Publications by authors named "Dane B Cook"

74 Publications

Cardiorespiratory fitness mitigates brain atrophy and cognitive decline in adults at risk for Alzheimer's disease.

Alzheimers Dement (Amst) 2021 12;13(1):e12212. Epub 2021 Jul 12.

William S. Middleton Memorial Veterans Hospital Madison Wisconsin USA.

Introduction: Cardiorespiratory fitness (CRF) may mitigate Alzheimer's disease (AD) progression. This study examined the longitudinal associations of CRF with brain atrophy and cognitive decline in a late-middle-aged cohort of adults at risk for AD.

Methods: One hundred ten cognitively unimpaired adults (66% female, mean age at baseline 64.2 ± 5.7 years) completed a baseline graded treadmill exercise test, two brain magnetic resonance imaging scans (over 4.67 ± 1.17 years), and two to three cognitive assessments (over 3.26 ± 1.02 years). Linear mixed effects models examined the longitudinal associations adjusted for covariates.

Results: Participants with higher baseline CRF had slower annual decline in total gray matter volume (= .013) and cognitive function (= .048), but not hippocampal volume (= .426). Exploratory analyses suggested these effects may be stronger among apolipoprotein E ε4 carriers.

Discussion: CRF is a modifiable physiological attribute that may be targeted during the preclinical phase of AD in effort to delay disease progression, perhaps most effectively among those with genetic risk.
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http://dx.doi.org/10.1002/dad2.12212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274307PMC
July 2021

Safety and efficacy of short-term structured resistance exercise in Gulf War Veterans with chronic unexplained muscle pain: A randomized controlled trial.

Life Sci 2021 Oct 10;282:119810. Epub 2021 Jul 10.

William S. Middleton Memorial Veterans Hospital, Madison, WI, United States of America; University of Wisconsin-Madison, Madison, WI, United States of America.

Aims: Chronic widespread musculoskeletal pain (CMP) is a primary condition of Veterans suffering from Gulf War illness. This study evaluated the influence of resistance exercise training (RET) on symptoms, mood, perception of improvement, fitness, and total physical activity in Gulf War Veterans (GWV) with CMP.

Main Methods: Fifty-four GWV with CMP were randomly assigned to 16 weeks of RET (n = 28) or wait-list control (n = 26). Supervised exercise was performed twice weekly starting at a low intensity. Outcomes, assessed at baseline, 6, 11 and 17 weeks and 6- and 12-months post-intervention, were: pain, fatigue, mood, sleep quality, perception of improvement, and physical activity via self-report and accelerometry. Muscular strength was assessed at baseline, 8 and 16 weeks. Accelerometer data yielded estimates of time spent in sedentary, light, and moderate-to-vigorous physical activities. Analyses used separate linear mixed models with group and time point as fixed effects. All models, except for perceived improvement, included baseline values as a covariate.

Key Findings: Participants assigned to RET completed 87% of training sessions and exhibited strength increases between 16 and 34% for eight lifts tested (Hedges' g range: 0.47-0.78). The treatment by time interaction for perceived improvement (F = 16.94, p < 0.001) was characterized by greater perceived improvement since baseline for RET at each time point, until the 12-month follow-up. Effects were not significant for other outcomes (p > 0.05). RET caused no adverse events.

Significance: After 16 weeks of RET, GWV with CMP reported improvements in their condition and exhibited increases in muscular strength, without symptom exacerbation or reductions in total physical activity.
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http://dx.doi.org/10.1016/j.lfs.2021.119810DOI Listing
October 2021

Predicting post-exertional malaise in Gulf War Illness based on acute exercise responses.

Life Sci 2021 Sep 10;280:119701. Epub 2021 Jun 10.

William S. Middleton Memorial Veterans Hospital, Madison, WI, United States of America; Department of Kinesiology, University of Wisconsin-Madison, Madison, WI, United States of America. Electronic address:

Aims: Post-exertional malaise (PEM) is poorly understood in Gulf War Illness (GWI). Exercise challenges have emerged as stimuli to study PEM; however, little attention has been paid to unique cardiorespiratory and perceptual responses during exercise. This study tested whether select exercise parameters explained variability in PEM responses.

Main Methods: Visual analog scale (0-100) versions of the Kansas questionnaire were used for daily symptom measurements one week before and one week after 30-min of cycling at 70% heart rate reserve in 43 Veterans with GWI and 31 Veteran controls (CON). Cardiopulmonary exercise testing (CPET) methods were used to measure oxygen (VO), carbon dioxide (VCO), ventilation (VE), heart rate, work rate, and leg muscle pain. Symptom changes and CPET parameters were compared between groups with independent samples t-tests. Linear regression (GLM) with VE/VCO, cumulative work, leg muscle pain, and self-reported physical function treated as independent variables and peak symptom response as the dependent variable tested whether exercise responses predicted PEM.

Key Findings: Compared to CON, Veterans with GWI had greater ventilatory equivalent for oxygen (VE/VO), peak leg muscle pain, fatigue, and lower VCO, VO, power, and cumulative work during exercise (p < 0.05), and greater peak symptom responses (GWI = 38.90 ± 29.06, CON = 17.84 ± 28.26, g = 0.70, p < 0.01). The final GLM did not explain significant variance in PEM (Pooled R = 0.15, Adjusted R = 0.03, p = 0.34).

Significance: The PEM response was not related to the selected combination of cardiorespiratory and perceptual responses to exercise.
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http://dx.doi.org/10.1016/j.lfs.2021.119701DOI Listing
September 2021

Effects of Aerobic Exercise Training on Systemic Biomarkers and Cognition in Late Middle-Aged Adults at Risk for Alzheimer's Disease.

Front Endocrinol (Lausanne) 2021 20;12:660181. Epub 2021 May 20.

Lab of Neurosciences, National Institute on Aging (NIA), Baltimore, MD, United States.

Increasing evidence indicates that physical activity and exercise training may delay or prevent the onset of Alzheimer's disease (AD). However, systemic biomarkers that can measure exercise effects on brain function and that link to relevant metabolic responses are lacking. To begin to address this issue, we utilized blood samples of 23 asymptomatic late middle-aged adults, with familial and genetic risk for AD (mean age 65 years old, 50% female) who underwent 26 weeks of supervised treadmill training. Systemic biomarkers implicated in learning and memory, including the myokine Cathepsin B (CTSB), brain-derived neurotrophic factor (BDNF), and klotho, as well as metabolomics were evaluated. Here we show that aerobic exercise training increases plasma CTSB and that changes in CTSB, but not BDNF or klotho, correlate with cognitive performance. BDNF levels decreased with exercise training. Klotho levels were unchanged by training, but closely associated with change in VOpeak. Metabolomic analysis revealed increased levels of polyunsaturated free fatty acids (PUFAs), reductions in ceramides, sphingo- and phospholipids, as well as changes in gut microbiome metabolites and redox homeostasis, with exercise. Multiple metabolites (~30%) correlated with changes in BDNF, but not CSTB or klotho. The positive association between CTSB and cognition, and the modulation of lipid metabolites implicated in dementia, support the beneficial effects of exercise training on brain function. Overall, our analyses indicate metabolic regulation of exercise-induced plasma BDNF changes and provide evidence that CTSB is a marker of cognitive changes in late middle-aged adults at risk for dementia.
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http://dx.doi.org/10.3389/fendo.2021.660181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173166PMC
May 2021

Nociceptive stress interferes with neural processing of cognitive stimuli in Gulf War Veterans with chronic musculoskeletal pain.

