Uptake and outcomes of supervised exercise therapy for peripheral artery disease: The importance of vascular medicine specialists at a large midwestern health care system during the first 5 years of CMS reimbursement.

BACKGROUND: Supervised exercise therapy (SET) is the cornerstone of medical therapy for symptomatic peripheral artery disease (PAD). Despite the efficacy of SET, initial reports following the 2017 Centers for Medicare and Medicaid Services (CMS) reimbursement decision indicate low SET uptake, referral, and completion. Vascular medicine specialists are key to the success of such programs. We examined rates of SET referral, completion, and outcomes in a health system with a robust SET program during the first 5 years of CMS reimbursement. METHODS: A retrospective chart review of patients with PAD referred to SET between October 1, 2017 and December 31, 2022 was conducted. Patient demographic and medical characteristics, SET indication, referring provider specialty, SET participation (e.g., exercise modality, number of sessions, treadmill prescription), and outcomes were abstracted. Descriptive statistics, t-tests, and multiple linear regression were used to examine the sample, evaluate outcomes, and explore outcomes by relevant covariates (i.e., age, sex, referring provider specialty). RESULTS: Of 5320 patients with PAD, N = 773 were referred to SET; N = 415 enrolled and were included in the present study. Vascular medicine and vascular surgery specialists were the two primary sources of referrals (30.6% and 51.6%, respectively). A total of 207 patients (49.9%) completed SET. Statistically significant and clinically meaningful improvements were observed in all outcomes. CONCLUSION: SET referral and completion rates are low in the 5 years following CMS reimbursement, despite the advocacy of vascular medicine specialists. SET is effective in improving patient functional capacity and quality of life. Additional efforts are needed to increase both SET availability and referrals as part of comprehensive treatment of PAD.

Cardiorespiratory Fitness Assessment for Exercise Research in Mild Cognitive Impairment Due to Alzheimer's Disease.

PURPOSE: To analyze cardiorespiratory fitness (CRF) levels using the gold-standard, laboratory-based cardiopulmonary exercise test (CPET) in community-dwelling older adults (N = 145) with amnestic mild cognitive impairment (aMCI), specifically CPET feasibility, CRF prediction, and CRF status in comparison to published sedentary, cognitively normal, age- and sex-adjusted normative data. METHOD: Peak oxygen consumption (VO2Peak [mL/kg/min]) was assessed by CPET, which was categorized as submaximal, near-maximal, or maximal tests. VO2Max predicted was compared to VO2Max measured to assess its utility. Data were analyzed with t tests. RESULTS: Participants' mean age was 73.77 years (SD = 5.74 years), with 51.7% males, 91.7% Caucasian, 68.3% married, and 16.9 years (SD = 2.88 years) of education. Mean VO2Peak measured was 17.07 (SD = 4.92) for the total sample (18.29 [SD = 4.64] for males, 15.78 [SD = 4.91] for females). Sixteen (11.03%) CPETs were submaximal, 53 (36.55%) were near-maximal, and 76 (52.41%) were maximal. Mean VO2Max predicted was 28.59 (SD = 21.94) for the total sample (29.36 [SD = 22.3] for males, 27.76 [SD = 21.68] for females) and was significantly higher than VO2Max measured (p < 0.0001). Among participants with maximal CPETs, VO2Peak measured was significantly lower than sedentary normative data (p < 0.0001). CONCLUSION: CPET was feasible for older adults with aMCI. VO2Max predicted overly inflates CRF estimates. Low levels of CRF in older adults with aMCI suggest aerobic exercise as an important intervention. [Journal of Gerontological Nursing, 50(9), 31-36.].

Predictors of Usual and Peak Gait Speed in Community-Dwelling Older Adults With Mild-to-Moderate Alzheimer's Dementia.

