the true aerobic benefit of exergames such as Wii-Fit Plus, other evidence suggests that these weaker aerobic benefits may be offset by the greater novelty and interest level afforded by exergames. To address this question, we will compare the Wii-Fit and traditional exercise groups in terms of cognitive and non cognitive benefits, as well as changes in aerobic fitness (i.e., 6 minute walk test) and biological markers (i.e., BDNF).
6. Research Plan: Re-Design of MBI Cognitive-Exercise Study A. Design Overview
An overview of the study Screening design is shown in Figure 1. Baseline Evaluation This is a pilot study of the Biomarkers: BDNF, etc. efficacy of combined use of Randomization cognitive and exercise N=20 N=20 N=20 training programs on the 16 weeks cognitive status of normal Aerobic + Wii-Fit + Cognitive Training elders. We propose to Cognitive Cognitive Only conduct a randomized parallel-group study of Post-Treatment Monthly Regiment for Evaluation cognitive training combined Monthly Regiment for Exercise-Cognitive Groups Biomarkers Cognitive Group Wk 1: Exercise Wk 2: Exercise Wk 1: nothing 06.28.10 IRB # 179-2010 Wk 3: Exercise 12 weeks Wk 2: nothing Wk 4: Exercise + COGNITIVE Wk 3: nothing Monthly COGNITIVE PROBE 9 | P a g e Wk 4: COGNITIVE Monthly PROBE 3 month Followup with exercise in participants (age 60 +) recruited from The Villages Retirement Community (See Appendix 10 Letter of Support) and others from the surrounding Gainesville, Florida area. Participants will be randomly assigned to one of 3 treatment groups that vary according to exercise. As shown in the figure, the three groups include: a) Cognitive Training + Traditional Aerobic Exercise; b) Cognitive Training + Wii-Fit; and c) Cognitive Training alone. The overall goal is for 60 participants to complete the study (i.e., N=20/group).
For cognitive training, we have chosen the Insight program from Posit Science. Insight is a well validated cognitive training program that appears particularly effective in influencing visual processing, attention, and memory. This program was originally developed around a model of effective learning anchored in “brain plasticity” research (Mancke et al., 2006). For exercise training, we have selected traditional aerobic exercise (either treadmill walking or recumbent biking) and the Nintendo Wii Fit Plus module because of its ease of use and widespread appeal among seniors.
The primary outcome is the change in functional cognition from pre to post-training as measured by the Timed Instrumental Activities of Daily Living Measure. The latter is an empirically validated measure from the NIH funded ACTIVE trial. Secondary outcomes include performance on more traditional domains of neurocognition (verbal recent memory, visual recent memory, working memory, visual attention and processing speed, executive functioning) including built in tests that are part of the Insight Program.
B. Participants
Participants will include individuals age 60 + who are relatively healthy and able to undergo cognitive and exercise training. Our recruitment goal is for 60 participants to complete the study (i.e., 20 per group). Based on a 20% attrition rate (i.e., 72 participants) and up to 40 screen failures, we anticipate consenting up to 112 participants.
Informed Consent: Informed consent will be obtained according to university and federal guidelines. The informed consent process will begin with the initial telephone screening call, when a prospective participant calls to find out more information about the study. (Please see Appendix 3 Telephone Pre- Screening Script.) After that first phone contact, the participant will be invited to meet in a discrete and private office setting at The Villages Retirement Community or the McKnight Brain Institute. The Study Coordinator will explain the project in detail, and review line by line through the Informed Consent Form (ICF) very slowly for ease of comprehension. The participant is welcome to bring along a friend or family to the appointment to help them with understanding the project and the commitment required for their participation to be successful. The participant will be given the opportunity to ask questions, and offered the opportunity to review the informed consent paperwork with family or to take it home for review. No study interventions will begin until the Informed Consent (ICF) paperwork is signed. Participant
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will be given a signed copy of the ICF paperwork, and a copy will be kept on file with the Primary Investigator.
Specific inclusion and exclusion criteria are shown below.
Inclusion criteria: a) 60 + years of age and able to walk; b) able to provide informed consent and perform cognitive and exercise interventions; c) willing and able to have time availability for completing the study; d) absence of significant behavioral or cognitive dysfunction based on the Mini-Mental State Exam (MMSE)> 24 . No significant dementia. e) medical clearance from primary care provider or specialist to safely undergo moderate to strenuous physical activity (See Appendix 1-Physician Clearance Form); f) on stable doses of major medications; g) ability to read on 8th grade level based on scores on the Weschler Test of Adult Reading; or a reading test at 14 pt. text. h) willing to be randomized to either treatment group; i) sedentary to moderately active lifestyle.