Life Sci 2021 Aug 26;279:119653. Epub 2021 May 26.

William S. Middleton Memorial Veterans Hospital, Madison, WI, USA; Department of Kinesiology, University of Wisconsin-Madison, Madison, WI, USA.

Aims: Disrupted cognition and chronic musculoskeletal pain (CMP) are prevalent experiences among Gulf War Veterans (GWV). A negative association between CMP and cognition (i.e., chronic pain-related cognitive interference) has been observed in some chronic pain populations but has not been evaluated in GWV. Additional research suggests that disrupted cognition in GWV with CMP may be exacerbated by stressing the nociceptive system. Therefore, we compared cognitive performance and related neural activity between CMP and healthy control (CO) GWV in the absence and presence of experimental pain.

Main Methods: During functional magnetic resonance imaging (fMRI), Veterans (CMP = 29; CO = 27) completed cognitive testing via congruent and incongruent conditions of a modified Stroop task (Stroop-only). A random subset (CMP = 13; CO = 13) also completed cognitive testing with experimental pain (Pain+Stroop). Yuen's modified t-test and robust mixed-model analysis of variance (ANOVA) models were used for analyzing cognitive performance data. Independent t-tests and repeated-measures ANOVA models were employed for fMRI data with thresholding for multiple-comparisons (p < 0.005) and cluster size (> 320 mm).

Key Findings: Functional MRI analysis revealed significant between-group differences for the incongruent but not congruent-Stroop run. Neither correct responses nor reaction time differed between groups in either Stroop condition (all p ≥ 0.21). Significant group (CMP, CO) by run (Stroop-only, Pain+Stroop) interactions revealed greater neural responses in CMP Veterans during Pain+Stroop runs. No significant interactions were observed for correct responses or reaction time (p ≥ 0.31).

Significance: GWV with CMP require a greater amount of neural resources to sustain cognitive performance during nociceptive stress.
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http://dx.doi.org/10.1016/j.lfs.2021.119653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243383PMC
August 2021

Cardiorespiratory Fitness Associates with Cerebral Vessel Pulsatility in a Cohort Enriched with Risk for Alzheimer's Disease.

Brain Plast 2020 Oct 1;5(2):175-184. Epub 2020 Oct 1.

Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.

Background: There is increasing evidence that vascular disease risk factors contribute to evolution of the dementia syndrome of Alzheimer's disease (AD). One important measure of cerebrovascular health is pulsatility index (PI) which is thought to represent distal vascular resistance, and has previously been reported to be elevated in AD clinical syndrome. Physical inactivity has emerged as an independent risk factor for cardiovascular disease.

Objective: This study aims to examine the relationship between a measure of habitual physical activity, cardiorespiratory fitness (CRF), and PI in the large cerebral vessels.

Methods: Ninety-two cognitively-healthy adults (age = 65.34±5.95, 72% female) enrolled in the Wisconsin Registry for Alzheimer's Prevention participated in this study. Participants underwent 4D flow brain MRI to measure PI in the internal carotid artery (ICA), basilar artery, middle cerebral artery (MCA), and superior sagittal sinus. Participants also completed a self-report physical activity questionnaire. CRF was calculated using a previously-validated equation that incorporates sex, age, body-mass index, resting heart rate, and self-reported physical activity. A series of linear regression models adjusted for age, sex, APOE4 status, and 10-year atherosclerotic cardiovascular disease risk were used to analyze the relationship between CRF and PI.

Results: Inverse associations were found between CRF and mean PI in the inferior ICA (p = .001), superior ICA (p = .035), and basilar artery (p = .040). No other cerebral vessels revealed significant associations between CRF and PI (p≥.228).

Conclusions: Higher CRF was associated with lower PI in several large cerebral vessels. Since increased pulsatility has been associated with poor brain health and reported in persons with AD, this suggests that aerobic fitness might provide protection against cerebrovascular changes related to the progression of AD clinical syndrome.
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http://dx.doi.org/10.3233/BPL-190096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685671PMC
October 2020

An analysis of 2-day cardiopulmonary exercise testing to assess unexplained fatigue.

Physiol Rep 2020 09;8(17):e14564

VA Airborne Hazards and Burn Pits Center of Excellence, War Related Illness and Injury Study Center, VA New Jersey Health Care System, East Orange, NJ, USA.

Two consecutive maximal cardiopulmonary exercise tests (CPETs) performed 24 hr apart (2-day CPET protocol) are increasingly used to evaluate post-exertional malaise (PEM) and related disability among individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This protocol may extend to other fatiguing illnesses with similar characteristics to ME/CFS; however, 2-day CPET protocol reliability and minimum change required to be considered clinically meaningful (i.e., exceeding the standard error of the measure) are not well characterized. To address this gap, we evaluated the 2-day CPET protocol in Gulf War Illness (GWI) by quantifying repeatability of seven CPET parameters, establishing their thresholds of clinically significant change, and determining whether changes differed between veterans with GWI and controls. Excluding those not attaining peak effort criteria (n = 15), we calculated intraclass correlation coefficients (ICCs), the smallest real difference (SRD%), and repeated measures analysis of variance (RM-ANOVA) at the ventilatory anaerobic threshold (VAT) and peak exercise in 15 veterans with GWI and eight controls. ICC values at peak ranged from moderate to excellent for veterans with GWI (mean [range]; 0.84 [0.65 - 0.92]) and were reduced at the VAT (0.68 [0.37 - 0.78]). Across CPET variables, the SRD% at peak exercise for veterans with GWI (18.8 [8.8 - 28.8]) was generally lower than at the VAT (28.1 [9.5 - 34.8]). RM-ANOVAs did not detect any significant group-by-time interactions (all p > .05). The methods and findings reported here provide a framework for evaluating 2-day CPET reliability, and reinforce the importance of carefully considering measurement error in the population of interest when interpreting findings.
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http://dx.doi.org/10.14814/phy2.14564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507580PMC
September 2020

Collective effects of age, sex, genotype, and cognitive status on fitness outcomes.

Alzheimers Dement (Amst) 2020 13;12(1):e12058. Epub 2020 Jul 13.

Department of Medicine University of Wisconsin-Madison Madison Wisconsin USA.

Introduction: Individuals with Alzheimer's disease (AD) broadly exhibit lower cardiorespiratory fitness (CRF) compared to cognitively healthy older adults. Other factors, such as increasing age and female sex, are also known to track with lower CRF levels. However, it is unclear how these factors together with AD diagnosis and genetic risk (apolipoprotein e4 ; ) collectively affect CRF.

Methods: Our primary objective was to characterize the collective relationship of age, sex, carrier status , and cognitive status (nondemented or AD) with two commonly reported CRF outcomes, VO max and oxygen uptake efficiency slope (OUES). To interrogate the unique and combined effect of age, sex, , and cognitive status on CRF, we pooled multiple datasets and tested several statistical models allowing all possible interactions.

