bims-empneu 2021-05-09 papers

bims-empneu

Biomed News

on Exercise and Molecular Pathways Involved in Neuroprotection

Issue of 2021–05–09
thirteen papers selected by
Navabeh Zare-Kookandeh, Victoria University

Toward a neuroprotective shift: eight weeks of high intensity interval training reduces the neurotoxic kynurenine activity concurrently to impulsivity in emotionally impulsive humans - A randomized controlled trial.
Multiple Roles in Neuroprotection for the Exercise Derived Myokine Irisin.
Regular aerobic exercise increased VEGF levels in both soleus and gastrocnemius muscles correlated with hippocampal learning and VEGF levels.
The Effect of Two Types of Exercise Preconditioning on the Expression of TrkB, TNF-α, and MMP2 Genes in Rats with Stroke.
Exercise Training-Increased FBXO32 and FOXO1 in a Gender-Dependent Manner in Mild Cognitively Impaired African Americans: GEMS-1 Study.
Acute exercise increases BDNF serum levels in patients with Parkinson's disease regardless of depression or fatigue.
Exercise, Arterial Stiffness, and Cerebral Vascular Function: Potential Impact on Brain Health.
Neurobiological effects of forced swim exercise on the rodent hippocampus: a systematic review.
The Benefits of High-Intensity Interval Training on Cognition and Blood Pressure in Older Adults With Hypertension and Subjective Cognitive Decline: Results From the Heart & Mind Study.
The Effects of Aerobic Exercise in Patients with Early-Onset Dementia: A Scoping Review.
Resistance training improves cognitive function in older adults with different cognitive status: a systematic review and Meta-analysis.
The Effect of Exercise on the Total Number of BrdU+ Cell Counts in Rats' Hippocampal Dentate Gyrus: A Meta-Analysis Study.
How to Address Physical Activity Participation After Stroke in Research and Clinical Practice.

Brain Behav Immun. 2021 Apr 28. pii: S0889-1591(21)00178-1. [Epub ahead of print]

Toward a neuroprotective shift: eight weeks of high intensity interval training reduces the neurotoxic kynurenine activity concurrently to impulsivity in emotionally impulsive humans - A randomized controlled trial.

Florian Javelle, Wilhelm Bloch, Andre Knoop, Gilles J Guillemin, Philipp Zimmer.

BACKGROUND: Previous findings suggest that impulsivity is related to a chronic low-grade inflammation. Inflammation is known to trigger the kynurenine pathway to a pathological level in various impulsivity-related disorders. Nonetheless, murine models and recent human studies have shown that physical exercise, in particular High Intensity Interval Training (HIIT), could counterbalance the negative effects of inflammation on the kynurenine pathway.
AIM: This study evaluates the effects of eight weeks of HIIT versus an active control group on impulsivity levels and accompanying alterations of inflammatory-mediated changes of the kynurenine pathway in a sample of emotionally-impulsive humans.
METHODS: Participants were randomly allocated to either HIIT or stretching conditions (three trainings per week for eight weeks). Fitness level was evaluated via VO2peak values at the beginning at the end of the intervention. Kynurenine metabolites, pro-inflammatory cytokines, and impulsivity levels were evaluated at T0, T4 and T8 weeks. Statistical analyses were realized using mixed models.
RESULTS: Fifty-three participants were included in the modified Intention To Treat analysis (45 finished the intervention). The HIIT group (n=28) largely increased the aerobic fitness of its participants and produced physiological changes while the stretching group (n=25) did not. HIIT reduced IL-6 levels (small to moderate interaction) and reduced the activity of the neurotoxic branch of the kynurenine pathway (small to moderate interaction for KYNA/QA and KYN/QA) after eight weeks of training while the active control did not change. Both interventions were effective to decrease emotion-related impulsivity, however only the HIIT group decreased participants' emotion-unrelated levels. Changes in emotion-related and unrelated impulsivity were moderately correlated to changes of KYNA/KYN.
CONCLUSION: This study demonstrated that HIIT was able to switch the kynurenine pathway from its neurotoxic branch to its neuroprotective one. This shift was associated with a decrease of impulsivity. Based on these findings, future work may consider investigating more intensively the effect of HIIT on impulsivity-related disorders.

DOI: https://doi.org/10.1016/j.bbi.2021.04.020
Front Aging Neurosci. 2021 ;13 649929

Multiple Roles in Neuroprotection for the Exercise Derived Myokine Irisin.

Mohammad Jodeiri Farshbaf, Karina Alviña.