Gait speed significantly affects functional status and health outcomes in older adults. This cross-sectional study evaluated cognitive and physical fitness contributors to usual and peak gait speed in persons with Alzheimer's dementia. Multiple hierarchal linear regression was used to obtain squared semipartial correlation coefficients (sr2) and effect sizes (Cohen's ƒ2). Participants (n = 90; 56% male) averaged 77.1 ± 6.6 years of age and 21.8 ± 3.4 on Mini-Mental State Examination. Demographic/clinical, physical fitness, and cognition variables explained 45% and 39% of variance in usual and peak gait speed, respectively. Muscle strength was the only significant contributor to both usual (sr2 = .175; Cohen's ƒ2 = 0.31; p < .001) and peak gait speed (sr2 = .11; Cohen's ƒ2 = 0.18; p < .001). Women who were "slow" walkers (usual gait speed <1.0 m/s) had significantly lower cardiorespiratory fitness and executive functioning compared with "fast" walkers. In conclusion, improving muscle strength may modify gait and downstream health outcomes in Alzheimer's dementia.

The MN RIDE pilot: feasibility of a synchronous, remotely delivered, aerobic exercise training program for rural-dwelling adults with subjective cognitive decline.

INTRODUCTION: Out of all the modifiable risk factors for Alzheimer's disease and related dementias (ADRD), physical inactivity is the strongest. Rural residents have an increased risk for dementia and face significant barriers to accessing ADRD information, caregiving support, and memory-related services, which contributes to substandard care. Rural communities have greater barriers to participating in physical activity, and in particular exercise, due to lack of social support, travel/weather problems, and lack of facilities/equipment. The purpose of this pilot study was to implement and evaluate the feasibility and safety of a synchronous, remotely delivered, aerobic exercise (AEx) telerehabilitation program in persons with subjective cognitive decline (SCD) living in rural areas. METHODS: The Minnesota Rehabilitation Intervention for Dementia Evasion for rural residents (MN RIDE) pilot study was one of five pilot studies conducted through the Center for Community Engaged Rural Dementia and Alzheimer's Research, conducted in collaboration with the Memory Keepers Medical Discovery Team. The Memory Keepers Medical Discovery Team employs a community-based participatory research model and uses a community advisory group, community-based researchers and a rural community engagement specialist to ensure research studies are aligned with rural community needs and to facilitate the recruitment of participants living in rural northern Minnesota. The MN RIDE study employed a single group, pretest-post-test design to test the feasibility and safety of an AEx-focused synchronous telerehabilitation program in rural-living middle-aged or older adults (>45 years) with SCD (indicated by answering yes to both, 'Do you perceive memory or cognitive difficulties?' and 'In the last two years, has your cognition or memory declined?'). All 36 AEx sessions (conducted over 12 weeks) were supervised remotely via smart devices and Zoom. The AEx program was classified as moderate intensity stationary cycling starting at a rating of perceived exertion (RPE) 11-12 or for 30-35 minutes in session 1, and was alternatively increased by 1-point RPE or 5-minute increments as tolerated up to RPE 12-14 for 50 minutes a session over time (by session 18). Secondarily, moderate intensity was defined as achieving an exercise heart rate of 64-76% of age-predicted maximum heart rate (HRmax). Feasibility and safety outcomes were assessed by session attendance, intensity adherence, presence of adverse events, and participant satisfaction. RESULTS: The average age of the study sample (n=9) was 57.44±7.16 years (average age of SCD onset 53.44±7.47 years) with 14.00±5.57 years of education and 88.9% female. All patients completed the study, resulting in a dropout rate of 0%. Out of the possible 324 sessions scheduled, 276 were attended (85% session adherence). Average intensity metrics achieved over the AEx sessions were RPE 13.2±0.5 and HRmax 72.0±7.9%, which both represent of moderate intensity AEx metrics. No adverse events were reported. CONCLUSION: This pilot study further provides the first evidence of preliminary feasibility of synchronous audiovisual, telerehabilitation programs delivered to rural residents at risk for ADRD. Thus, exercise telerehabilitation programs that focus on AEx could be viable and useful tools to overcome situations with limited access to healthcare services such as in rural communities. Further controlled studies with greater sample size could help further expand our results.

Total body recumbent stepping vs treadmill walking in supervised exercise therapy: A pilot study.