Results: AD diagnosis was consistently associated with lower maximal CRF, which declined with increasing age. was also associated with lower maximal CRF (VO), but only in male subjects. Submaximal CRF (OUES) was lower in carriers of both sexes, although this difference converged in male subjects with advancing age.

Discussion: This multi-cohort analysis (n = 304) suggests that carrier status and sex are important considerations for studies that evaluate maximal and submaximal CRF.
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http://dx.doi.org/10.1002/dad2.12058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364859PMC
July 2020

Protocol of Aerobic Exercise and Cognitive Health (REACH): A Pilot Study.

J Alzheimers Dis Rep 2020 May 2;4(1):107-121. Epub 2020 May 2.

Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.

A growing body of evidence supports that aerobic exercise can decrease the risk of future cognitive impairment and Alzheimer's disease (AD). There is a pressing need to rigorously determine whether cognitively normal yet at-risk individuals stand to benefit from the protective effects of exercise. The present study will test the feasibility of an aerobic exercise intervention in such a population and inform the design of a larger-scale randomized, controlled trial examining the effect of aerobic exercise on biomarkers of AD in late-middle-aged, at-risk individuals. This was a single-site, 1 : 1 block-randomized, parallel, two-arm trial. Cognitively normal participants aged 45-80 with documentation of familial and genetic AD risk factors were randomly assigned to one of two interventions. The Usual Physical Activity group was provided educational materials about exercise. The Enhanced Physical Activity intervention delivered 26 weeks of individualized and supervised aerobic exercise. Exercise duration and intensity were incrementally increased to 150 min/week and 70-80% of heart rate reserve, respectively. Retention and adherence were measured to assess study feasibility. In addition, pre- and post- intervention differences between the two arms were evaluated for cardiorespiratory fitness, physical activity, brain glucose metabolism, cerebral structure, vascular health, memory, executive function, and mood. Data from randomized controlled trials of exercise training are needed to identify the proper exercise prescription for reducing accumulation of AD biomarkers in cognitively normal individuals. The current trial will contribute to filling that gap while informing the design of large-scale trials.
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http://dx.doi.org/10.3233/ADR-200180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306918PMC
May 2020

Elevated Perceived Exertion in People with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia: A Meta-analysis.

Med Sci Sports Exerc 2020 12;52(12):2615-2627

Purpose: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are two debilitating illnesses primarily characterized by chronic symptoms of fatigue and musculoskeletal pain, respectively. Some investigators have observed an elevated sense of effort in these patient groups; however, this effect has not been substantiated via quantitative review. As such, we conducted a meta-analysis of RPE responses to aerobic exercise in ME/CFS and FM compared with healthy adults.

Methods: Case-control studies involving adults with ME/CFS or FM that measured RPE and heart rate responses to acute aerobic exercise were included. Data sources included PubMed, Scopus/Embase, CINAHL, CENTRAL, and Google Scholar. Risk of bias was assessed by evaluating each study's description of participant characteristics, matching procedures, and administration of RPE scales. Hedges' d effect sizes for RPE were calculated and aggregated using random-effects models, and potential moderators were explored with meta-regression analysis.

Results: Forty-one effects were extracted from 37 studies involving 1016 patients and 686 healthy controls. We observed a large (Hedges' d = 0.85, 95% confidence interval = 0.62-1.08) effect indicating higher RPE in patients than controls. The mean effect size was significantly moderated (P < 0.001, R = 0.38) by whether RPE data were analyzed at a peak or submaximal intensity (b = 0.60, z = 4.6, P < 0.001) and the type of patient group that was studied (b = 0.25, z = 2.08, P = 0.04).

Conclusions: People with ME/CFS and FM perceive aerobic exercise as more effortful than healthy adults, but the exact causes are unclear. The large magnitude of this effect merits further exploration of underlying mechanisms that could provide insight into the pathophysiology of ME/CFS and FM or the broader debate about the nature of central and/or peripheral signals that influence RPE.
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http://dx.doi.org/10.1249/MSS.0000000000002421DOI Listing
December 2020

Sedentary Time Accumulated in Bouts is Positively Associated with Disease Severity in Fibromyalgia: The Al-Ándalus Project.

J Clin Med 2020 Mar 9;9(3). Epub 2020 Mar 9.

Department of Physical Education and Sport, Faculty of Sport Sciences, University of Granada, 18071 Granada, Spain.

To examine the associations of prolonged sedentary time (ST) with disease severity in women with fibromyalgia, and to analyse the combined association of total ST and prolonged ST with the disease severity in this population. Women ( = 451; 51.3 ± 7.6 years old) with fibromyalgia participated. Sedentary time and moderate-to-vigorous physical activity (MVPA) were measured using triaxial accelerometry and ST was processed into 30- and 60-min bouts. Dimensions of fibromyalgia (function, overall, symptoms) and the overall disease impact were assessed with the Revised Fibromyalgia Impact Questionnaire (FIQR). Body fat percentage was assessed using a bio-impedance analyser, and physical fitness was assessed with the Senior Fitness Tests Battery. Greater percentage of ST in 30-min bouts and 60-min bouts were associated with worse function, overall, symptoms and the overall impact of the disease (all, < 0.05). Overall, these associations were statistically significant when additionally controlling for MVPA and overall physical fitness. Participants with low levels of total ST and prolonged ST (>60-min bouts) presented lower overall impact compared to participants with high levels of total ST and prolonged ST (mean difference = 6.56; 95% confidence interval (CI) = 1.83 to 11.29, = 0.002). Greater percentage of ST accumulated in 30- and 60-min bouts and a combination of high levels of total and prolonged ST are related to worse disease severity. Although unable to conclude on causality, results suggest it might be advisable to motivate women with fibromyalgia to break prolonged ST and reduce their total daily ST.
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http://dx.doi.org/10.3390/jcm9030733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141225PMC
March 2020

Cytokine responses across submaximal exercise intensities in women with major depressive disorder.

Brain Behav Immun Health 2020 Feb 5;2:100046. Epub 2020 Feb 5.

Department of Kinesiology, Iowa State University, Ames, IA, USA.

Background: Major depressive disorder (MDD) is associated with chronic inflammation. Exercise training can treat depression in adults with MDD, potentially through reducing inflammatory activity. This improvement may occur through adaptations to repeated acute inflammatory responses. Cytokine responses to acute steady-state exercise of varying intensities were determined in women with different levels of depression.

Methods: This analysis included 19 women with MDD who each participated in four sessions consisting of 30 ​min of quiet rest, light, moderate, or hard intensity exercise. Blood samples were collected pre- and within 10 ​min post-session. Changes in the levels of IL-6, IL-8, IL-10, and TNF were evaluated in each session.

Results: Serum concentrations of IL-6, IL-8 and TNF were all significantly elevated following vigorous exercise (i.e., hard) compared to the quiet rest session. No changes in cytokine levels occurred after light and moderate exercise. Depression severity did not appear to influence the acute inflammatory response to exercise.

Limitations: The sample size was small, all female, and from a secondary data analysis, which limits the generalizability of the findings.

