A methodology for an acute exercise clinical trial called dementia risk and dynamic response to exercise

AbstractExercise likely has numerous benefits for brain and cognition. However, those benefits and their causes remain imprecisely defined. If the brain does benefit from exercise it does so primarily through cumulative brief, “acute” exposures over a lifetime. The Dementia Risk and Dynamic Response to Exercise (DYNAMIC) clinical trial seeks to characterize the acute exercise response in cerebral perfusion, and circulating neurotrophic factors in older adults with and without the apolipoprotein e4 genotype (APOE4), the strongest genetic predictor of sporadic, late onset Alzheimer’s disease. DYNAMIC will enroll 60 older adults into a single moderate intensity bout of exercise intervention, measuring pre- and post-exercise cerebral blood flow (CBF) using arterial spin labeling, and neurotrophic factors. We expect that APOE4 carriers will have poor CBF regulation, i.e. slower return to baseline perfusion after exercise, and will demonstrate blunted neurotrophic response to exercise, with concentrations of neurotrophic factors positively correlating with CBF regulation. Preliminary findings on 7 older adults and 9 younger adults demonstrate that the experimental method can capture CBF and neurotrophic response over a time course. This methodology will provide important insight into acute exercise response and potential directions for clinical trial outcomes.ClinicalTrials.gov NCT04009629, Registered 05/07/2019.

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Dementia Risk and Dynamic Response to Exercise: Methodology for an Acute Exericise Clinical Trial

10.1101/2020.08.22.20179564 ◽

2020 ◽

Author(s):

Dreu White ◽

Casey S John ◽

Ashley Kucera ◽

Bryce Truver ◽

Rebecca J Lepping ◽

...

Keyword(s):

Older Adults ◽

Clinical Trial ◽

Dynamic Response ◽

Neurotrophic Factors ◽

Acute Exercise ◽

Moderate Intensity ◽

Dementia Risk ◽

Exercise Response ◽

Exercise Induced ◽

Response To Exercise

Background: Exercise likely has numerous, meaningful benefits for brain and cognition. However, those benefits and their causes remain imprecisely defined, especially in the context of cognitive disorders associated with aging, such as Alzheimer disease (AD). If the brain does benefit from exercise it does so primarily through exposure to brief, acute exposures to exercise over a lifetime. Methods: The Dementia Risk and Dynamic Response to Exercise (DYNAMIC) clinical trial seeks to characterize the acute exercise response in cerebral perfusion, and circulating neurotrophic factors in older adults with and without the apolipoprotein e4 genotype (APOE4), the strongest genetic predictor or sporadic, late onset AD. DYNAMIC will enroll 60 older adults into a single moderate intensity bout of exercise intervention. We will measure pre- and post-exercise cerebral blood flow using arterial spin labeling, and neurotrophic factors. We expect that APOE4 carriers will have poor CBF regulation, i.e. slower return to baseline perfusion after exercise, and will demonstrate blunted neurotrophic response to exercise, with concentrations of neurotrophic factors positively correlating with CBF regulation. If exercise-induced changes in perfusion and circulating factors can be detected, DYNAMIC will contribute to our understanding of exercise-induced brain change and potential biomarker outcomes of exercise interventions. Results: Preliminary proof-of-concept findings on 7 older adults and 9 younger adults. We have found that this experimental method can capture CBF and neurotrophic response over a time course, and best practices following exercise. Conclusions: This methodology will provide important insight into acute exercise response and potential directions for clinical trial outcomes. ClinicalTrials.gov NCT04009629

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Dynamics of middle cerebral artery blood flow velocity during moderate-intensity exercise

Journal of Applied Physiology ◽

10.1152/japplphysiol.00995.2016 ◽

2017 ◽

Vol 122 (5) ◽

pp. 1125-1133 ◽

Cited By ~ 13

Author(s):

Sandra A. Billinger ◽

Jesse C. Craig ◽

Sarah J. Kwapiszeski ◽

Jason-Flor V. Sisante ◽

Eric D. Vidoni ◽

...