Background: Treadmill walking is the most commonly recommended exercise modality in supervised exercise therapy (SET) for peripheral artery disease (PAD); however, other modalities may be equally effective and more tolerable for patients. The primary aim of this single-blind, randomized pilot study was to compare the feasibility, safety, and preliminary efficacy of a treadmill walking (TM) versus a total body recumbent stepping (TBRS) exercise program for treatment of PAD (i.e., "Stepper Study").. Methods: Participants (n = 19) enrolled in a 12-week SET program and were randomized to either a TM (n = 9) or TBRS (n = 10) exercise group that followed current SET exercise guidelines. Feasibility, safety, and efficacy outcomes were assessed. Results: SET attendance was 86% and 71%, respectively, for TBRS and TM groups (p = 0.07). Session exercise dose (metabolic equivalents of task [MET] minutes) (mean [SD]) for TM was 117.6 [27.4] compared to 144.7 [28.7] in the TBRS group (p = 0.08). Study-related adverse events were nine in 236 training hours and three in 180 training hours for the TBRS and TM groups, respectively. There were no significant differences between groups for improvement in 6-minute walk distance (mean [SD]) (TM: 133.2 ft [53.5] vs TBRS: 154.8 ft [49.8]; p = 0.77) after adjusting for baseline 6-minute walk distance. Conclusion: This is the first randomized study comparing TBRS to TM exercise in SET using current SET guidelines. This pilot study showed that TBRS is a feasible and safe exercise modality in SET. This study provides preliminary efficacy of the use of TBRS exercise in SET programs following current guidelines. Larger studies should be conducted to confirm these findings.

Exercise Dose and Aerobic Fitness Response in Alzheimer's Dementia: Findings from the FIT-AD Trial.

The purpose of this study was to examine the effects of a 6-month cycling aerobic exercise intervention on cardiorespiratory fitness and the dose-response relationship in community-dwelling older adults with mild-to-moderate Alzheimer's dementia. The FIT-AD trial was a single blind, 2-parallel group, pilot randomized controlled trial. The aerobic exercise group participated in a 6-month, thrice weekly, moderate-vigorous intensity cycling intervention while control group performed stretching. Cardiorespiratory fitness was evaluated by peak oxygen consumption from cardiopulmonary exercise test and peak walking distance from the shuttle walk test and 6-minute walk test. Aerobic exercise dose was calculated using the novel heart rate physical activity score. The aerobic exercise group significantly increased peak oxygen consumption (1.28 ml/kg/min; p=0.03) in subgroup who achieved maximal criteria on cardiopulmonary exercise test. Changes in peak oxygen consumption and peak walking distance on the shuttle walk and 6-minute walk tests did not significantly differ between aerobic exercise and stretching groups. Notably, the aerobic exercise dose was strongly and significantly correlated to change in peak oxygen consumption (r=0.60; n=16; p=0.01), in subset who met maximal test criteria. Emphasis on exercise dose is needed in aerobic exercise programs to maximize cardiorespiratory fitness gains in persons with mild-moderate Alzheimer's dementia.

Implementation of Supervised Exercise Therapy for Patients With Symptomatic Peripheral Artery Disease: A Science Advisory From the American Heart Association.

Patients with lower-extremity peripheral artery disease (PAD) have greater functional impairment, faster functional decline, increased rates of mobility loss, and poorer quality of life than people without PAD. Supervised exercise therapy (SET) improves walking ability, overall functional status, and health-related quality of life in patients with symptomatic PAD. In 2017, the Centers for Medicare & Medicaid Services released a National Coverage Determination (CAG-00449N) for SET programs for patients with symptomatic PAD. This advisory provides a practical guide for delivering SET programs to patients with PAD according to Centers for Medicare & Medicaid Services criteria. It summarizes the Centers for Medicare & Medicaid Services process and requirements for referral and coverage of SET and provides guidance on how to implement SET for patients with PAD, including the SET protocol, options for outcome measurement, and transition to home-based exercise. This advisory is based on the guidelines established by the Centers for Medicare & Medicaid Services for Medicare beneficiaries in the United States and is intended to assist clinicians and administrators who are implementing SET programs for patients with PAD.