Conclusions: Repeat, acute increases in inflammatory activity following hard exercise sessions may prompt adaptations and lead to reductions in chronic inflammation over time. This dose-response study identified an exercise intensity threshold to induce acute inflammatory responses in women with MDD.
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http://dx.doi.org/10.1016/j.bbih.2020.100046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474480PMC
February 2020

Brain Glucose Metabolism, Cognition, and Cardiorespiratory Fitness Following Exercise Training in Adults at Risk for Alzheimer's Disease.

Brain Plast 2019 Dec 26;5(1):83-95. Epub 2019 Dec 26.

Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.

Aerobic exercise has been associated with reduced burden of brain and cognitive changes related to Alzheimer's disease (AD). However, it is unknown whether exercise training in asymptomatic individuals harboring risk for AD improves outcomes associated with AD. We investigated the effect of 26 weeks of supervised aerobic treadmill exercise training on brain glucose metabolism and cognition among 23 late-middle-aged adults from a cohort enriched with familial and genetic risk of AD. They were randomized to Usual Physical Activity (PA) or Enhanced PA conditions. Usual PA received instruction about maintaining an active lifestyle. Enhanced PA completed a progressive exercise training program consisting of 3 sessions of treadmill walking per week for 26 weeks. By week seven, participants exercised at 70- 80% heart rate reserve for 50 minutes per session to achieve 150 minutes of moderate intensity activity per week in accordance with public health guidelines. Before and after the intervention, participants completed a graded treadmill test to assess VOpeak as a measure of cardiorespiratory fitness (CRF), wore an accelerometer to measure free-living PA, underwent F-fluorodeoxyglucose positron emission tomography imaging to assess brain glucose metabolism, and a neuropsychological battery to assess episodic memory and executive function. VOpeak increased, sedentary behavior decreased, and moderate-to-vigorous PA increased significantly in the Enhanced PA group as compared to Usual PA. Glucose metabolism in the posterior cingulate cortex (PCC) did not change significantly in Enhanced PA relative to Usual PA. However, change in PCC glucose metabolism correlated positively with change in VOpeak. Executive function, but not episodic memory, was significantly improved after Enhanced PA relative to Usual PA. Improvement in executive function correlated with increased VOpeak. Favorable CRF adaptation after 26 weeks of aerobic exercise training was associated with improvements in PCC glucose metabolism and executive function, important markers of AD.
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http://dx.doi.org/10.3233/BPL-190093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971821PMC
December 2019

Post-exertional malaise in veterans with gulf war illness.

Int J Psychophysiol 2020 01 28;147:202-212. Epub 2019 Nov 28.

William S. Middleton Memorial Veterans Hospital, 2500 Overlook Terrace, Madison, WI 53705, United States of America; Department of Kinesiology, University of Wisconsin-Madison, 2000 Observatory Dr, Madison, WI 53706, United States of America. Electronic address:

Post-exertional malaise (PEM) is a potentially debilitating aspect of Gulf War Illness (GWI) that has received limited research attention. The purpose of the present investigation was to determine symptom severity changes following exercise in Veterans with GWI compared to control Veterans without GWI (CO). Sixty-seven Veterans (n = 39 GWI; n = 28 CO) underwent a 30-minute submaximal exercise challenge at 70% of heart rate reserve. Symptom measurements (e.g. fatigue, pain) occurred pre-, immediately post-, and 24-hour post-exercise. Self-reported physical and mental health, and physiological and perceptual responses to exercise were compared between groups using descriptive statistics, independent samples t-tests and repeated measures Analysis of Variance (RM-ANOVA). Post-exertional malaise was modeled using Group by Time (2 × 3) doubly-multivariate, RM-MANOVAs for (1) mood, (2) pain and (3) GWI-related symptoms, respectively (α = 0.05). Data were analyzed for the full sample of Veterans with GWI (n = 39) compared to CO (n = 28) and a subsample of Veterans (n = 18) who endorsed "feeling unwell after physical exercise or exertion" ("PEM endorsers") during screening. Veterans with GWI reported significantly lower physical and mental health. Groups exercised at similar relative exercise intensities, but GWI perceived exercise as more painful and fatiguing. Group-by-Time interactions were not significant for the entire sample for the three PEM models, however limiting the GWI sample to "PEM endorsers" resulted in significant interactions for Pain- and GWI-related PEM models. These results indicate that not all GVs with GWI experience PEM 24 h after exercise, and that more research is needed to determine the extent that exercise worsens symptoms in GWI.
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http://dx.doi.org/10.1016/j.ijpsycho.2019.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957714PMC
January 2020

Veterans with Gulf War Illness exhibit distinct respiratory patterns during maximal cardiopulmonary exercise.

PLoS One 2019 12;14(11):e0224833. Epub 2019 Nov 12.

War Related Illness and Injury Study Center, Department of Veterans Affairs New Jersey Health Care System, East Orange, New Jersey, United States of America.

Introduction: The components of minute ventilation, respiratory frequency and tidal volume, appear differentially regulated and thereby afford unique insight into the ventilatory response to exercise. However, respiratory frequency and tidal volume are infrequently reported, and have not previously been considered among military veterans with Gulf War Illness. Our purpose was to evaluate respiratory frequency and tidal volume in response to a maximal cardiopulmonary exercise test in individuals with and without Gulf War Illness.

Materials And Methods: 20 cases with Gulf War Illness and 14 controls participated in this study and performed maximal cardiopulmonary exercise test on a cycle ergometer. Ventilatory variables (minute ventilation, respiratory frequency and tidal volume) were obtained and normalized to peak exercise capacity. Using mixed-design analysis of variance models, with group and time as factors, we analyzed exercise ventilatory patterns for the entire sample and for 11 subjects from each group matched for race, age, sex, and height.

Results: Despite similar minute ventilation (p = 0.57, η2p = 0.01), tidal volume was greater (p = 0.02, η2p = 0.16) and respiratory frequency was lower (p = 0.004, η2p = 0.24) in Veterans with Gulf War Illness than controls. The findings for respiratory frequency remained significant in the matched subgroup (p = 0.004, η2p = 0.35).

Conclusion: In our sample, veterans with Gulf War Illness adopt a unique exercise ventilatory pattern characterized by reduced respiratory frequency, despite similar ventilation relative to controls. Although the mechanism(s) by which this pattern is achieved remains unresolved, our findings suggest that the components of ventilation should be considered when evaluating clinical conditions with unexplained exertional symptoms.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224833PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850551PMC
March 2020

Characterising the gut microbiome in veterans with Gulf War Illness: a protocol for a longitudinal, prospective cohort study.

BMJ Open 2019 08 19;9(8):e031114. Epub 2019 Aug 19.

Research, William S Middleton Memorial Veterans Hospital, Madison, Wisconsin, USA.

Introduction: Approximately 25%-35% of the 1991 Gulf War Veteran population report symptoms consistent with Gulf War Illness (GWI), a chronic, multi-symptom illness characterised by fatigue, pain, irritable bowel syndrome and problems with cognitive function. GWI is a disabling problem for Gulf War Veterans, and there remains a critical need to identify innovative, novel therapies.Gut microbiota perturbation plays a key role in the symptomatology of other chronic multi-symptom illnesses, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Given similarities between ME/CFS and GWI and the presence of gastrointestinal disorders in GWI patients, Veterans with GWI may also have gut abnormalities like those seen with ME/CFS. In this longitudinal cohort study, we are comparing the diversity (structure) and the metagenomes (function) of the gut microbiome between Gulf War Veterans with and without GWI. If we find differences in Veterans with GWI, the microbiome could be a target for therapeutic intervention to alleviate GWI symptoms.