  Exercise has multiple beneficial effects on health including decreasing the risk of neurodegenerative diseases. Such effects are thought to be mediated (at least in part) by myokines, a collection of cytokines and other small proteins released from skeletal muscles. As an endocrine organ, skeletal muscle synthesizes and secretes a wide range of myokines which contribute to different functions in different organs, including the brain. One such myokine is the recently discovered protein Irisin, which is secreted into circulation from skeletal muscle during exercise from its membrane bound precursor Fibronectin type III domain-containing protein 5 (FNDC5). Irisin contributes to metabolic processes such as glucose homeostasis and browning of white adipose tissue. Irisin also crosses the blood brain barrier and initiates a neuroprotective genetic program in the hippocampus that culminates with increased expression of brain derived neurotrophic factor (BDNF). Furthermore, exercise and FNDC5/Irisin have been shown to have several neuroprotective effects against injuries in ischemia and neurodegenerative disease models, including Alzheimer's disease. In addition, Irisin has anxiolytic and antidepressant effects. In this review we present and summarize recent findings on the multiple effects of Irisin on neural function, including signaling pathways and mechanisms involved. We also discuss how exercise can positively influence brain function and mental health via the "skeletal muscle-brain axis." While there are still many unanswered questions, we put forward the idea that Irisin is a potentially essential mediator of the skeletal muscle-brain crosstalk.

Keywords:  brain; exercise; myokine; neuroprotection; skeletal muscle

DOI:  https://doi.org/10.3389/fnagi.2021.649929
Acta Neurobiol Exp (Wars). 2021 ;81(1): 1-9

Regular aerobic exercise increased VEGF levels in both soleus and gastrocnemius muscles correlated with hippocampal learning and VEGF levels.

Asli Karakilic, Oguz Yuksel, Servet Kizildag, Ferda Hosgorler, Birsu Topcugil, Rabia Ilgin, Hikmet Gumus, Guven Guvendi, Basar Koc, Sevim Kandis, Mehmet Ates, Nazan Uysal.

Physical exercise improves learning and memory abilities by increasing the levels of several growth factors in the hippocampus. One growth factor, vascular endothelial growth factor (VEGF), is primarily produced in the muscles and not only increases in the periphery during exercise but can also cross the blood-brain barrier. The aim of this study is to investigate the effects of regular aerobic chronic exercise on different types of muscle fibers and the relationships between learning/memory and muscle induced-VEGF. Following a one-week adaptation period, male rats underwent treadmill training at a speed of 8 m/min for 30 min daily, 3 days a week for 6 weeks. Memory functions were evaluated using the Morris water maze. VEGF, superoxide dismutase (SOD), glutathione peroxidase (GPx), and malondialdehyde (MDA) levels were measured in type 1 and type 2 muscle fibers and VEGF levels were also measured in the hippocampus. Exercise positively affected both learning and memory and also increased VEGF levels in both muscle fiber types. Muscle VEGF levels positively correlate with hippocampal learning and hippocampal VEGF levels. Exercise reduced both SOD and MDA levels in type 1 and type 2 muscle fibers, whereas GPx levels decreased only in type 2 muscle fibers. Our findings suggest that regular aerobic exercise elevates VEGF levels and diminishes oxidative stress in both fiber types. Exercise-induced VEGF levels in both type 1 and 2 muscle fibers appear to be associated with the positive effect of exercise on learning and memory function and is accompanied by an increase in VEGF levels in the hippocampus. Further research is needed to elucidate the exact mechanism by which fiber type-specific VEGF mediates hippocampal neurogenesis and angiogenesis.
Physical exercise improves learning and memory abilities by increasing the levels of several growth factors in the hippocampus. One growth factor, vascular endothelial growth factor (VEGF), is primarily produced in the muscles and not only increases in the periphery during exercise but can also cross the blood-brain barrier. The aim of this study is to investigate the effects of regular aerobic chronic exercise on different types of muscle fibers and the relationships between learning/memory and muscle induced-VEGF. Following a one-week adaptation period, male rats underwent treadmill training at a speed of 8 m/min for 30 min daily, 3 days a week for 6 weeks. Memory functions were evaluated using the Morris water maze. VEGF, superoxide dismutase (SOD), glutathione peroxidase (GPx), and malondialdehyde (MDA) levels were measured in type 1 and type 2 muscle fibers and VEGF levels were also measured in the hippocampus. Exercise positively affected both learning and memory and also increased VEGF levels in both muscle fiber types. Muscle VEGF levels positively correlate with hippocampal learning and hippocampal VEGF levels. Exercise reduced both SOD and MDA levels in type 1 and type 2 muscle fibers, whereas GPx levels decreased only in type 2 muscle fibers. Our findings suggest that regular aerobic exercise elevates VEGF levels and diminishes oxidative stress in both fiber types. Exercise-induced VEGF levels in both type 1 and 2 muscle fibers appear to be associated with the positive effect of exercise on learning and memory function and is accompanied by an increase in VEGF levels in the hippocampus. Further research is needed to elucidate the exact mechanism by which fiber type-specific VEGF mediates hippocampal neurogenesis and angiogenesis.