A Comparison of Cardiopulmonary Exercise Testing and Field Walking Tests in Community-Dwelling Older Adults With Mild-to-Moderate Alzheimer's Dementia.

The purpose of this study was to investigate the relationships among peak exercise parameters on 6-min walk test, shuttle walk test, and laboratory-based cardiopulmonary exercise testing in persons with Alzheimer's dementia. This study is a cross-sectional analysis of the baseline data of 90 participants (age 77.1 [6.6] years, 43% female) from the FIT-AD trial. Cardiopulmonary exercise testing produced significantly higher peak heart rate (118.6 [17.5] vs. 106 [22.8] vs. 106 [18.8] beats/min), rating of perceived exertion (16 [2.1] vs. 12 [2.3] vs. 11 [2.1]), and systolic blood pressure (182 [23.7] vs. 156 [18.9] vs. 150 [16.9] mmHg) compared with the shuttle walk test and 6-min walk test, respectively. Peak walking distance on shuttle walk test (241.3 [127.3] m) and 6-min walk test (365.0 [107.9] m) significantly correlated with peak oxygen consumption (17.1 [4.3] ml·kg-1·min-1) on cardiopulmonary exercise testing (r = .449, p ≤ .001 and r = .435, p ≤ .001), respectively, which is considerably lower than what is seen in older adults and persons with cardiopulmonary diseases.

Factors Predicting the Onset of Amnestic Mild Cognitive Impairment or Alzheimer's Dementia in Persons With Subjective Cognitive Decline.

The objective of the current retrospective cohort study was to identify vascular and/or neuropsychiatric risk factors predicting clinical progression in persons with subjective cognitive decline (SCD). Information on 1,525 persons with SCD (mean age = 73.8 [SD = 8.1] years) was obtained from the National Alzheimer's Coordinating Center. Clinical progression occurred from SCD to either amnestic mild cognitive impairment or Alzheimer's dementia over an average of 4.7 (SD = 2.9) years. Stepwise Cox regression was used. Compared to obesity (hazard ratio [HR] = 0.59) in the univariate unadjusted model, obesity (HR = 0.64), current smoking (HR = 2.02), and depressive symptoms (HR = 1.35) were significant after adjusting for covariates in the univariate model. In the multivariate adjusted model, obesity (HR = 0.64), current smoking (HR = 2.04), and depressive symptoms (HR = 1.36) remained significant predictors. Interventions should be designed to minimize transition by managing smoking and depressive symptoms. Further research is required for associations between obesity and clinical progression to test the hypothesis of obesity paradox. [Journal of Gerontological Nursing, 46(8), 28-36.].

Measurement of peripheral blood flow in patients with peripheral artery disease: Methods and considerations.

Peripheral artery disease (PAD) is a manifestation of generalized atherosclerosis which results in hemodynamic compromise of oxygen and substrate delivery to the lower extremity skeletal muscles. Hemodynamic assessments are vital in PAD diagnosis and in the evaluation of strategies aimed at treating claudication (i.e. exercise training, revascularization, and pharmacological agents). Venous occlusion plethysmography (VOP) is a century-old, non-invasive technique used to quantify limb blood flow and has been used to evaluate hemodynamic compromise in patients with PAD. However, the literature suggests a wide array of methodological variability in the measurement and analysis of limb blood flow using VOP. In this manuscript, we overview the clinical application of VOP measurement, and secondly we review the methodological variation that occurs during the measurement and analysis of VOP in healthy individuals and in patients with claudication.

Reactive oxygen and nitrogen species: impact on endothelial dysfunction.

BACKGROUND: Reactive oxygen and nitrogen species, known as free radicals, play a key role in the etiology and progression of atherosclerotic cardiovascular disease by creating vascular oxidative stress. PURPOSE: This review will discuss current biological research about the enzymatic and nonenzymatic sources of oxidative stress, free radical chemistry, and how it pertains to endothelial dysfunction-a hallmark of cardiovascular disease. METHODS: An integrative review of the literature was conducted. FINDINGS: Free radicals lower the bioavailability of the potent vasodilator nitric oxide and therefore, through numerous chemical reactions, negatively affect vascular biology and endothelial function. Endothelial dysfunction is considered to be integral in the initiation of atherosclerosis. CONCLUSIONS: The success and failures of current therapies to reduce oxidative stress are discussed in terms of implications for nursing research on exogenous antioxidants, pharmacotherapy, and lifestyle change.