Methods And Analysis: Participants answer questions about diet, exercise and lifestyle factors. Participants also complete a questionnaire (based on the Kansas case definition of GWI) regarding their medical history and symptoms; we use this questionnaire to group participants into GWI versus healthy control cohorts. We plan to enrol 52 deployed Gulf War Veterans: 26 with GWI and 26 healthy controls. Participants provide stool and saliva samples weekly for an 8-week period for microbiome analyses. Participants also provide blood samples at the beginning and end of this period, which we will use to compare measures of inflammation markers between the groups.

Ethics And Dissemination: The protocol was approved by the University of Wisconsin-Madison Health Sciences Institutional Review Board and the William S. Middleton Memorial Veterans Hospital Research and Development Committee. Results of this study will be submitted for publication in a peer-reviewed journal.
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http://dx.doi.org/10.1136/bmjopen-2019-031114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707676PMC
August 2019

Influence of pain anticipation on brain activity and pain perception in Gulf War Veterans with chronic musculoskeletal pain.

Psychophysiology 2019 12 20;56(12):e13452. Epub 2019 Aug 20.

William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.

Anticipation of a painful experience can influence brain activity and increase sensitivity to experimental somatosensory stimuli in healthy adults, but this response is poorly understood among individuals with chronic musculoskeletal pain (CMP). Studies of brain and perceptual responses to somatosensory stimuli are used to make inferences about central nervous system dysfunction as a potential mechanism of symptoms. As such, we sought to (a) determine the influence of pain anticipation on pain-relevant brain regions and pain perception, and (b) characterize potential differences in these responses between Gulf War Veterans with CMP and matched healthy control (CO) Veterans. CMP (N = 30) and CO Veterans (N = 31) were randomized to conditions designed to generate expectations that either painful (pain) or nonpainful (no pain) stimuli would be administered. Brain responses to five nonpainful thermal stimuli were measured during fMRI, and each stimulus was rated for pain intensity and unpleasantness. In the pain condition, an incremental linear decrease in activity across stimuli was observed in the posterior cingulate cortex, cingulate cortex, and middle temporal gyrus. Further, in the pain condition, differential responses were observed between CMP and CO Veterans in the middle temporal gyrus. These findings indicate that brain responses to nonpainful thermal stimuli in Veterans with CMP are sensitive to pain anticipation, and we recommend accounting for the influence of pain anticipation in future investigations of central nervous system dysfunction in CMP.
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http://dx.doi.org/10.1111/psyp.13452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6803046PMC
December 2019

Serum Endocannabinoid and Mood Changes after Exercise in Major Depressive Disorder.

Med Sci Sports Exerc 2019 09;51(9):1909-1917

Department of Kinesiology, University of Wisconsin-Madison, Madison WI.

The endocannabinoid (eCB) system is implicated in the pathophysiology of depression and is responsive to acute exercise in healthy adults.

Purpose: We aimed to describe acute changes in serum eCB across a prescribed moderate (MOD) and a self-selected/preferred (PREF) intensity exercise session in women with major depressive disorder (MDD) and determine relationships between changes in eCB and mood states.

Methods: Women with MDD (n = 17) exercised in separate sessions for 20 min on a cycle ergometer at both MOD or PREF in a within-subjects design. Blood was drawn before and within 10 min after exercise. Serum concentrations of eCB (anandamide [AEA], 2-arachidonoylglycerol) and related lipids (palmitoylethanolamine, oleoylethanolamine, 2-oleoylglycerol) were quantified using stable isotope-dilution, liquid chromatography/mass spectrometry/mass spectrometry. The profile of mood states and state-trait anxiety inventory (state only) were completed before, 10 min and 30 min postexercise.

Results: Significant elevations in AEA (P = 0.013) and oleoylethanolamine (P = 0.024) occurred for MOD (moderate effect sizes: Cohen's d = 0.58 and 0.41, respectively). Significant (P < 0.05) moderate negative associations existed between changes in AEA and mood states for MOD at 10 min (depression, confusion, fatigue, total mood disturbance [TMD] and state anxiety) and 30 min postexercise (confusion, TMD and state anxiety). Significant (P < 0.05) moderate negative associations existed between 2-arachidonoylglycerol and mood states at 10 min (depression and confusion) and 30 min postexercise (confusion and TMD). Changes in eCB or related lipids or eCB-mood relationships were not found for PREF.

Conclusion: Given the broad, moderate-strength relationships between improvements in mood states and eCB increases after MOD, it is plausible that the eCB system contributes to the mood-enhancing effects of prescribed acute exercise in MDD. Alternative mechanisms are likely involved in the positive mood state effects of preferred exercise.
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http://dx.doi.org/10.1249/MSS.0000000000002006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727944PMC
September 2019

Cardiorespiratory Fitness Modifies Influence of Sleep Problems on Cerebrospinal Fluid Biomarkers in an At-Risk Cohort.

J Alzheimers Dis 2019 ;69(1):111-121

Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.

Background: Previous studies indicate that cardiorespiratory fitness (CRF) and sleep are each favorably associated with Alzheimer's disease (AD) pathophysiology, including reduced amyloid-β (Aβ) and tau pathology. However, few studies have examined CRF and sleep in the same analysis.

Objective: To examine the relationship between sleep and core AD cerebrospinal fluid (CSF) biomarkers among at-risk healthy late-middle-aged adults and determine whether CRF modifies this association.

Methods: Seventy-four adults (age = 64.38±5.48, 68.9% female) from the Wisconsin Registry for Alzheimer's Prevention participated. Sleep was evaluated using the Medical Outcomes Study Sleep Scale, specifically the Sleep Problems Index I (SPI), which incorporates domains of sleep disturbance, somnolence, sleep adequacy, and shortness of breath. Higher scores indicate greater sleep problems. To assess CRF, participants underwent a graded exercise test. CSF was collected via lumbar puncture, from which Aβ42, total-tau (t-tau), and phosphorylated-tau (p-tau) were immunoassayed. Regression analyses examined the association between SPI and CSF biomarkers, and the interaction between SPI and CRF on these same biomarkers, adjusting for relevant covariates.

Results: Higher SPI scores were associated with greater p-tau (p = 0.027) and higher t-tau/Aβ42 (p = 0.021) and p-tau/Aβ42 (p = 0.009) ratios. Analyses revealed significant SPI*CRF interactions for t-tau (p = 0.016), p-tau (p = 0.008), and p-tau/Aβ42 (p = 0.041); with a trend for t-tau/Aβ42 (p = 0.061). Specifically, the relationship between poorer sleep and these biomarkers was significant among less fit individuals, but not among those who were more fit.