Exclusion Criteria: a) unstable medical conditions such as uncontrolled diabetes, uncontrolled cardiac disease, and hypertension that would increase the risk of side effects performing aerobic exercise; b) inability to perform exercise due to physical impairments that would limit ability to complete physical training; c) history of multiple significant falls; greater than 2 in the past month that would increase fall risk while performing exercise; d) history of neurodegenerative disorder (Parkinson disease), previous major strokes, or other known significant brain abnormalities; moderate to severe Traumatic Brain Injury; e) previous participation in a cognitive training or exercise study within the last 3 months; f) currently engaging in moderate to heavy physical activity (ie: running, bicycling etc.) >125 mins. per week at 75% maximum target heart rate. g) history of substance abuse within the past six months; ie: alcoholism h) history of receiving neuropsychological testing within the last 6 months; i) vision or hearing loss that would preclude participation.
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C. Protocol
C1. Screening Interview and Measures (Please see Table 1.0 below)
Participants will be screened for the inclusion/exclusion criteria, as described above. To screen for dementia, participants will receive the Mini Mental State Exam. Participants will also complete additional measures and questionnaires related to mood, premorbid cognitive status, general health, exercise and activities.
Table 1.0 Screening Measures
Dementia Mini Mental State Exam (MMSE) > 24 Screen Geriatric Depression Scale (GDS): 30 item True-False scale that indexes severity of Mood depression symptoms Measures State-Trait Anxiety Inventory (STAI)); 40 item scale that assesses current (state) and more enduring (trait) levels of anxiety Wechsler Test of Adult Reading (WTAR): This single word reading test provides an Premorbid estimate of premorbid intellect; it is also a measure of reading and be use to establish Cognitive reading levels. Estimate Barona: The Barona equation provides estimate of premorbid functioning based on education, occupation, gender, and other demographic factors. A composite premorbid estimate will be derived by averaging the WTAR and the Barona estimate. Charleston Co-morbidity Index ; Health SF-36 Health Survey – 36 item scale that yields 8-scale profile of functional health and well-being, Color Vision Screening Leisure-Time Exercise Questionnaire (LTEQ): This is a scale that measures leisure Other time exercise (strenuous, moderate, mild) more than 20 minutes over the past 7 days International Physical Activity Questionnaire (IPAQ) This is brief well-validated questionnaire that gauges overall physical activity.
C.2. Baseline and Post-Treatment Measures
Participants who meet study criteria and are interested in participating will undergo additional baseline evaluation. All participants will receive the measures listed below at baseline, immediately following completion of the 16 week training program intervention, and again 3 months later. Anticipated time to complete these measures is approximately 6 hours, though it will depend on the talkativeness and speed of processing of the participant. In addition to these measures, participants will undergo blood draw by a licensed phlebotomist for the purpose of extracting exercise related biomarkers, including plasma BDNF [brain derived neurotrophic factor] and analysis of proteins that may be involved in red blood cell gas transport, such as RhAG, AQP1 and AE1 (Please see Table 2.0 Schedule of Study Activities and Interventions.) All participants will be provided pedometers and asked to wear them throughout the course of the study. This is being done because of preliminary findings by Cameron et al. (personal communication) that
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overall daily movement may be a greater predictor of cognitive change than specific type of physical exercise.
Specific functional measures include tests designed to measure aspects of a participant‟s functional status, speed of processing, and ability to solve everyday problems. Both measures below were used as part of the 10 year NIA sponsored ACTIVE trial with normal elders. Timed Instrumental Activities of Daily Living: This is a timed performance based task consisting of five common activities of daily living, including telephone communication, shopping, financial, medication, and understanding nutritional value of food items. Instrumental Activities of Daily Living (IADL)- Self Report on Activities of Daily Living
Specific neurocognitive tests include measures of Auditory Attention/Working Memory: Digit Span and Letter Number Sequencing subtests from Wechsler Memory Scale (WMS) Visual Attention/Working Memory: Spatial Span subtest from WMS Verbal Recent Memory: Hopkins Verbal Learning Test-R, Logical Memory subtest from Wechsler Memory Scale Visual Recent Memory: Family Pictures, Face Memory, and Visual Reproduction subtests from Weschler Memory Scale, Spatial Cognition: Judgment of Line Orientation, Mental Rotations Test Processing Speed: Digit Symbol and Symbol Search subtests from the Weschler Intelligence Tests Executive: Verbal Fluency from the Delis Kaplan Executive Functioning battery, Trail Making Test, Stroop Test, FlankerTest
Specific affect and mood measures include screening for Depression Beck Depression Inventory-II, Geriatric Depression Scale Anxiety : State-Trait Anxiety Inventory (STAI) Apathy: Starkstein Apathy Scale (AS) Snaith Hamilton Pleasure Scale (SHPS) Current affect: Profile of Mood States (POMS), Daily Perceived Exertion Rating
Patient self-ratings related to overall well-being, memory fitness, and specific fatigue, sleep, and pain measures. Overall Quality of Life: Participant Reported Outcome (PRO) Memory Fitness: Memory Functioning Questionnaire (MFQ) Fatigue: Fatigue Severity Scale Sleep quality: Pittsburgh Index of Sleep Quality, Epworth Sleepiness Scale Pain: Visual Analogue Scale Driving: Driving History Survey Cognitive Locus of Control Exercise History Survey