Inflammation and immune system contribution to the etiology of atherosclerosis: mechanisms and methods of assessment.

BACKGROUND: Immune system activation and inflammation are intricately involved in the development and progression of atherosclerosis. PURPOSE: The purposes of this review are to (a) discuss effects of inflammation and the immune system across the lifespan of atherosclerotic plaque, (b) review current recommended testing techniques for assessing inflammation using blood and within the atherosclerotic plaque, and (c) link basic research in inflammation and immunology with ongoing clinical research with potential to impact prevention and treatment interventions in atherosclerotic disease. RESULTS: The atherosclerotic process is typically initiated in the presence of endothelial dysfunction by increased uptake, entrapment, and deposition of lipids, especially low-density lipoprotein (LDL). Once inside the intima, LDL can become oxidized (LDLox), which promotes further endothelial cell activation/injury, stimulates adhesion molecule expression, and releases chemotactic factors that promote leukocyte-endothelial interactions. The process of atherogenesis is highly regulated by the innate and adaptive immune systems and systemic inflammatory response. In addition, proinflammatory mediators play a key role in the lifespan of the atherosclerotic plaque and its vulnerability, favoring eventual plaque fissure when exposed to increasing hemodynamic stress. DISCUSSION: The complex atherosclerotic process involves the innate and adaptive immune systems and systemic inflammatory activation. Incorporation of advances in understanding inflammation and immune system contributions to the etiology of atherosclerosis into intervention research allows the development of novel approaches to prevention and treatment.

The Effects of Exergame Telerehabilitation in Persons With Subjective Cognitive Decline.

BACKGROUND AND OBJECTIVES: The primary aim of this Stage IB randomized controlled trial (RCT) was to test the preliminary effects of a dual-task exergaming telerehabilitation intervention on cognition and aerobic fitness, compared to aerobic exercise (AEx) only and attention control (stretching) in older adults with subjective cognitive decline. RESEARCH DESIGN AND METHODS: This RCT randomized 39 participants on a 2:1:1 allocation ratio to supervised exergame (n = 20), AEx (n = 11), and stretching (n = 8) for 12 weeks. The dual-task exergaming was concurrent moderate-intensity cycling and BrainFitRx cognitive telerehabilitation. Cognition was assessed by NIH Toolbox Cognitive Battery and aerobic fitness by 6-minute walk test (6MWT) and shuttle walk test. RESULTS: The participants were 74.6 (7.4) years old and 69% were female. The effect of time was significant, F(1, 23.9) = 13.16, p = .001, for the Fluid Composite score, and significant within-group changes were seen for the exergame group, t(14.08) = 2.53, p = .024, d = 0.33. Between-group changes did not reach significant levels for any cognitive test. Between-group changes for the 6MWT were not significant. DISCUSSION AND IMPLICATIONS: The exergame participants further improved their fluid cognition, whereas the AEx and stretching groups did not, indicating a potential synergistic effect from AEx and cognitive training. The aerobic fitness changes were similar between the exergame and AEx-only groups, indicating that the feasibility of adding cognitive training to AEx concurrently without sacrificing gains in aerobic fitness from AEx. This study shows the flexibility of exergame delivery and its potentially therapeutic effects in persons at risk for Alzheimer's dementia. CLINICAL TRIAL REGISTRATION NUMBER: NCT04311736.

Relations Between Cardiorespiratory Fitness and Cognition in Older Adults With Amnestic Mild Cognitive Impairment From the Aerobic Exercise and Cognitive Training (ACT) Trial: Sex Differences.