Conclusion: In a late-middle-aged at-risk cohort, CRF attenuated the association between poor sleep and levels of select CSF biomarkers. This suggests fitness may play an important role in preventing AD by protecting against pathology, even in impaired sleep.
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http://dx.doi.org/10.3233/JAD-180291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675618PMC
September 2020

Fitness, independent of physical activity is associated with cerebral blood flow in adults at risk for Alzheimer's disease.

Brain Imaging Behav 2020 Aug;14(4):1154-1163

William S. Middleton Memorial Veterans Hospital, Madison, WI, 53705, USA.

Patterns of decreased resting cerebral blood flow (CBF) within the inferior temporal gyri, angular gyri, and posterior cingulate are a feature of aging and Alzheimer's disease (AD) and have shown to be predictive of cognitive decline among older adults. Fitness and physical activity are both associated with many indices of brain health and may positively influence CBF, however, the majority of research to date has examined these measures in isolation, leaving the potential independent associations unknown. The purpose of this study was to determine the unique contributions of fitness and physical activity when predicting CBF in cognitively healthy adults at risk for AD. One hundred participants (63% female) from the Wisconsin Registry for Alzheimer's Prevention underwent a maximal exercise test, physical activity monitoring, and a 3-D arterial spin labeling magnetic resonance imaging scan. For the entire sample, fitness was significantly associated with CBF while accounting for physical activity, age, gender, APOE ε4, family history of AD, education, and handedness (p = .026). Further, fitness explained significantly more variance than the combined effect of the covariates on CBF (R change = .059; p = .047). These results appear to be gender dependent, our data suggest fitness level, independent of physical activity, is associated with greater CBF in regions that are known to decline with age and AD for female (p = .011), but not male participants.
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http://dx.doi.org/10.1007/s11682-019-00068-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733668PMC
August 2020

Cardiorespiratory fitness attenuates age-associated aggregation of white matter hyperintensities in an at-risk cohort.

Alzheimers Res Ther 2018 09 24;10(1):97. Epub 2018 Sep 24.

Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, WI, 53705, USA.

Background: Age is the cardinal risk factor for Alzheimer's disease (AD), and white matter hyperintensities (WMH), which are more prevalent with increasing age, may contribute to AD. Higher cardiorespiratory fitness (CRF) has been shown to be associated with cognitive health and decreased burden of AD-related brain alterations in older adults. Accordingly, the aim of this study was to determine whether CRF attenuates age-related accumulation of WMH in middle-aged adults at risk for AD.

Methods: One hundred and seven cognitively unimpaired, late-middle-aged adults from the Wisconsin Registry for Alzheimer's Prevention underwent 3 T magnetic resonance imaging and performed graded maximal treadmill exercise testing from which we calculated the oxygen uptake efficiency slope (OUES) as our measure of CRF. Total WMH were quantified using the Lesion Segmentation Tool and scaled to intracranial volume. Linear regression adjusted for APOE4 carriage, family history, body mass index, systolic blood pressure, and sex was used to examine relationships between age, WMH, and CRF.

Results: As expected, there was a significant association between age and WMH (p < .001). Importantly, there was a significant interaction between age and OUES on WMH (p = .015). Simple main effects analyses revealed that the effect of age on WMH remained significant in the Low OUES group (p < .001) but not in the High OUES group (p = .540), indicating that higher CRF attenuates the deleterious age association with WMH.

Conclusions: Higher CRF tempers the adverse effect of age on WMH. This suggests a potential pathway through which increased aerobic fitness facilitates healthy brain aging, especially among individuals at risk for AD.
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http://dx.doi.org/10.1186/s13195-018-0429-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6154903PMC
September 2018

Greater fear of reinjury is related to stiffened jump-landing biomechanics and muscle activation in women after ACL reconstruction.

Knee Surg Sports Traumatol Arthrosc 2018 Dec 26;26(12):3682-3689. Epub 2018 Apr 26.

University of Wisconsin Madison, 2000 Observatory Dr, Madison, WI, 53706, USA.

Purpose: Fear of reinjury is an important factor in determining who returns to sport following anterior cruciate ligament reconstruction (ACLR). Evidence from other musculoskeletal injuries indicates fear of reinjury may be related to stiffened movement patterns observed in individuals following ACLR. The relationship between fear of reinjury and performance on dynamic tasks, however, has not been investigated. Therefore, the purpose of this study was to investigate the relationship between fear of reinjury and jump-landing biomechanics.

Methods: Thirty-six females (height = 168.7 ± 6.5 cm, body mass = 67.2 ± 10.0 kg, age = 18.9 ± 1.5 years) with a history of ACLR (time from surgery = 26.1 ± 13.3 months) participated in the study. Each participant performed five trials of a standard jump-landing task. 3D motion capture and surface electromyography was used to record peak kinematics and lower extremity muscle activation on the injured limb during the jump landings. Spearman's rank correlations established the relationship between TSK-11 scores and each biomechanical variable of interest.

Results: There was a significant, negative relationship between fear of reinjury (TSK-11: 19.9 ± 4.5) and knee (p = 0.006), hip (p = 0.003), and trunk flexion (p = 0.013). There was also a significant, positive relationship between hip adduction (p = 0.007), and gluteus maximus preparatory activation (p = 0.001).

Conclusions: The results of this study indicate that higher fear of reinjury is associated with stiffened movement patterns that are associated with increased risk of a second ACL injury. Similar movement patterns have been observed in patients with low back pain. Clinicians should evaluate psychological and emotional consequences of injury in addition to the physical consequences as they appear to be related.

Level Of Evidence: III.
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http://dx.doi.org/10.1007/s00167-018-4950-2DOI Listing
December 2018

Moderate intensity physical activity associates with CSF biomarkers in a cohort at risk for Alzheimer's disease.

Alzheimers Dement (Amst) 2018 6;10:188-195. Epub 2018 Feb 6.

Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.

Introduction: Alzheimer's disease (AD) is characterized by the presence of amyloid β (Aβ) plaques, neurofibrillary tangles, and neurodegeneration, evidence of which may be detected in vivo via cerebrospinal fluid (CSF) sampling. Physical activity (PA) has emerged as a possible modifier of these AD-related pathological changes. Consequently, the aim of this study was to cross-sectionally examine the relationship between objectively measured PA and CSF levels of Aβ42 and tau in asymptomatic late-middle-aged adults at risk for AD.

Methods: Eighty-five cognitively healthy late-middle-aged adults (age = 64.31 years, 61.2% female) from the Wisconsin Registry for Alzheimer's Prevention participated in this study. They wore an accelerometer (ActiGraph GT3X+) for one week to record free-living PA, yielding measures of sedentariness and various intensities of PA (i.e., light, moderate, and vigorous). They also underwent lumbar puncture to collect CSF, from which Aβ42, total tau, and phosphorylated tau were immunoassayed. Regression analyses were used to examine the association between accelerometer measures and CSF biomarkers, adjusting for age, sex, and other relevant covariates.

Results: Engagement in moderate PA was associated with higher Aβ42 ( = .008), lower total tau/Aβ42 ( = .006), and lower phosphorylated tau/Aβ42 ( = .030). In contrast, neither light nor vigorous PA was associated with any of the biomarkers. Increased sedentariness was associated with reduced Aβ42 ( = .014).