Keyword(s):

Blood Flow ◽

Steady State ◽

Dynamic Response ◽

Moderate Intensity ◽

Artery Blood Flow ◽

Moderate Intensity Exercise ◽

Cerebrovascular Function ◽

Exercise Response ◽

Response Profile ◽

Health And Disease

The dynamic response to a stimulus such as exercise can reveal valuable insights into systems control in health and disease that are not evident from the steady-state perturbation. However, the dynamic response profile and kinetics of cerebrovascular function have not been determined to date. We tested the hypotheses that bilateral middle cerebral artery blood flow mean velocity (MCAV) increases exponentially following the onset of moderate-intensity exercise in 10 healthy young subjects. The MCAV response profiles were well fit to a delay (TD) + exponential (time constant, τ) model with substantial agreement for baseline [left (L): 69, right (R): 64 cm/s, coefficient of variation (CV) 11%], response amplitude (L: 16, R: 13 cm/s, CV 23%), TD (L: 54, R: 52 s, CV 9%), τ (L: 30, R: 30 s, CV 22%), and mean response time (MRT) (L: 83, R: 82 s, CV 8%) between left and right MCAV as supported by the high correlations (e.g., MRT r = 0.82, P < 0.05) and low CVs. Test-retest reliability was high with CVs for the baseline, amplitude, and MRT of 3, 14, and 12%, respectively. These responses contrasted markedly with those of three healthy older subjects in whom the MCAV baseline and exercise response amplitude were far lower and the kinetics slowed. A single older stroke patient showed baseline ipsilateral MCAV that was lower still and devoid of any exercise response whatsoever. We conclude that kinetics analysis of MCAV during exercise has significant potential to unveil novel aspects of cerebrovascular function in health and disease. NEW & NOTEWORTHY Resolution of the dynamic stimulus-response profile provides a greater understanding of the underlying the physiological control processes than steady-state measurements alone. We report a novel method of measuring cerebrovascular blood velocity (MCAv) kinetics under ecologically valid conditions from rest to moderate-intensity exercise. This technique reveals that brain blood flow increases exponentially following the onset of exercise with 1) a strong bilateral coherence in young healthy individuals, and 2) a potential for unique age- and disease-specific profiles.

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Regulation of hepatic glutamine metabolism during exercise in the dog

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1998.275.4.e655 ◽

1998 ◽

Vol 275 (4) ◽

pp. E655-E664 ◽

Cited By ~ 3

Author(s):

Amy E. Halseth ◽

Nathalie Rhéaume ◽

Allison B. Messina ◽

Erica K. Reed ◽

Mahesh G. Krishna ◽

...

Keyword(s):

Portal Vein ◽

Acute Exercise ◽

Vena Cava ◽

Sampling Period ◽

Glutamine Metabolism ◽

Moderate Intensity ◽

Moderate Intensity Exercise ◽

Arterial Blood ◽

Exercise Period ◽

Response To Exercise

The goal of this study was to determine how liver glutamine (Gln) metabolism adapts to acute exercise in the 18-h-fasted dogs ( n = 7) and in dogs that were glycogen depleted by a 42-h fast ( n = 8). For this purpose, sampling (carotid artery, portal vein, and hepatic vein) and infusion (vena cava) catheters and Doppler flow probes (portal vein, hepatic artery) were implanted under general anesthesia. At least 16 days later an experiment, consisting of a 120-min equilibration period, a 30-min basal sampling period, and a 150-min exercise period was performed. At the start of the equilibration period, a constant-rate infusion of [5-15N]Gln was initiated. Arterial Gln flux was determined by isotope dilution. Gut and liver Gln release into and uptake from the blood were calculated by combining stable isotopic and arteriovenous difference methods. The results of this study show that 1) in the 18-h-fasted dog, ∼10% and ∼35% of the basal Gln appearance in arterial blood is due to Gln release from the gut and liver, respectively, whereas ∼30% and ∼25% of the basal Gln disappearance is due to removal by these tissues; 2) extending the fast to 42 h does not affect basal arterial Gln flux or the contribution of the gut to arterial Gln fluxes but decreases hepatic Gln release, causing a greater retention of gluconeogenic carbon by the liver; 3) moderate-intensity exercise increases hepatic Gln removal from the blood regardless of fast duration but does not affect the hepatic release of Gln; and 4) Gln plays an important role in channeling nitrogen into the ureagenic pathway in the basal state, and this role is increased by ∼80% in response to exercise. These studies illustrate the quantitative importance of the splanchnic bed contribution to arterial Gln flux during exercise and the ability of the liver to acutely adapt to changes in metabolic requirements induced by the combined effects of fasting and exercise.