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TEPS- Temporal Experience of Pleasure Scale BIS/BAS- Behavioral Inhibition System, Behavioral Approach System
Additional measures includes indices related to expectations and treatment credibility Training Credibility & Expectation questionnaire
Specific physical exercise assessments and scales include the following:
6 Minute Walk Test. (6MWD). This is a measure of functional capacity. This test measures the distance that a person can quickly walk on a flat, hard surface in a period of 6 minutes. It evaluates the global and integrated responses of all the systems involved during exercise, including the pulmonary and cardiovascular systems, systemic circulation, peripheral circulation, blood, neuromuscular units, and muscle metabolism. Its results are highly correlated with those of ergometer or treadmill based exercise tests (Peters 1996). Further, it correlates with maximal oxygen uptake (Canning, Alison, Allen, & Groeller, 1997)
6 Minute WALK/TALK test (6MWT) -This is a dual task which measures the distance that a person can quickly walk on a flat, hard surface in a period of 6 minutes, while doing a secondary simultaneous task of cognitive activity and talking. An approved Hopkins Verbal Learning Test will be administered while the participant is actively walking the above described 6 min. test. This WALK/TALK test will be administered in addition to the plain 6 minute walk test.
GAIT-RITE Assessment (GRA)- This walking protocol requires participants to walk at self-selected speed along a flat walkway containing a 6 meter instrumented GAITRite mat (CIR Systems Inc., Havertown, PA, USA). The participant will be asked to start walking in response to a „go‟ signal and stop at a designated finish position. The start and finish positions are indicated by markers placed two body lengths before and after the mat so as to ensure steady-state walking across the GAITRite. After completing the trial, participants will pause at the finish position while the data is processed, and then walk back to the start position in response to a „go‟ command for the next trial. Data will be recorded for each traverse of the walkway. Walking velocity, step and stride length, step and stride time and step width will be collected by the GAITRite system.
Motor Function and Balance - First, we will observe you performing several movements you do every day (i.e., standing still, walking, standing from sitting). To study how you move, we will place reflective markers on your arms, legs and body. The reflective markers are small and lightweight and once in place you may not notice them. You will then be asked to walk for 20 feet several times over the ground or on the treadmill for several minutes. You will also stand in different positions for two minutes (feet close together or feet staggered) so we can evaluate your balance. Participants will be asked to perform movements familiar to them including walking on the treadmill or over ground, and standing in different 06.28.10 IRB # 179-2010 14 | P a g e
positions (feet shoulder width apart, feet together, tandom stance). While performing these tasks, we will record movements from 12 motion analysis cameras from force plates and pressure mats embedded in a floor plate,
The Activities-Specific Balance Confidence (ABC) Scale- J Gerontol. Med. Sci. 1995; 50(1): M28-34. Powell, L.E. & Myers, A.M. This is a 16 item scale that evaluates fear of falling. This is being evaluated in participants to determine if improvements in cognition or motor function improve fear of falling.
Modified Falls Efficacy Scale- Adapted from Tinetti et al, 1990; Hill et al, 1996. This measure consists of 14 questions each related to a particular activity the questions aim to determine how confidently seniors feel they are able to undertake each activity on a scale of 0 (not confident at all) to 10 (completely confident).
Exercise Self-Efficacy Scale- Mc Auley, E. (1993). Self-efficacy and the maintenance of exercise participation in older adults. Journal of Behavioral Medicine, 16, 103-113. This is an 8 item self-report questionnaire that assesses confidence and ability to exercise regularly at the upper end of perceived exertion.
Mental Readiness Form (MRF) is as three item self report measure that will be completed immediately prior to initiation of gait assessments, to examine state anxiety levels of the participant.
C.3 Cognitive and Exercise Interventions (16 weeks)
Cognitive Training
All participants will be asked to complete 40 hours of cognitive training, spread out over a 16 week period. Cognitive training will occur only during weeks 4, 8, 12, and 16 . During these weeks, training will take place every day (5 days a week, for approximately 90 minutes/ day). Participants will receive multiple breaks during the 90 minute period to minimize fatigue. Cognitive training will involve use of Insight, a commercially available training program from Posit Science. The Insight program engages participants in game- like experiences designed to exercise sensory and cognitive skills. To progress through an exercise, the participant must perform increasingly difficult discrimination, recognition or sequencing tasks under conditions of close attentional control. These programs use sophisticated adaptive tracking methods that enable difficulty level to change in accordance with the participant‟s performance level, typically locking in on 80-90% correct. Each exercise employs a carefully chosen set of stimulus sets designed to allow the enhancement of cognitive function driven by training to generalize to real-world stimuli and behaviors. In general, this is done by using multiple categories of stimuli to ensure that learning is not stimulus specific, and by moving from emphasized (e.g., high contrast,
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temporally stretched) stimuli in early training to ecologically relevant stimuli (e.g., real speech, complex realistic visual stimuli) in later training.