Discussions: In this cohort, moderate PA, but not light or vigorous, was associated with a favorable AD biomarker profile, while sedentariness was associated with greater Aβ burden. These findings suggest that a physically active lifestyle may play a protective role against the development of AD.
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http://dx.doi.org/10.1016/j.dadm.2018.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842318PMC
February 2018

Catastrophizing Interferes with Cognitive Modulation of Pain in Women with Fibromyalgia.

Pain Med 2018 12;19(12):2408-2422

William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.

Background: Pain modulation is a critical function of the nociceptive system that includes the ability to engage descending pain control systems to maintain a functional balance between facilitation and inhibition of incoming sensory stimuli. Dysfunctional pain modulation is associated with increased risk for chronic pain and is characteristic of fibromyalgia (FM). Catastrophizing is also common in FM. However, its influence on pain modulation is poorly understood.

Objective: To determine the role of catastrophizing on central nervous system processing during pain modulation in FM via examining brain responses and pain sensitivity during an attention-distraction paradigm.

Methods: Twenty FM patients and 18 healthy controls (CO) underwent functional magnetic resonance imaging while receiving pain stimuli, administered alone and during distracting cognitive tasks. Pain ratings were assessed after each stimulus. Catastrophizing was assessed with the Pain Catastrophizing Scale (PCS).

Results: The ability to modulate pain during distraction varied among FM patients and was associated with catastrophizing. This was demonstrated by significant positive relationships between PCS scores and pain ratings (P < 0.05) and brain responses in the dorsolateral prefrontal cortex (P < 0.01). Relationships between catastrophizing and pain modulation did not differ between FM and CO (P > 0.05).

Conclusions: FM patients with higher levels of catastrophizing were less able to distract themselves from pain, indicative of catastrophizing-related impairments in pain modulation. These results suggest that the tendency to catastrophize interacts with attention-resource allocation and may represent a mechanism of chronic pain exacerbation and/or maintenance. Reducing catastrophizing may improve FM symptoms via improving central nervous system regulation of pain.
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http://dx.doi.org/10.1093/pm/pny008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659027PMC
December 2018

An Objective Method to Accurately Measure Cardiorespiratory Fitness in Older Adults Who Cannot Satisfy Widely Used Oxygen Consumption Criteria.

J Alzheimers Dis 2018 ;61(2):601-611

William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.

Cardiorespiratory fitness (CRF) is routinely investigated in older adults; however, the most appropriate CRF measure to use for this population has received inadequate attention. This study aimed to 1) evaluate the reliability and validity of the oxygen uptake efficiency slope (OUES) as a sub-maximal measurement of CRF; 2) examine demographic, risk-factor, and exercise testing differences in older adults who satisfied standardized criteria for a peak oxygen consumption (V̇O2peak) test compared to those who did not; and 3) determine the difference between directly measured V̇O2peak values and OUES-predicted V̇O2peak values. One hundred ten enrollees from the Wisconsin Registry for Alzheimer's Prevention participated in this study. Participants performed a graded maximal exercise test and wore an accelerometer for 7 days. For each participant, the OUES was calculated at 75%, 90%, and 100% of exercise duration. V̇O2peak was recorded at peak effort, and one week of physical activity behavior was measured. OUES values calculated at separate relative exercise durations displayed excellent reliability (ICC = 0.995; p < 0.001), and were strongly correlated with V̇O2peak (rrange = 0.801-0.909; p < 0.001). As hypothesized, participants who did not satisfy V̇O2peak criteria were significantly older than those who satisfied criteria (p = 0.049) and attained a directly measured V̇O2peak that was 2.31 mL·kg·min-1 less than the value that was predicted by OUES V̇O2peak (p = 0.003). Older adults are less likely to satisfy V̇O2peak criteria, which results in an underestimation of their CRF. Without adhering to standardized criteria, V̇O2peak measurement error may lead to misinterpretation of CRF and age-related associations. Here, we conclude that OUES is a reliable, valid measurement of CRF which does not require achievement of standardized criteria.
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http://dx.doi.org/10.3233/JAD-170576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745283PMC
January 2019

Cerebral white matter structure is disrupted in Gulf War Veterans with chronic musculoskeletal pain.

Pain 2017 Dec;158(12):2364-2375

Department of Veterans Affairs, William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.

Chronic musculoskeletal pain (CMP) affects ∼25% of the 700,000 Veterans deployed during the Persian Gulf War (1990-1991). The cause of their pain is unknown, and there are no efficacious treatments. A small body of literature suggests that brain abnormalities exist in Gulf War Veterans (GVs), yet relationships between brain abnormalities and disease symptoms remain largely unexplored. Our purpose was to compare white matter (WM) integrity between GVCMP and matched, healthy Veteran controls (GVCO) and investigate relationships between cerebral WM integrity and symptoms. Thirty GVCMP and 31 controls completed magnetic resonance imaging with diffusion tensor imaging. Tract-based spatial statistics estimated WM fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity over the whole brain (P < 0.05) and were corrected using threshold-free cluster enhancement. GVCMP had greater pain symptoms and mood disturbance and lower quality of life and physical function compared with GVCO (P < 0.05). GVCMP had lower WM integrity across several brain regions implicated in chronic pain (P < 0.05) including the middle and inferior frontal gyrus, corpus callosum, corona radiata, precentral gyrus, external capsule, and posterior thalamic radiation. For GVCMP, WM integrity was associated with pain and mood symptoms in widespread brain areas that were found to be different between groups (P < 0.05). Results indicate widespread WM microstructure disruption across brain regions implicated in pain processing and modulation in chronic pain. The observed relationships between WM microstructure and symptoms encourage the testing of treatments designed to improve the brain health of affected Veterans.
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http://dx.doi.org/10.1097/j.pain.0000000000001038DOI Listing
December 2017

Cognitive Resilience and Psychological Responses across a Collegiate Rowing Season.

Med Sci Sports Exerc 2017 Nov;49(11):2276-2285

1Department of Kinesiology, University of Wisconsin-Madison, Madison, WI; and 2Research Service, Department of Veterans Affairs, William S. Middleton Memorial Veterans Hospital, Madison, WI.

Introduction: Student-athletes face numerous challenges across their competitive season. Although mood states have been previously studied, little is known about adaptations in other psychological responses, specifically cognition. The purpose of this study was to characterize cognitive function, mood, sleep, and stress responses at select time points of a season in collegiate rowers. It was hypothesized that during baseline, typical training, and recovery, athletes would show positive mental health profiles, in contrast to decreases in cognition with increases in negative mood and measurements of stress during peak training.

Methods: Male and female Division I rowers (N = 43) and healthy controls (N = 23) were enrolled and assessed at baseline, typical training, peak training, and recovery. At each time point, measures of cognitive performance (Stroop color-naming task), academic and exercise load, perceived cognitive deficits, mood states, sleep, and stress (via self-report and salivary cortisol) were recorded.

Results: Repeated-measures ANOVA revealed significant group-time interactions for perceived exercise load, cognitive deficits, mood states, and perceived stress (P < 0.05). For athletes during peak training, the perception of cognitive deficits was positively correlated with mood disturbance (r = 0.54, P < 0.05) and perceived stress (r = 0.55, P < 0.05) and negatively correlated with response accuracy during incongruent Stroop trials (r = -0.38, P < 0.05). Cognitive performance did not change over the course of the season for either group. Cortisol and sleepiness changed over the course of the season but no significant interactions were observed.

