Investigating Gains in Neurocognition in an Intervention Trial of Exercise

Investigators are assessing change in cognitive function from baseline to 12 months. A comprehensive neuropsychological battery will be used that assesses 5 domains of cognitive function (Working Memory, Processing Speed, Episodic Memory, Attentional Control, and Visuospatial Function). We will perform a confirmatory factor analysis on the cognitive data and determine whether the exercise intervention influences performance as measured by these factors. There is no min and max values. These are generated from a confirmatory factor analysis that normalizes the scores around 0 (being the mean). As such, positive values reflect better performance and negative values reflect poorer cognitive performance. Since the scores are standardized we can calculate the changes in standard deviations - e.g., a shift of 0.5 would be an improvement of ½ standard deviation in performance based on the sample average.

MRI will be used to measure average hippocampal volume and determine changes in volume over the course of the intervention.

MRI will be used to measure the number of white matter lesions before and after the intervention.

MRI will be used to measure volumetric changes in hippocampal subfields.

MRI will be used to measure average cortical thickness over the course of the intervention.

MRI will be used to measure changes in cerebral blood flow. Total cerebral blood flow changes over the course of the intervention will be evaluated.

MRI will be used to measure changes in resting state brain function. We will examine whether the intervention alters resting state connectivity metrics.

MRI will be used to measure changes in white matter microstructure in relation to the intervention.

MRI will be used to measure changes in encoding and retrieval during a relational memory task.

MRI will be used to measure changes in brain activity task-evoked patterns using an N-back working memory task.

The APOE e4 carrier status increases risk for Alzheimer's disease. We will be examining whether any outcomes are moderated by carriage of the APOE e4 allele.

BDNF helps regulate synaptic plasticity, which is important for learning and memory and might change in response to exercise. We will be evaluating whether changes in BDNF mediate changes in brain or cognitive outcomes.

Exercise might alter cognitive and brain processes by influencing markers of systemic inflammation including TNF-alpha. We will examine whether exercise alters this marker and whether it relates to changes in neurocognitive outcomes.

Exercise might alter cognitive and brain processes by influencing markers of systemic inflammation including IL-6. We will examine whether exercise alters this marker and whether it relates to changes in neurocognitive outcomes.

IGF-1 is responsive to exercise and might influence brain and cognitive outcomes in late adulthood. We will examine whether exercise alters this marker and whether it relates to changes in neurocognitive outcomes.

VEGF is responsive to exercise and might influence brain and cognitive outcomes in late adulthood. We will examine whether exercise alters this marker and whether it relates to changes in neurocognitive outcomes.

Amyloid levels measured via blood samples will be examined to determine whether the exercise intervention altered this marker of neuropathology.

p-Tau levels measured via blood samples will be examined to determine whether the exercise intervention altered this marker of neuropathology.

p-Tau levels measured via blood samples will be examined to determine whether the exercise intervention altered this marker of neuropathology.

p-Tau levels measured via blood samples will be examined to determine whether the exercise intervention altered this marker of neuropathology.

GFAP levels measured via blood samples will be examined to determine whether the exercise intervention altered this marker of neuropathology.

NFL levels measured via blood samples will be examined to determine whether the exercise intervention altered this marker of neuropathology.

We will examine whether changes in markers of insulin resistance (HOMA-IR) change over the course of the intervention and whether these changes mediate neurocognitive outcomes.

We will examine whether changes in markers of insulin resistance change over the course of the intervention and whether these changes mediate neurocognitive outcomes.

Fitness is assessed by maximal graded exercise testing. Oxygen uptake (VO2) will be measured from expired air samples taken at 15 second intervals until a peak VO2, the highest VO2, is attained at the point of test termination due to symptom limitation and/or volitional exhaustion.

We will examine whether changes in cardiorespiratory fitness mediates changes to neurocognitive function.

Florbetapir F 18 or Amyvid PET scans are obtained to establish the presence or absence of cerebral amyloidosis. We will examine whether the presence of amyloid moderates the effectiveness of the intervention to influence neurocognitive outcomes.