Objective: To examine the associations of cardiorespiratory fitness with executive function, episodic memory, and global cognition and sex differences in these associations in community-dwelling older adults with amnestic mild cognitive impairment. Design: A cross-sectional study using baseline data from the aerobic exercise and cognitive training (ACT) trial. Setting: The ACT trial conducted exercise testing in an exercise laboratory and data collections in a research facility. Participants: ACT trial participants were recruited through referrals, registries, exhibits, flyers, media, and advertisements and screened for eligibility. To be eligible for this study, ACT enrollees needed complete data on all study variables. Among 146 ACT enrollees, 142 met eligibility for this study (N=142). Interventions: None. Main Outcome Measures: Cardiorespiratory fitness was measured as peak oxygen consumption (Vo2peak) with a peak cycle-ergometer test, executive function with the EXAMINER, episodic memory with the Brief Visuospatial Memory Test-Revised, and global cognition with Montreal Cognitive Assessment. Results: The average age of the sample was 73.8±5.8 years with 16.9±2.9 years of education, with 87.3% White, 51.4% men, and 69.7% married. After controlling for covariates, Vo2peak was significantly related to executive function (b=.037, standard error [SE]=0.015, P=.0154, semipartial [sr] correlation coefficient=.239) and episodic memory (b=.590, SE=0.226, P=.0102, sr=.216), but not global cognition (b=.074, SE=0.055, P=.1837, sr=.125). For men, Vo2peak was significantly associated with executive function (b=.063, SE=0.024, P=.0099, r=.430) and episodic memory (b=1.088, SE=0.312, P=.0009, r=.382). Conclusions: Our findings show that Vo2peak was associated with executive function and episodic memory in the overall sample and in men. Future studies can examine the longitudinal relations between cardiorespiratory fitness and cognition.

Clinical Effectiveness of a Supervised Exercise Therapy Program for Treatment of Peripheral Artery Disease: A Translational Study.

PURPOSE: National guidelines for the treatment and management of symptomatic peripheral artery disease (PAD) recommend supervised exercise therapy (SET) as a first line of therapy. However, it is unknown how these expert opinion-based SET guidelines work in clinical practice as SET programs become established following the 2017 Centers for Medicare & Medicaid Services coverage announcement. The purpose of this prospective, nonrandomized translational study was to evaluate the clinical effectiveness of a SET program and specifically walking exercise modalities that did not incorporate a treadmill (TM). METHODS: Participants enrolled in a 12-wk SET program housed in four rural Midwest cardiac rehabilitation settings and were prescribed an exercise program by an exercise physiologist or nurse based on current SET guidelines. Groups included TM walking, total body recumbent stepping (TBRS), TM walking + TBRS, and multimodal. Pre- and post-tests of walking capacity, physical function, and quality of life were administered. RESULTS: The sample (n = 93) was all White, with 55% female representation, age of 73.7 ± 9.0 yr, and mild-moderate PAD (ankle-brachial index = 0.71 ± 0.19). Collectively, SET significantly improved the 6-min walk test (32.1 ± 6.6 m; P < .01). Within-group changes in the 6-min walk test were seen for all groups except the multimodal group; there were no significant between-group differences in change scores ( P = .30). No significant between-group changes were seen for the TM walking, TBRS, and TM walking + TBRS groups for physical function measures. CONCLUSION: This study demonstrates the clinical effectiveness of SET programs following current guidelines and potential utilization of non-TM walking modalities in SET programs.

Supervised Exercise Therapy for Symptomatic Peripheral Artery Disease: A REVIEW OF CURRENT EXPERIENCE AND PRACTICE-BASED RECOMMENDATIONS.

PURPOSE: This review encompasses several practical components of supervised exercise therapy (SET) for patients with claudication including referral, exercise training, and billing issues. Real-life SET session examples are also provided. SET was approved for reimbursement by the Centers for Medicare & Medicaid Services (CMS) in 2017, and there is continual growth of programs offering SET and in participation. The purpose of this review is to provide useful information for the clinical exercise professionals working with these patients. REVIEW METHODS: The 2016 ACC/AHA Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease (PAD) provided a class I (highest level) recommendation for the use of SET in those with symptomatic PAD. Since there has been much growth in the literature about the utility of SET, the literature was reviewed (PubMed) to provide information for this article. Topics reviewed include the benefits of exercise training, exercise prescription, billing, referral and participation, and best practices. SUMMARY: SET should be offered to all patients with symptomatic PAD who are not at risk of acute limb ischemia. For optimal results, SET should be implemented several times per week and in a progressive process to increase exercise intensity as tolerated. For best results, programs should recommend patients supplement SET with home exercise. Considerations for utilizing reimbursed sessions should also be discussed because patients have a maximum of 72 sessions/lifetime. Referral practices need refinement, and participation rates remain extremely low and may be influenced by demographics. Research on best practices and home or hybrid training must continue to address issues related to common enrollment and participation barriers. CONDENSED ABSTRACT: Supervised exercise training (SET) for symptomatic peripheral artery disease is a class IA recommendation and reimbursable by most insurances. Improvements in walking performance can be dramatic. However, referral and participation in SET remain very low and thus SET is vastly underutilized.