Conclusion: These results demonstrate that various psychological responses change over the course of a season, but they also highlight adaptation indicative of cognitive resilience among student-athletes.
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http://dx.doi.org/10.1249/MSS.0000000000001363DOI Listing
November 2017

Moderate Physical Activity is Associated with Cerebral Glucose Metabolism in Adults at Risk for Alzheimer's Disease.

J Alzheimers Dis 2017 ;58(4):1089-1097

Wisconsin Alzheimer's Disease Research Center.

The objective of this study was to investigate the relationship between accelerometer-measured physical activity (PA) and glucose metabolism in asymptomatic late-middle-aged adults. Ninety-three cognitively healthy late-middle-aged adults from the Wisconsin Registry for Alzheimer's Prevention participated in this cross-sectional study. They underwent 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging and wore an accelerometer (ActiGraph GT3X+) to measure free-living PA. Accelerometer data yielded measures of light (LPA), moderate (MPA), and vigorous (VPA) intensity PA. FDG-PET images were scaled to the cerebellum and pons, and cerebral glucose metabolic rate was extracted from specific regions of interest (ROIs) known to be hypometabolic in AD, i.e., hippocampus, posterior cingulate, inferior temporal cortex, and angular gyrus. Regression analyses were utilized to examine the association between PA and glucose metabolism, while adjusting for potential confounds. There were associations between MPA and glucose metabolism in all ROIs examined. In contrast, LPA was not associated with glucose uptake in any ROI and VPA was only associated with hippocampal FDG uptake. Secondary analyses did not reveal associations between sedentary time and glucose metabolism in any of the ROIs. Exploratory voxel-wise analysis identified additional regions where MPA was significantly associated with glucose metabolism including the precuneus, supramarginal gyrus, amygdala, and middle frontal gyrus. These findings suggest that the intensity of PA is an important contributor to neuronal function in a late-middle-aged cohort, with MPA being the most salient. Prospective studies are necessary for fully elucidating the link between midlife engagement in PA and later life development of AD.
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http://dx.doi.org/10.3233/JAD-161067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5703045PMC
May 2018

Objectively Measured Physical Activity in Patients After Anterior Cruciate Ligament Reconstruction.

Am J Sports Med 2017 Jul 18;45(8):1893-1900. Epub 2017 Apr 18.

Department of Kinesiology, Michigan State University, East Lansing, Michigan, USA.

Background: Returning to a healthy level of physical activity is among the most commonly discussed clinical goals for patients recovering from anterior cruciate ligament reconstruction (ACLR). However, physical activity has not been objectively measured in this population.

Purpose: To investigate differences in the mean time (min/d) spent in moderate-to-vigorous physical activity (MVPA) as well as the daily step count (steps/d) between patients who underwent ACLR and matched controls. A second purpose was to investigate relationships between MVPA and objective assessments of the daily step count and Tegner and Marx activity scales.

Study Design: Cross-sectional study; Level of evidence, 3.

Methods: Physical activity was assessed using ActiGraph accelerometers in 33 participants with a history of primary unilateral or bilateral ACLR (mean time from surgery, 27.8 ± 17.5 months; range, 6-67 months) as well as in 33 healthy controls (matched on age, sex, and activity level). Participants wore the accelerometer for 7 days and completed the International Knee Documentation Committee subjective form and the Tegner and Marx activity scales. Independent t tests were used to determine differences in each dependent variable per group.

Results: Patients who underwent ACLR spent less time in MVPA (ACLR: 79.37 ± 23.95 min/d; control: 93.12 ± 23.94 min/d; P = .02) and had a lower daily step count (ACLR: 8158 ± 2780 steps/d; control: 9769 ± 2785 steps/d; P = .02) compared with healthy matched controls. However, the Marx (ACLR median: 11.0 [interquartile range (IQR), 7-14]; control median: 12.0 [IQR, 8-13]; P = .85) and Tegner (ACLR median: 6.0 [IQR, 5-8]; control median: 7.0 [IQR, 6-8]; P = .12) scores did not differ between the groups, and no relationships were observed between objectively measured physical activity and scale measures ( P > .05), except for a moderate relationship between the Tegner score and daily step count in the ACLR group ( r = 0.36, P = .04). Only 24% of patients who underwent ACLR met the guideline of 10,000 steps per day compared with 42% of controls.

Conclusion: Patients who underwent ACLR spent less time in MVPA and had a lower daily step count compared with highly matched controls (age, sex, and activity level) with no history of knee injuries. This was true despite being similar in activity levels, which brings into question the utility of the Tegner and Marx activity scales.
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http://dx.doi.org/10.1177/0363546517698940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5586218PMC
July 2017

The Effects of Exercise Training on Anxiety in Fibromyalgia Patients: A Meta-analysis.

Med Sci Sports Exerc 2017 09;49(9):1868-1876

1Department of Physical Education and Sport Sciences, University of Limerick, University of Limerick, Ireland, IRELAND; 2Department of Kinesiology, School of Education, University of Wisconsin-Madison, Madison, WI; 3Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI; and 4Health Research Institute, University of Limerick, Limerick, IRELAND.

Physical inactivity and comorbid anxiety symptoms are prevalent among fibromyalgia (FM) patients. Exercise training may be an effective alternative therapy to reduce these symptoms.

Purpose: This study aimed to evaluate the effects of exercise training on anxiety symptoms in patients with FM and to examine whether variables of theoretical or practical importance moderate the estimated mean effect.

Methods: Twenty-five effects were derived from 10 articles published before June 2016 located using Google Scholar, MEDLINE, PsycINFO, PubMed, and Web of Science. Trials involved 595 patients with FM (mean age = 47.6 yr, 97.5% female) and included both randomization to exercise training (n = 297) or a nonexercise control condition (n = 298) and an anxiety outcome measured at baseline and during and/or after exercise training. Hedges' d effect sizes were computed, data for moderator variables were extracted, and random effects models were used to estimate sampling error and population variance for all analyses. Meta-regression quantified the extent to which patient and trial characteristics moderated the mean effect.

Results: Exercise training significantly reduced anxiety symptoms by a mean effect Δ of 0.28 (95% confidence interval [CI] = 0.16-0.40). No significant heterogeneity was observed (Q24 = 30.79, P = 0.16, I = 25.29%). Program duration (β = 1.44, z = 2.50, P ≤ 0.01) was significantly related to the overall effect, with significantly larger anxiety improvements resulting from programs lasting greater than 26 wk (Δ = 0.35, 95% CI = 0.05-0.66) compared with those lasting less than 26 wk (Δ = 0.26, 95% CI = 0.13-0.39).

Conclusion: Exercise training improves anxiety symptoms among FM patients. The findings also suggest that larger anxiety symptom reductions will be achieved by focusing on longer exercise programs while promoting long-term adherence. Future well-designed investigations are required to examine the potential moderating effect of pain-related improvements in FM patients.
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http://dx.doi.org/10.1249/MSS.0000000000001290DOI Listing
September 2017
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