A subset of the cognitive tests are administered at a midpoint session. These tests will be used to examine trajectories of change on particular cognitive tests. The scores will be generated using similar approaches as for the primary aim but because the tests slightly differ from the baseline and post-intervention assessment, we will have to generate these scores separately. The scores will be normalized so that a 0 represents the mean performance for the sample. Higher values reflect better performance and lower values represent poorer performance

We will examine whether the intervention altered BMI and whether these changes mediate any changes in behavioral or neurocognitive outcomes.

This will be assessed using a dual-energy x-ray absorptiometer (DXA). The DXA will provide a measure of VAT from a total body scan. We will examine whether the intervention altered VAT levels.

This will be assessed using a dual-energy x-ray absorptiometer (DXA). The DXA will provide a measure of SAT from a total body scan. We will examine whether the intervention altered SAT levels.

This will be assessed using a dual-energy x-ray absorptiometer (DXA). The DXA will provide a measure of lean mass from a total body scan. We will examine whether the intervention altered lean mass levels.

Health History assesses medical history and lifestyle habits such as alcohol and tobacco use. We will examine whether any neurocognitive outcomes vary as a function of these health conditions and behaviors.

We will be recording all prescribed and OTC medications that the study participant is currently taking and will examine whether the intervention effects vary as a function of medication use.

We will use the Satisfaction with Life Scale (SWLS) as a global cognitive judgement of study participants life satisfaction. We will examine whether the exercise intervention altered SWLS measures. Total score range is 5 -35 with higher scores equal to greater satisfaction with life.

The Perceived Stress Scale (PSS) is one of the most widely used psychological instruments for measuring the perception of stress. It measures the degree to which situations in the participants life are gauged as stressful. We will examine whether the exercise intervention modified PSS levels. Score range is 0 - 40 with a higher scores equal to more stress.

The SF-36 taps into eight health concepts: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. It also includes a single item that provides an indication of perceived change in health. We will examine whether the exercise intervention modified measures of health related quality of life. Each concept has a score range of 0-100 with higher scores equal to more favorable health traits.

The Hospital Anxiety and Depression Scale (HADS) will be used to measure depressive symptoms. We will examine whether the exercise intervention improved measures of mood and reduced depressive symptoms. Total score range is 0 -21 with lower scores equal to less depressive symptoms.

The MAAS assesses a core characteristic of mindfulness mainly open or receptive awareness of and attention to what is taking place in the present. We will examine whether the exercise intervention altered measures of mindfulness. Score scale runs 15 -90 with higher scores reflecting more mindfulness.

The Hospital Anxiety and Depression Scale (HADS) will be used to measure anxiety symptoms. We will examine whether the exercise intervention improved measures of mood and reduced anxiety.

Total score range 0-21 with lower scores equal to less anxiety symptoms.

Combining information from MacArthur questionnaire to develop Social Economic status of participants. We will examine whether the effectiveness of the intervention varied by SES levels of the participants. The SES composite was generated using a confirmatory factor analysis of various SES indicators - e.g., income, debt, savings, etc. The scores are normalized so that 0 is the average for the sample and higher numbers reflect higher SES and lower numbers indicate lower SES.

Exercise frequency will be measured using Actigraph Link physical activity monitoring device. This device is small and lightweight. It is worn around the non-dominant wrist(touching the skin) for approximately 7 days during all waking and sleeping hours. We will examine whether the intervention altered this measure of daily activity.

Exercise intensity will be measured using the Actigraph Link physical activity monitoring device. This device is small and lightweight. It is worn around the non-dominant wrist (touching the skin) for approximately 7 days during all waking and sleeping hours. We will examine whether the exercise intervention altered amount of time spent in moderate-to-vigorous activities during daily life.

Exercise duration will be measured using Actigraph Link physical activity monitoring device. This device is small and lightweight. It is worn around the non-dominant wrist (touching the skin) for approximately 7 days during all waking and sleeping hours.. The duration is measured in minutes. We will examine whether the exercise intervention altered amount of time spent in moderate-to-vigorous activities during daily life.