The Insight program consists of five different modules that focus on visual processing , attention, and memory. Each of these is described below.
a. Bird Safari:. This module involves identifying and ordering simple visual stimuli that flash on a screen. Goal is to improve ability to respond quickly to visual stimuli and to segment rapidly changing visual pictures. b. Jewel Diver: This module involves tracking objects as they become hidden by distractors. Goal is to improve ability of visual system to rapidly identify/discriminate objects in the visual periphery. c. Master Gardener: This module involves visual working memory and matching pairs of pictures . d. Road Tour: This is a simulated driving exercise that involves divided attention to oncoming cars and road signs. Goal is to improve ability of visual system to continusouly track multiple objects against a field of distractors. e. Sweep Seeker: In this exercise, participants identify complex moving visual stimuli. Goal is to improve rapid, sequential eye movements to salient visual targets, process relevant information and then make rapid decisions to identify, discrminate and classify targets.
Following completion of each week‟s cognitive training with Insight, participants will receive select neurocognitive “probes” to assess their cognitive status. Probe testing will occur on the day after completion of the 5 day cognitive training set, and immediately following completion of Weeks 4, 8, 12, and 16. Participants will also receive mood measures before and after cognitive training.
Exercise Training
Exercise training will involve traditional exercise (treadmill walking, recumbent bicycling) or the use of the Nintendo WiiFit Plus suite of programs (See Appendix 11 for Exercise Training Games.) For both, the exercise intervention will follow the guidelines provided by the American College of Sports Medicine for optimizing cardiovascular fitness. Participants will exercise 4 times a week, up to 45 minutes a day, for 16 weeks. On every 4th week, they will engage in the Insight cognitive training program, for an additional 90 minutes/day.
Exercise intensity will begin at low levels (50% of maximal heart rate reserve) calculated utilizing the Karvonen method (Karvonen, Kentala, & Mustala, 1957). Intensity will be increased by 5% every week to a maximum of 75% of heart rate (HR). Exercise time will progress from an initial 20 minutes per session to the maximum 45 minutes by increasing duration by 5 minutes every week. Ratings of perceived exertion (RPE) will be collected at the midpoint of each session and during the last minute of exercise. Each session will
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be monitored by CPR-certified staff. Cooling fans will be setup in the room, and participants will be encouraged to drink at least 8 oz of water every 20 minutes.
1. Virtual Exercise (WiiFit Plus): Participants assigned to this exercise group will use a variety of WiiFit Plus exercise games. Each session will begin with 5 minutes of low intensity balance exercises such as “soccer heading” and “ski slalom” to “warm up”. These activities will help slowly increase heart rate and blood flow to the muscles. Thereafter, participants will choose from a variety of WII activities that have been shown to maintain heart rate within the appropriate training zone. These simulated games include activities such as dancing, inline skating, tennis, boxing and volleyball, stepping in place and hula hooping.
2. Traditional Exercise ( Stationary Bike and Treadmill): Participants assigned to this group will have the option of using either a motor driven treadmill or a recumbent or traditional stationary bike. Participants are given a choice between treadmill and stationary bike in order to increase exercise compliance. We suspect more participants will choose to use a treadmill based on previous studies in older adults. (Baker et al., 2010). Each session will begin with 5 minutes of low intensity exercise.
Prior to beginning each day‟s activities, participants will have their vital signs recorded and exercise will be monitored by the Clinical Coordinator and staff. Participants will sign- in and sign-out on a Daily and Weekly Activity Log to track compliance. (See Appendix 15.) Participants will be requested to participate 4 days per week, with a required 80% participation rate to stay involved in the study.
All participants will be monitored with Polar Heart Rate Monitor. Average and maximum heart rate will be recorded on the daily and weekly activity log. Participants will be encouraged to maintain a Target Heart Rate zone (50-75% of maximum) for a minimum of 20 minutes (but no more than 45 minutes) once they have progressed through the initial training weeks. During training, our coordinators and staff will monitor participants to ensure they do not exceed their maximal Target Heart Rate using the Karvonen Formula. Each participant will wear a name badge with their personal Target Heart Rate Zone for ease of recall during exercise training. (Please see Appendix 8 for Name Badge Sample.) Per the Informed Consent, participants are given an option as to wearing the name badge or not, depending on personal preference..)