Aerobic Exercise, Training Dose, and Cardiorespiratory Fitness: Effects and Relationships with Resting Plasma Neurotrophic Factors in Alzheimer's Dementia.

Background: Vascular health is increasingly recognized for its roles in the pathogenesis and progression of Alzheimer's disease (AD). The objective of this study was to investigate effects of exercise training, dose, and cardiorespiratory fitness (CRF) on neurotrophic factors in community-dwelling, older adults with mild-to-moderate AD dementia. Methods: This was a pilot blood ancillary study of the FIT-AD trial. Participants in the parent study were randomized to 6-month aerobic exercise (AEx) or stretching control. For this ancillary study, resting plasma brain-derived neurotrophic factor (BDNF), irisin, fibroblast growth factor-21 (FGF-21), and insulin-like growth factor-1 (IGF-1) biomarkers were assessed at baseline, 3, and 6 months. Estimates of within- and between-group effect sizes were calculated (Cohen's d). Relationships of biomarker change with dose and CRF change were explored with multivariable linear regression and repeated measures correlations. Results: The sample (n = 26, 18 AEx/8 stretching) averaged 77.6 ± 6.9 years old, with the majority being male (65.4%), and non-Hispanic White (92.3%); between-group effect sizes were generally small except for irisin (d = -0.44)), AEx group relative to stretching group. Associations of dose and changes in CRF with changes in neurotrophic biomarker were weak (r2 ≤ 0.025). Conclusions: The effects of exercise on BDNF, irisin, IGF-1, and FGF-21 were heterogeneous in AD. Our findings need validation in future, adequately powered exercise studies in AD.

Feasibility and preliminary effects of exercise interventions on plasma biomarkers of Alzheimer's disease in the FIT-AD trial: a randomized pilot study in older adults with Alzheimer's dementia.

BACKGROUND: Alzheimer's disease (AD) biomarkers have provided a unique opportunity to understand AD pathogenesis and monitor treatment responses. However, exercise trials show mixed effects on imagining and cerebrospinal fluid biomarkers of AD. The feasibility and effects of exercise on plasma biomarkers remain unknown. The primary objective of this study was to examine the feasibility of recruitment, retention, and blood sample collection in community-dwelling older adults with mild-to-moderate AD dementia. Secondarily, it estimated the preliminary effects of 6-month aerobic and stretching exercise on plasma amyloid-ß42 and Aß40 (Aß42/40) ratio, phosphorylated tau (p-tau) 181, and total tau (t-tau). METHODS: This pilot study was implemented in year 2 of the 2-parallel group FIT-AD trial that randomized 96 participants on a 2:1 allocation ratio to moderate-intensity cycling or low-intensity stretching for 20-50 min, 3 times/week for 6 months with 6-month follow-up. Investigators (except for the statistician) and data collectors were blinded to group assignment. Fasting blood samples were collected from 26 participants at baseline and 3 and 6 months. Plasma Aß42, Aß40, p-tau181, and t-tau were measured using Simoa™ assays. Data were analyzed using intention-to-treat, Cohen's d, and linear mixed models. RESULTSS: The sample averaged 77.6±6.99 years old and 15.4±3.00 years of education with 65% being male and 96.2% being apolipoprotein epsilon 4 gene carriers. The recruitment rate was 76.5%. The retention rate was 100% at 3 months and 96.2% at 6 months. The rate of blood collection was 88.5% at 3 months and 96.2% at 6 months. Means (standard deviation) of within-group 6-month difference in the stretching and cycling group were 0.001 (0.012) and -0.001 (0.010) for Aß42/40 ratio, 0.609 (1.417) pg/mL and 0.101(1.579) pg/mL for p-tau181, and -0.020 (0.279) pg/mL and -0.075 (0.215) pg/mL for t-tau. Effect sizes for within-group 6-month difference were observed for p-tau181 in stretching (d=0.43 [-0.33, 1.19]) and t-tau in cycling (-0.35 [-0.87, 0.17]). CONCLUSIONS: Blood collections with fasting were well received by participants and feasible with high recruitment and retention rates. Plasma biomarkers of AD may be modifiable by exercise intervention. Important design considerations are provided for future Phase III trials. TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT01954550 and posted on October 1, 2013.