Fatigue Symptom Inventory (FSI) is a 14-item self-report measure designed to assess the severity, frequency, and daily pattern of fatigue as well as its perceived interference with quality of life. We will examine whether the exercise intervention impacted perceived daily fatigue. Severity scale score is 0-40 with higher value equal to more severe fatigue. Frequency scale score is 0-21 with higher values meaning more frequent fatigue. Perceived interference scale range is 0-70 with higher values meaning more interference with life.

Pittsburgh Sleep Quality Index (PSQI) will be used to assess perceived sleep quality. We will examine whether the exercise intervention alters perceived sleep quality. All components have score range 0-3 with lower number equal to better sleep quality.

The Composite Scale of Morningness assess diurnal preference, sleep times, preferred times for physical and mental activity, and times of subjective alertness. We will examine whether the exercise intervention alters this metric of optimal time of day. scale is 16-86. Score of 70-86 equal morning type, score 59-669 equals moderate morning type, score 42-58 is neither, score 31-41 equals moderate evening type and score 16-30 equal evening type.

Cognitive Function Index (CFI) asks 15 questions in which the participant answers Yes or No to memory items compared to one year prior. We will examine whether the exercise intervention alters subjective cognitive performance. Scoring scale runs 0 - 15 with higher values equal to better cognitive function.

The McGill Pain Questionnaire is used to evaluate a person's perception of pain. It can be used to monitor the pain over time and to determine the effectiveness of any intervention. We will examine whether the intervention alters perceptions of pain in late adulthood. Score scale runs 0-45 with higher values meaning more pain.

The UCLA Loneliness Scale (UCLA-L) asks subjects to rate, on a scale from 1-4, how often they experience certain feelings. There are 20 feelings listed (e.g. "How often do you feel left out?"). We will examine whether the intervention alters perceptions of loneliness in late adulthood. Scale score is 20-80 with higher values equal to more loneliness.

The Brief Fatigue Inventory (BFI) assesses the severity of fatigue and the impact of fatigue on daily functioning. We will examine whether the intervention alters the impact of fatigue on daily function. Higher scores on subscales reflect that participants has that personality. Subscales scores are 8-40 or 9-45.

Work Design Questionnaire (WDQ) gathers information related to the nature and responsibilities of the participant's job. Asks the participant to rate the degree to which he or she agrees (or disagrees) with various questions by "domains" such as job autonomy and complexity, task variety and significance, and cooperative components such as social interactions inside and outside of the organization. We will examine whether changes in cognitive performance varies in relation to the job complexity history.

The investigators will use the Exercise Self-Efficacy Scale (EXSE) to assess belief in the ability to continue exercising three times a week at a moderate intensity for 40 plus minutes a session into the future. We will examine whether this measure predicts long-term adherence outcomes. Score scale runs 0 - 100 with higher values = higher confidence to continue to exercise (3X's week for 40 + minutes) in the future 8 weeks

Short Physical Performance Battery (SPPB) will be used to evaluate this outcome. We will examine whether the exercise intervention alters SPPB performance.

The Florida Cognitive Activity Scale (FCAS) will examine whether the exercise intervention altered engagement in cognitively stimulating activities or whether any outcomes varied as a function of cognitively stimulating activities. Scale 0-100, higher values = performing more cognitive stimulating activities.

Senior Fitness Test will be used to measure various aspects of fitness - e.g., balance, flexibility, strength. We will examine whether the exercise intervention improves any marker of fitness.

Health resource utilization and quality of life measures will be used to calculate the costs per quality of adjusted life years. We will examine whether the intervention altered this metric.

Health resource utilization and quality of life measures will be used to calculate the costs per quality of adjusted life years. We will examine whether the intervention altered this metric.

Hair samples will be used to examine whether the exercise intervention altered hair cortisol, a measure of accumulated cortisol over several months.

PROMIS Applied Cognition: (Abilities) This is a brief self-report of perceived cognitive abilities for daily functioning. We will examine whether the intervention alters this subjective/perceived level of cognitive function. Scale 8 -40, assess ppt. perceived functional abilities in regard to cognitive tasks. Higher value = higher self-perceived ability in cognition.