Target Heart Rate(THR) = [(max HR − resting HR) × %Intensity] + resting HR
For the above formula, the Maximum HR will be calculated as 220-age, and the Resting HR will be determined for each patient at the 1st visit appointment. These Target H.R. numbers will be reflected on the participant‟s subject binder, and name badge for easy reference during interventions.
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Table 2.0 The Village Wellness Study Schedule of Activities/Interventions Measures Pre- Baseline Intervention Post- Screen Testing Intervention Testing Day Day Weeks # 1 thru # 16 Week 3 -30 to -7 to 0 # 17+ month -7 follow- up Screening Process Telephone X Screening Inclusion/ X X Exclusion Criteria Informed X Consent Physician X Clearance Medical History X Medication list X X X X Target Heart X X X Rate Calc. Mini Mental X Status Exam Mood Measures Geriatric X X X X X X X X X X Depression STAI X X X X X X X X X X
Pre-Morbid Cognitive Estimate WTAR X Barona X Equation Health SF-36 Quality X of Life Health Survey Vision Screen X Color Vision X
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Screen Charleston Co X Morb. IPAQ X X X Leisure Time X X X Exercise Questionnaire Functional Measures Timed X X X Instrumental Activities of Daily Living Instrumental X X X Activities of Daily Living Neurocognitive X X X Measures Battery* Specific Affect and Mood Apathy Scale X X X X X X X X X X
Beck X X X X X X X X X X Depression Inventory POMS X X X X X X X X X X
Self Reporting Scales Fatigue X X X X Severity Scale Pittsburgh X X X X Sleep Scale Pain VAS X X X Driving History X X X Cognitive X X X Locus of Control Perceived X X X X X X X X X X X X X X X X Exertion Scale BIS/BAS X X X
Snaith Pleasure X X X
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Scale Temporal X X X Experience of Pleasure Physical Measures Exercise X X X History Survey Blood Draw for X X X BioMarkers Activity X X X Specific Balance Confidence Modified Falls X X X Efficacy Scale Exercise Self X X X Efficacy Scale Mental X X X Readiness 6 minute walk X X X test 6 Minute X X X WALK/TALK Motor Function X X X and Balance GAIT-RITE X X X Assessment Pedometer X X X X X X X X X X X X X X X X X X X Exercise X X X X X X X X X X X X X X X X Training (Traditional or WII Fit Plus ) Cognitive X X X X Training
Probe X X X X X X Measures ** Adverse Events X X X X X X X X X X X X X X X X X X X Monitored
Participant X X X Reported Outcome/ 06.28.10 IRB # 179-2010 20 | P a g e
Credibility and Expectations
*Neurocognitive Measures by Domain: Auditory Attention/Working Memory: Digit Span and Letter Number Sequencing subtests from Wechsler Memory Scale (WMS) Visual Attention/Working Memory: Spatial Span subtest from WMS Verbal Recent Memory: Hopkins Verbal Learning Test-II, Logical Memory subtest from Wechsler Memory Scale Visual Recent Memory: Family Pictures and Face Memory subtests from WMS, Visual reproductions(WMS- IV) Spatial Cognition: Judgment of Line Orientation, Mental Rotations Test , Visual Search Processing Speed: Digit Symbol &Symbol Search subtests from the Wechsler Intelligence Tests Executive: Verbal Fluency from the Delis Kaplan Executive Functioning battery, Trail Making Test, Stroop Test, Flanker Test
**Probe Measures Memory: Hopkins Verbal Learning Test-R (alternate versions), Visual reproductions (WMS-IV) Spatial: Visual Search Executive: Flanker Test, Stroop Test, Mood: Profile of Mood States
D. Outcome Measures
The primary outcome measure for Aims 1 and 4 will be the mean change in the functional cognition score from pre-treatment to post-treatment across the 3 cognitive intervention-exercise groups. Secondary outcome variables for Aim 1 will include composite scores for the following neurocognitive domains: auditory and visual working memory, verbal and visual recent memory, spatial cognition, processing speed, and executive functioning. See Table 2.0 for specific tests that comprise these domains. For Aim 2, the primary outcome variables include changes in the cognitive probe measures.
Outcome variables for Aim 3 include pre-post treatment changes in quality of life (patient reported outcome (PRO)), mood (POMS, BDI, AS, STAI), fatigue and sleep (FSS, PSQI), fitness measures (6MWD, GRA, ABC Scale, Modified Falls Scale, Exercise Self Efficacy, MRF), and biological markers (BDNF, RhAG, AQP1,AE1).
E. Randomization, Sample Size, and Statistical Methods
Randomization: After enrollment and assessment, participants will be stratified by sex and education and randomly assigned to one of the treatment groups using MAPLE 9.0 software (Waterloo, Canada). Procedures will be followed so that treatment assignments
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will not be available to individuals involved in administering, scoring, and analyzing the baseline/pre-treatment and post-treatment data.