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Post-Stroke Physical Activity Improves Middle Cerebral Artery Dynamic Response

10.1101/2020.05.13.20100883 ◽

2020 ◽

Author(s):

Sandra A Billinger ◽

Alicen A Whitaker ◽

Allegra Morton ◽

Carolyn S Kaufman ◽

Sophy J Perdomo ◽

...

Keyword(s):

Physical Activity ◽

Dynamic Response ◽

Middle Cerebral Artery ◽

Cerebral Artery ◽

Aerobic Fitness ◽

Acute Exercise ◽

Exercise Bout ◽

Moderate Intensity ◽

Post Stroke ◽

Arterial Blood

Background and Purpose: The primary aim was to characterize the middle cerebral artery blood velocity (MCAv) dynamic response to an acute bout of exercise at 3- and 6-months post stroke. As a secondary objective, we grouped individuals according to the MCAv dynamic response to the exercise bout as responder or non-responder. We tested whether physical activity, aerobic fitness and exercise mean arterial blood pressure (MAP) differed between groups. Methods: Transcranial Doppler ultrasound measured MCAv during a 90-second baseline (BL) followed by a 6-minute moderate intensity exercise bout. Heart rate (HR), MAP and end tidal CO2 (PETCO2) were additional variables of interest. The MCAv dynamic response variables included: BL, time delay (TD), amplitude and time constant (τ). Results: Individuals enrolled in the study at 3 months post-stroke and the follow up visit commenced at 6 months post-stroke. Linear mixed model revealed no significant differences in our selected outcomes across between 3- and 6-months post-stroke. Individuals characterized as responders demonstrated a faster TD, higher amplitude, reported higher levels of physical activity and aerobic fitness when compared to the non-responders. No between group differences were identified for BL, τ or exercise MAP. In the non-responders, we observed an immediate rise in MCAv following exercise onset followed by an immediate decline to near BL values while the responders showed an exponential rise until steady state was reached. Conclusions: The MCAv dynamic response profile has the potential to provide valuable information during an acute exercise bout following stroke. Individuals with a greater MCAv response to the exercise stimulus reported regular participation in exercise than those who reported being sedentary.

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The Acute Effects of Different Exercise Intensities on Associative Novel Word Learning in Healthy Older Adults: A Randomized Controlled Trial

Journal of Aging and Physical Activity ◽

10.1123/japa.2020-0093 ◽

2020 ◽

pp. 1-14

Author(s):

Marie-Pier McSween ◽

Katie L. McMahon ◽

Kylie Maguire ◽

Jeff S. Coombes ◽

Amy D. Rodriguez ◽

...

Keyword(s):

Older Adults ◽

Word Learning ◽

Acute Exercise ◽

Word Recall ◽

Moderate Intensity ◽

Acute Effects ◽

Learning Abilities ◽

Healthy Older Adults ◽

Continuous Exercise ◽

Lower Baseline

Recent studies show positive effects of acute exercise on language learning in young adults with lower baseline learning abilities; however, this is yet to be investigated in older adults. This study investigated the acute effects of different exercise intensities on new word learning in healthy older adults with lower and higher baseline learning abilities. Sixty older adults (mean age = 66.4 (4.6); 43 females) performed either a single bout of stretching exercise, moderate-intensity continuous exercise, or high-intensity interval exercise followed by a word learning task. In lower baseline learners, between-group differences were observed on immediate new word recall success, with the moderate-intensity continuous exercise group performing better than the stretching group. These findings suggest immediate benefits of moderate-intensity continuous exercise that are limited to word learning performance of older adults with lower baseline learning abilities. Further investigation into underlying mechanisms could lead to a better understanding of individual differences in responding to acute exercise.

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Dual Trajectories of Social Isolation and Dementia in Older Adults: A Population-Based Longitudinal Study

Journal of Aging and Health ◽

10.1177/0898264320953693 ◽

2020 ◽

pp. 089826432095369

Author(s):

Xiaoling Xiang ◽

Patrick Ho Lam Lai ◽

Luoman Bao ◽

Yihang Sun ◽

Jieling Chen ◽

...