We will examine whether the intervention alters measures of gait speed under both single task and dual-task conditions.

We will examine whether the intervention alters measures of gait variability under both single task and dual-task conditions.

MRI will be used to measure GSH levels. We will examine whether the exercise intervention alters levels of GSH.

Only given to female study participants. This questionnaire asks a variety of questions to gather information as it relates to menopause. We will examine whether any marker of neurocognitive performance or change in performance from the intervention varies in relation to reproductive history. We expect this to be used as a moderator in IGNITE. There is no scoring from this form, only recording in a yes:no fashion as to whether something happened or not. The frequency of any event will be examined as an effect moderator of the intervention.

PROMIS Applied Cognition: (General Concerns) This is a brief self-report of perceived difficulties with cognition for daily functioning. We will examine whether the intervention alters this subjective/perceived level of cognitive function. Scale 8 -40. Lower score = less cognitive concerns

Everyday Cognition (ECOG)(Short version) measures subjective cognitive performance. We will examine whether the intervention alters this subjective/perceived level of cognitive function. Score range is 1 - 4 with lower scores equal to better daily function.

Godlin Leisure Time Exercise questionnaire is used to ask participants about usual leisure-time exercise habits. We will examine whether the intervention alters time spent in leisure time activities. Calculation of weekly minutes of activity into activity score, higher the score is equivalent to more active.

Cumulative Illness Rating Scale (CIRS): This scale is used to indicate the health status of older adults. Clinicians rate the pathology and impairment of major organ systems and also psychological, metabolic, neurological and musculoskeletal aspects of the individual. The CIRS consists of 14 aspects of health which are rated from 0 (no impairment to that organ/ system) to 4 (impairment is life threatening). We will examine whether the effectiveness of the intervention varies based on the comorbidity of various health conditions. Score range is 0-56 with lower score reflecting better health.

Sitting Time Questionnaire scores how much time is spent sitting during 5 different events on a weekday and weekend day. We will examine whether participating in the intervention alters amount of time spent sitting. Calculate weekly minutes with higher values in minutes = more sedentary (sitting time)

Self Esteem (PSPP): A 30-item instrument used to assess self-esteem relative to several domains of physical functioning in a hierarchical, multidimensional fashion. The instrument contains a general physical self-worth scale (PSW) which subsumes four more specific scales of perceived sport competence (SPORT), physical condition (COND), attractive body (BODY), and strength (STRENGTH), with six items per scale. Participants indicated on a four-point scale the degree to which each item is characteristic or true of them. Responses range from 1 (not at all true) to 4 (completely true).We will examine whether participating in the intervention alters measures of self-esteem. 4 subscales with score range 6 -24, higher number reflects more self esteem.

Rosenberg Self-Esteem Scale (RSE): Widely-used scale in several domains of self- esteem research including physical activity. We will examine whether participating in the intervention alters measures of self-esteem. Scale 10 -50, higher values = higher levels of self esteem

Social Goal Importance: Asks the participant to name a friend, then rate how much that person helps or harms their pursuit of a personal goal. For this study, the goal in question is exercising/fitness. We will examine whether social goal importance relates to adherence to the intervention. Higher scores reflect more social support for the goals and lower scores reflect less social support for maintaining the goals.

Social Provisions Scale (SPS):A 24-item scale assessing six relational provisions: attachment, or emotional support; social integration, or network support; reassurance of worth, or esteem support; reliable alliance, or tangible aid; guidance, or informational support; and the opportunity of nurturance.The items were modified for the exercise setting. For example, one of the statements used to assess social integration was "I feel part of the exercise group". We will examine whether social provisions relates to adherence to the intervention. Each subscale has range of 4 - 16 with total score range 24 - 96, higher values = higher social relationship (ppt. is receiving that provision)

Cohens Social Network Index: Self-report assessing the nature, quantity, and frequency of participants' social relationships. We will examine whether social provisions relates to adherence to the intervention or any of the neurocognitive outcomes. High contact in social networks have 0-12 score with higher number reflective of more social networks.