Sample Size: .Our recruitment goal is for 60 participants to complete the study (i.e., 20 per group). Based on a 20% attrition rate (i.e., 72 participants) and up to 40 screen failures, we anticipate consenting up to 112 participants. Sample size was based on a power analysis conducted on the primary and secondary outcome variables. Based on an F-test at the 0.05 level, such a sample size will yield 81% power to detect a difference of mean changes of (0.8, 0.4, 0.1, 0) times of SD for the four groups. A linear contrast test between the best and the two worst groups have power of 87% and 77%, respectively. Note that the main goal of this pilot study is to establish likely effect sizes for our interventions, thus we are not sure whether our training groups will achieve the detectable differences. On the other hand, Zelinski et al.(2008) reported that a similar cognitive training obtained an effect size of 0.09 in Rey Auditory Verbal Learning Test (delayed recall); Hillman et al (2008)84 documented positive exercise-training effect sizes ranging from 0.26 to 0.68 on four different cognitive tasks; and Fabre (1999) 69 showed that combined aerobic and mental training (CMT) improved quality of life (in the various domains of functional life) much more than mental training (MT), with differences of effect sizes around 1.0. Therefore, we expect that we may discover some significant differences among our three randomized groups in the cognitive performance or the health-related quality of life.
Statistical Methods: All data will be checked for missingness, out-of-range values, and distributional form (i.e., normality, homogeneity of variance). Decisions regarding use of parametric vs. nonparametric statistics will be based on the results of those analyses. Standard summary statistics will be provided for each intervention group (cognitive training + standard exercise; cognitive training +WiiFit; cognitive training alone) and time (baseline, immediately after the 16 weeks of training, and at 3 month follow-up).
Demographic and baseline clinical variables will be compared among the three randomized groups using analysis of variance (ANOVA) for comparison of means and chi-square tests for comparison of proportions. All statistical analyses will be performed on two data sets: 1) on all subjects who were successfully screened, randomized and able to participate in at least 1 week of the assigned intervention, regardless of study completion (intention-to-treat analysis); and 2) on subjects who were successfully screened, randomized and able to complete at least 80% of the cognitive and physical exercise treatment assignment.
F. Statistical Analyses
Specific Aim 1 To examine efficacy of exercise pre-dosing on cognitive training, we will conduct one-way analysis of variance to compare the three randomized groups. The dependent variable will be the change in functional cognition score from pre to immediate post-treatment. Linear contrast will be used to estimate and test the difference between
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groups at the 0.05 levels without adjustment for multiple testing. A similar analysis will be conducted, to determine the duration of benefit over a three month period. To examine impact of training on specific neurocognitive domains, we will conduct multivariate analyses using neurocognitive domain change scores as the dependent variables. This will be followed by appropriate univariate and post-hoc analyses, as appropriate.
Specific Aim 2: To determine the whether the benefits of exercise occur rather quickly or develop more slowly over time, we will conduct one-way ANOVA and MANOVA‟s from baseline over the various time points (4,8,12, 16, 3 months) with group as the between-S factor. The dependent variables will be changes in the experimental probe tests (Flanker Test, Visual Search, Hopkins VLT, Visual Designs, Profile of Mood States). These analyses will be followed by appropriate univariate and post-hoc analyses.
For both Aims 1 and Aims 2, we will perform sensitivity analyses by comparing results from the complete case analyses with those obtained with missing outcome predicted by a model that takes into account subject dropout bias. More specifically, we will perform the following four steps: (1) determine demographic and clinical variables that characterize differences between “completers” and “noncompleters”; (2) develop a model predicting outcomes for the “completers” using the significant independent variables from previous step; (3) use the resulting model to predict outcomes for the noncompleters; (4) redo the primary analyses for the full dataset
Specific Aim 3: To examine impact of training on everyday functioning, we will assess differences among the three groups in terms of participant-rated outcome (RCO), mood (BDI, STAI, AS, PANAS), fitness measures, biologic markers, and other factors (sleep, pain, fatigue) using univariate and MANOVA‟s. We will also use multiple regression techniques and hierarchical modeling to determine which non-cognitive factors are most influenced by cognitive, exercise training.
Specific Aim 4: To examine differences between effects of traditional exercise vs. Wii Fit, analyses similar to those described in Aim 1 will be conducted with primary emphasis on potential differences between the cognitive + standard exercise group vs cognitive + Wii- Fit group.
G. Methodologic Limitations
One concern is participant dropout and compliance in completing the treatment program. To minimize this issue, we plan to oversample our groups by at least 20%. In a previous NIH funded behavior treatment study involving inspiratory therapy, we had less than 10% dropout in our PD groups. The reasons for dropout could include unexpected illness, lack of compliance, change in medications, transportation difficulties, or unforseen circumstances. There will be 40 allowable screen fails built into the total numbers to allow for participants who may self enroll, but not meet the inclusion/exclusion criteria for physician clearance.