Inter-individual differences in the responses to aerobic exercise in Alzheimer's disease: Findings from the FIT-AD trial.

BACKGROUND: Despite the strong evidence of aerobic exercise as a disease-modifying treatment for Alzheimer's disease (AD) in animal models, its effects on cognition are inconsistent in human studies. A major contributor to these findings is inter-individual differences in the responses to aerobic exercise, which was well documented in the general population but not in those with AD. The purpose of this study was to examine inter-individual differences in aerobic fitness and cognitive responses to a 6-month aerobic exercise intervention in community-dwelling older adults with mild-to-moderate dementia due to AD. METHODS: This study was a secondary analysis of the Effects of Aerobic Exercise for Treating Alzheimer's Disease (FIT-AD) trial data. Aerobic fitness was measured by the shuttle walk test (SWT), the 6-min walk test (6MWT), and the maximal oxygen consumption (VO2max) test, and cognition by the AD Assessment Scale-Cognition (ADAS-Cog). Inter-individual differences were calculated as the differences in the standard deviation of 6-month change (SDR) in the SWT, 6MWT, VO2max, and ADAS-Cog between the intervention and control groups. RESULTS: Seventy-eight participants were included in this study (77.4 ± 6.3 years old, mean ± SD; 15.7 ± 2.8 years of education; 41% were female). VO2max was available for 26 participants (77.7 ± 7.1 years old; 14.8 ± 2.6 years of education; 35% were female). The SDR was 37.0, 121.1, 1.7, and 2.3 for SWT, 6MWT, VO2max, and ADAS-Cog, respectively. CONCLUSION: There are true inter-individual differences in aerobic fitness and cognitive responses to aerobic exercise in older adults with mild-to-moderate dementia due to AD. These inter-individual differences likely underline the inconsistent cognitive benefits in human studies.

Efficacy of simultaneous aerobic exercise and cognitive training in subjective cognitive decline: study protocol for randomized controlled trial of the Exergames Study.

BACKGROUND: Subjective cognitive decline (SCD) is an early manifestation of Alzheimer's disease (AD) and offers a therapeutic window where interventions have strong potential to prevent or delay the progression of AD. Aerobic exercise and cognitive training represent two promising interventions for AD prevention, but their synergistic effect has yet to be assessed in persons with SCD. METHODS/DESIGN: The purpose of this single-blinded, 3-parallel group randomized controlled trial is to test the synergistic efficacy of an exergame intervention (simultaneous moderate-intensity aerobic cycling and cognitive training) on cognition and aerobic fitness in community-dwelling older adults with SCD. The Exergames Study will randomize 96 participants on a 2:1:1 allocation ratio to 3-month exergame, cycling only, or attention control (stretching). Primary outcomes include global cognition and aerobic fitness, which will be assessed at baseline and after 3 months. The specific aims of the Exergames Study are to (1) determine the efficacy of the exergame in older adults with SCD and (2) assess the distraction effect of exergame on aerobic fitness. Data will be analyzed using ANOVA following intention-to-treat. DISCUSSION: This study will test the synergistic effects of exergame on cognition and aerobic fitness. It has the potential to advance prevention research for AD by providing effect-size estimates for future trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT04311736 . Registered on 17 March 2020.