Exercise Group Social Provisions Scale (EXSPS): 24 items related to the relationship between themselves and their exercise group/leader. Asks participants to rate on a scale of 1-4, with 1 being "strongly disagree" and 4 being "strongly agree." We will examine whether the relationship with the trainer influences adherence and compliance to the intervention. Score range 4 -16

Calculated via NCI Dietary (DHQ2). We will examine whether dietary habits moderate neurocognitive or physiological outcomes or change over the course of the intervention. Score range is 0-100 with higher numbers showing meeting key dietary recommendations and patterns.

BARSE questionnaire assess degrees of confidence that one could exercise despite a variety of limitations such as during bad weather, while on vacation, etc. This scale was designed to tap subjects' perceived capabilities to exercise three times per week for 40 minutes over the next two months in the face of commonly identified barriers to participation. We will examine whether measures of barriers predicts adherence and compliance to the intervention. Scale 1-100, higher values = higher level of perceived capability to overcome barriers to exercise

Calculated via NCI Dietary (DHQ2). We will examine whether the intervention alters measures of the glycemic index. It's a standardized score, range is -1 to 1. High scores mean that individuals consume a lot of the food items with high positive loading scores on the figure and low scores mean that people eat a low amount of food items with high positive loading scores (also likely more of the foods with negative loadings).

Lifestyle Self-Efficacy (LSE): A 6-item measure to assess an individual's beliefs in their ability to accumulate 30 minutes of physical activity on 5 or more days of the week in the future. For each item, participants indicate their confidence to execute the behavior on a 100- point percentage scale comprised of 10-point increments, ranging from 0% (not at all confident) to 100% (highly confident). We will examine whether measures of self-efficacy predicts adherence and compliance to the intervention. Scale 0 -100, higher values = increased confidence to exercise 5 or more days per week for 30 minutes

Exercise Self-Efficacy (EXSE): A 6-item measure to assess degrees of confidence in one's ability to continue exercising at moderate intensities 3 times per week for at least 40 minutes per session. We will examine whether measures of self-efficacy predicts adherence and compliance to the intervention. Scale 0 -100, higher values = higher confidence to continue to exercise (3X's week for 40 + minutes) in the future 8 weeks

Physical Activity Self-Regulation Scale, 12-item version (PASR-12): (PASR-12 FORM) A 12-item version of a popular 43-item self-regulation scale. Participants were asked to rate how often they used each strategy on a scale from 1 (never) to 5 (very often). We will examine whether measures of self-regulation predicts adherence and compliance to the intervention. Each subscale has range of 2 - 10, higher scores = greater use of self-regulation strategies. Summary score has range of 12 - 60

Measured as part of Pulse Wave Analysis. We will examine whether the intervention altered measures of blood pressure and whether these changes mediate neurocognitive changes.

We will calculate this measure from the maximal exercise test and determine whether the exercise intervention improves OUES.

Study Participant level of adherence to prescribed volume of exercise minutes. We will examine how our intervention related to adherence (minutes per week) and whether better adherence relates to better cognitive outcomes.

Study Participant level of adherence to prescribed intensity of exercise. We will examine how our intervention related to adherence (intensity zone) and whether better adherence relates to better cognitive outcomes.

This is measured by Carotid-Femoral Pulse Wave Velocity. This outcome is measured by capturing pulse pressure waveforms from the right carotid and femoral arteries using tonometry after 10 minutes of supine rest. We will examine whether the exercise intervention modified measures of arterial stiffness and how this relates to our various neurocognitive and physiological measures.

This will be assessed using a dual-energy x-ray absorptiometer (DXA). The DXA will provide a measure of fat mass from a total body scan. We will examine whether the exercise intervention alters measures of fat mass.

The measurement will be completed at the midpoint between the lower rib and top of the iliac crest (hip bone) at the mid-axillary line. We will examine whether the exercise intervention alters measures of waist circumference.

This will be assessed using a dual-energy x-ray absorptiometer (DXA). The DXA will provide a measure of Bone Density from a total body scan. We will examine whether the exercise intervention alters measures of bone density.