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H. Recruitment and Study Time Line Schedule of Activities
Recruitment efforts to reach healthy adults with minimal physical contraindications for this study will be primarily by advertisement flyers, posted in appropriate locations that are frequented by this population. Targeted locations might include bulletin boards at community grocery stores, physician‟s offices, medical centers, retirement homes, etc. Educational workshops on the topic of Alzheimers Disease and Dementia Prevention will be offered free of charge to interested participants in the community. The research background and design for this study will also be explained to workshop participants, with an opportunity for them to sign up for a future pre-screening telephone visit with the study coordinator. (Please see Appendix 4 Workshop Flyer for Workshop. Please see Appendix 5 for Alzheimer and Dementia Prevention Workshop Outline.)
PI‟s, Co-PI‟s and Unaffiliated Investigators may forward the name and phone number of their patients, who are interested potential study participants, to the Study Coordinator. In the majority of cases, Physicians will give the study flyer to their patients for them to contact the Study Coordinator directly. (See Addendum 6. Waiver of HIPPA Privacy Authorization for Research.) There has also been a Medical Release Form prepared, for the clinician to have their patient sign, if they would prefer to be contacted by the Study Coordinator directly. (Please see Addendum 8.)
The Schedule of Participant Activities for this study are as follows:
Call #1- Telephone Screening Visit to review the study details, and inclusion/exclusions. (See Appendix 3 for Telephone Script.)
Informed Consent Process visits- Informed Consent Process begins with the participant per UF, state and federal guidelines. Pre-enrollment visits will be offered as needed until participant chooses to join the study and signs the ICF, or opt out of the study.
Physician Clearance- The Form (Appendix 1) will be faxed to the Primary Care Provider (PCP) and the Physician will return the signed form by fax to the Study Coordinator before the baseline visit.
Baseline Visits #1-3 Complete medical history, inclusion/exclusion criteria, review, concomitant medications, target heart rate calculations, and a battery of cognitive questionnaires as listed on Table 2. This cognitive assessment period will be spread out over a minimum of 2-3 visits, depending on the comfort level and ability of the participant.
Intervention Weeks 1-16 For 16 weeks, participants will do cognitive and physical intervention, per their randomized group assignment. The 06.28.10 IRB # 179-2010 24 | P a g e
intervention will consist of 4 sets of 4 week long rotations as listed below. (See Table 3.)
Post-Intervention Visit (week 17+) Repeat the entire battery of cognitive tests and questionnaires listed in Table 2.
Three Month Visit- Repeat the entire battery of cognitive tests and questionnaires listed in Table 2.
Table 3.- Monthly Schedule of Activities
Week 1 Week 2 Week 3 Week 4 Group A Traditional Traditional Traditional Traditional Physical Physical Physical Physical Exercise Exercise Exercise Exercise
-BREAK-
Insight Brain Exercise Group B WII FIT WII FIT WII FIT WII FIT Plus Plus Plus Plus Exercise Exercise Exercise Exercise Games Games Games Games -BREAK-
Insight Brain Exercise Group C No No No Insight Exercise Exercise Exercise Brain Activity Activity Activity Exercise
The Timeline for the Study Protocol is as follows:
0-9 months: IRB approval, Site preparation, Creation of Case Report Forms, Investigator‟s Meeting, Creation of randomization scheme and assignments, etc.
9 months ++: recruitment starts; first participant recruited. Continuation of recruitment until 24 months.
2.0 years: last patient in 2.75 years: last patient exits the study
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2.5-3.0 years: data analysis and presentation
I. Data Management Plan
Data will be kept in a pass-word protected encrypted database which can only be accessed by the investigator and her staff. Case report forms (CRF) will be created for this study. (Please see Appendix 9 Index for Case Report Forms, and all CRF measures and questionnaires.) All reports, surveys and assessments will be under the direction of the Principal and Co-Principal Investigators who will supervise the Study Coordinator and Research Assistants. Recruitment, screening, and project implementation will be coordinated by the Study Coordinator. All outcome assessments (pre-treatment, immediate and 3 month post-intervention) will be administered by a research assistant who is blinded to group assignment. The existing data management group, supported by the McKnight Brain Institute, will manage the database, monitor subject recruitment and distribute monthly enrollment reports, and produce reports summarizing the status of data acquisition, the baseline characteristics and the blinded primary variables.
A kick-off Investigator‟s Meeting will be held prior to study initiation so that the PIs, Co- Investigators, Study Coordinator and other staff are on the same page. Study personnel will be instructed in detail as to the appropriate methods for entering data. All source documents will be maintained and organized in separate folders for each study subject.