Keyword(s):

Older Adults ◽

High Risk ◽

Social Isolation ◽

Late Onset ◽

Population Based ◽

Low Risk ◽

Steady Increase ◽

Steady Decrease ◽

Dementia Risk

Objectives: To identify the interrelations between the trajectories of social isolation and dementia in older adults. Methods: Data came from the National Health and Aging Trends Study 2011–2018 surveys. Group-based dual trajectory modeling was used to examine trajectories and their interrelations. Results: Four trajectories of social isolation—rarely isolated (62.2%), steady increase (13.5%), steady decrease (7.4%), and persistently isolated (16.9%) and dementia risk—persistently low risk (80.4%), increasing with early onset (3.9%), increasing with late onset (4.5%), and persistently high risk (11.2%) emerged. Two-thirds of the low-risk dementia group were in the rarely isolated group. The high-risk dementia group had the most overlap with the decreasing social isolation group (47%), followed by the persistently isolated group (28%). Conclusions: Social isolation and dementia mostly evolved in the same direction. However, the pattern of associations between these trajectories is intricate and may be reversed among long-term dementia survivors.

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Effects of Acute Exercise on Memory Performance in Middle-Aged and Older Adults

Journal of Aging and Physical Activity ◽

10.1123/japa.2020-0208 ◽

2020 ◽

pp. 1-8

Author(s):

Jennifer L. Etnier ◽

Jarod C. Vance ◽

Aiko Ueno

Keyword(s):

Older Adults ◽

Acute Exercise ◽

Memory Performance ◽

Moderate Intensity ◽

Long Term Memory ◽

Middle Aged ◽

Moderate Intensity Exercise ◽

Auditory Learning ◽

Verbal Test ◽

Within Subjects

Numerous studies show that exercise benefits memory and some show that acute exercise prior to encoding has larger benefits than exercise after encoding. This study was designed to investigate the effects of acute exercise on memory in middle-aged and older adults (Mage = 64.71 years) and to explore the influence of the timing of the exercise on these effects. Using a within-subjects design, moderate-intensity exercise (20 min) was either not performed (control), performed before the task (exercise prior), or performed after the task (exercise post). Memory was assessed using the Rey Auditory Learning Verbal Test. For short- and long-term memory and learning, significantly more words were remembered in the exercise-prior condition than the others. For 24-hr recall, participants remembered significantly more words in the exercise-prior condition than exercise post, which was better than control. Exercise benefits memory for healthy middle-aged and older adults, with the greatest benefits when performed prior to encoding.

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Dual Trajectories of Social Isolation and Dementia in Older Adults: A Population-Based Longitudinal Study

Innovation in Aging ◽

10.1093/geroni/igaa057.1022 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

pp. 319-319

Author(s):

Xiaoling Xiang ◽

Patrick Ho Lam Lai ◽

Yihang Sun ◽

Ruth Dunkle

Keyword(s):

Older Adults ◽

Social Isolation ◽

Late Onset ◽

Developmental Trajectories ◽

Population Based ◽

Steady Increase ◽

Dual Model ◽

Medicare Beneficiaries ◽

Dementia Risk

Abstract The purpose of this study was to identify patterns of changes in social isolation and dementia and the interrelations between these developmental trajectories. The study sample included 7,609 Medicare beneficiaries age 65 and older from the National Health and Aging Trends Study 2011 through 2018 surveys. A group-based dual trajectory modeling approach was used to identify distinct groups of developmental trajectories for social isolation and dementia status over the 8-year period. The dual model provided estimates of conditional and joint probabilities linking the two sets of trajectory groups. Changes in social isolation over an 8-year period followed four trajectories: rarely isolated (62.2%), steady increase (13.5%), steady decrease (7.4%), and persistently isolated (16.9%). Changes in dementia risk also followed four trajectories: persistently low risk (80.4%), increasing with early onset (3.9%), increasing with late onset (4.5%), and persistently high risk (11.2%). Over two-third (68%) of the persistently low dementia group were also in the rarely isolated group. Both increasing dementia groups were composed mainly of individuals from the increasing social isolation group (40-43%) and persistently isolated group (24-29%). The persistently high dementia group had the most overlap with the decreasing social isolation group (47%), followed by the persistently isolated group (28%). For the most part, social isolation and dementia evolve in the same direction for older adults over an 8-year period. However, the pattern of associations between these developmental trajectories is complex and may be reversed among long-term dementia survivors.

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