7. Possible Discomforts and Risks:
A. Repetitive Motion Injuries and Eyestrain
Playing video games can make muscles, joints, skin or eyes hurt. Participants will be instructed to take frequent breaks and stop and rest in order to avoid problems such as tendinitis, carpel tunnel syndrome, skin irritation, or eyestrain. They will be specifically told to rest if their hands, wrists, arms, or eyes become fatigued, or if they feel symptoms like tingling, numbness, burning or stiffness. If any of the above symptoms
B. Motion Sickness Playing video games can cause motion sickness in some players. Participants will be advised that if they feel dizzy or nauseous when playing the video games, stop playing and rest. They will be told not to drive or engage in other demanding activities until they feel better. C. Seizures Some people (about 1 in 4000) may have seizures or blackouts triggered by light flashes or patterns, and this may occur while they are watching TV or playing video games, even if they have never had a seizure before. 06.28.10 IRB # 179-2010 26 | P a g e
D. Radio Frequency Interference
The Wii console and Wii Remote can emit radio waves that can affect the operation of nearby electronics, including cardiac pacemakers. Since pacemakers are exclusionary, this should not affect our population.
E. Laser Product
The Wii console is a Class I laser product. Participants will not be permitted to disassemble the Wii console.
F. Electric Shock
To avoid electric shock when using this system, the participants will be advised to not use the WII during a lightning storm. There may be a risk of electric shock from lightening. Participants will be directed to use only the AC Adapter that comes with the system, and to not use it if it is damaged, has broken cords or wires.
G. Psychological
Participants may experience frustration or anxiety about their performance, or boredom from the training routine. We intend on keeping participants comfortable with their own performance by acknowledging their valuable participation and offering encouragement to meet their own personal goals of achievement each day. Breaks will be offered routinely during the cognitive assessment phase, to relieve participants of fatigue or boredom.
H. Physical
Physical exercise has documented benefits, and also possible associated risks. These include muscle fatigue, falls and associated injuries, sprains, exhaustion, fainting, frustration in performance, inflammation of joints or musculoskeletal system.
8. Possible Benefits:
Cognitive and Physical benefits can not be guaranteed. Some participants may experience possible cognitive benefits that include increased ability to organize thoughts, faster thinking ability, short term memory and reaction time. Posit Science has clinical research to support the improved cognitive function capability of its product. Some participants may experience physical benefits that would include stronger muscle tone, improved balance and walking ability, increased heart function and improvement in mood and energy level. Beneficial outcomes will be measured using the self reporting scales listed in Table 2. 06.28.10 IRB # 179-2010 27 | P a g e
9. Compensation:
There will be no compensation for participation or completion of the physical and brain exercise 16 week intervention. There will be compensation of a $25.00 gift card for participation in the 3 month follow up visit which consists of questionnaires, surveys, memory and mood measures as listed in Table 2.0 The Village Wellness Study Schedule of Activities and Interventions.
10. Conflict of Interest: There are no conflicts of interest involving any faculty or coordinator staff associated with this study.
11. Tables , Appendices and Addendums
Tables :
Table 1-Screening Measures rev. 7.08.10 Table 2- Schedule of All Study Activities and Interventions rev. rev.12.12.10 Table 3- Monthly Schedule of Interventionsrev. 7.08.10
Appendices:
Appendix 1- Physician Clearance Form rev. 12.12.10 Appendix 2- Study Information Sheet; Inclusion/Exclusion Criteria for Clinicians rev.12.12.10 Appendix 3 -Telephone Script for Telephone Pre-Screening rev.12.12.10 Appendix 4- Flyer for Alzheimer Prevention Workshop by Dr. Slaton and Dr. Bowers rev. 7.08.10 Appendix 5- Outline for Alzheimer Prevention Workshop Seminar Appendix 6- Flyer for Alzheimer Prevention Study (text option 1) rev. 7.08.10 Appendix 7- Flyer for Memory and Thinking Study (text option2) rev. 7.08.10 Appendix 8- Name Badge Sample for Intervention Participates Appendix 9- Case Report Form Index and Case Report Form Documents Appendix 10- Letter of Support from Santa Fe HealthCare CEO, Michael Gallagher Appendix 11- Exercise Activity List rev. 7.08.10 Appendix 12- Study Coordinator Business Card rev. 12.12.10 Appendix 13- Craig‟s List Volunteer Enrollment and Recruitment Appendix 14-Certificate of Appreciation Appendix 15-Weekly Activity Log Appendix 16- Video List for Sham Cognitive Activity- Omited/no longer needed
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Addendums:
1. RAC Forms/ FLA Letter rev. 7.08.10 2. Addendum A- Conflict of Interest rev. 7.08.10 3. Addendum S- Behavioral and Psychological Review rev. 7.08.10 4.. Psychological and Survey Measures Form 12.12.10 6. Waiver of HIPPA Privacy Authorization for Research 7. Unaffiliated Investigator Agreement 8. Medical Release Form
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