DOI: https://doi.org/10.21307/ane-2021-001
Biomed Res Int. 2021 ;2021 5595368

The Effect of Two Types of Exercise Preconditioning on the Expression of TrkB, TNF-α, and MMP2 Genes in Rats with Stroke.

Mostafa Teymuri Kheravi, Shila Nayebifar, Seyedeh Motahareh Aletaha, Sara Sarhadi.

Despite the beneficial effects of exercise and physical activity, there is little knowledge about the effects of different types of physical activity on neural function. The present study assessed the effects of two types of selected aerobic exercises prior to stroke induction and characterized the expression of TrkB, TNF-α, and MMP2 genes in vivo. Forty male adult Wistar rats were exposed to aerobic exercises following randomization into four groups, including swimming + MCAO (Middle Cerebral Artery Occlusion) (n = 10), treadmill training + MCAO (n = 10), MCAO (n = 10), and control (n = 10). The swimming + MCAO group included swimming for 30 minutes each day, while the treadmill training + MCAO group program involved running for 30 minutes each day at an intensity of 15 m/min, for three weeks, five days a week. Neurological deficit was assessed using modified criteria at 24 h after the onset of cerebral ischemia. In the control group, the animals worked freely for three weeks without undergoing ischemia. The MCAO group also operated freely for three weeks after they underwent a stroke. Both training groups underwent ischemia after three weeks of training. TrkB, TNF-α, and MMP2 gene expressions were increased in the MCAO+ swimming training and in the MCAO + running training group compared to the control and MCAO groups, respectively. Preconditioning aerobic exercises significantly increased brain trophic support and reduced brain damage conditions in exercise groups, which support the importance of aerobic exercise in the prevention and treatment of stroke.

DOI: https://doi.org/10.1155/2021/5595368
Front Aging Neurosci. 2021 ;13 641758

Exercise Training-Increased FBXO32 and FOXO1 in a Gender-Dependent Manner in Mild Cognitively Impaired African Americans: GEMS-1 Study.

Fikru B Bedada, Oyonumo E Ntekim, Evaristus O Nwulia, Thomas V Fungwe, Sheeba Raaj Nadarajah, Thomas O Obisesan.

  The ubiquitin proteasome system (UPS) and FOXOs transcription factors play a pivotal role in cellular clearance and minimizing the accumulation of Aβ in neurodegeneration (ND). In African Americans (AAs) with mild cognitive impairment (MCI), the role of components of UPS and FOXOs; and whether they are amenable to exercise effects is unknown. We hypothesized that exercise can enhance cellular clearance systems during aging and ND by increasing expressions of FBXO32 and FOXO1. To test this hypothesis, we used TaqMan gene expression analysis in peripheral blood (PB) to investigate the component of UPS and FOXOs; and provide mechanistic insight at baseline, during exercise, and in both genders. At baseline, levels of FBXO32 were higher in women than in men. In our attempt to discern gender-specific exercise-related changes, we observed that levels of FBXO32 increased in men but not in women. Similarly, levels of FOXO1 increased in men only. These data suggest that a graded dose of FBXO32 and FOXO1 may be beneficial when PB cells carrying FBXO32 and FOXO1 summon into the brain in response to Alzheimer's disease (AD) perturbation (docking station PB cells). Our observation is consistent with emerging studies that exercise allows the trafficking of blood factors. Given the significance of FBXO32 and FOXO1 to ND and associated muscle integrity, our findings may explain, at least in part, the benefits of exercise on memory, associated gait, and balance perturbation acknowledged to herald the emergence of MCI.

Keywords:  FBXO32/atrogin-1; FoxO transcription factor; aging; cellular clearance system; immune cells; mild cognitive impairment; neurodegeneration; ubiquitin proteasome system (UPS)

DOI:  https://doi.org/10.3389/fnagi.2021.641758
Eur J Sport Sci. 2021 May 04. 1-21

Acute exercise increases BDNF serum levels in patients with Parkinson's disease regardless of depression or fatigue.

Lílian Viana Dos Santos Azevedo, Jéssica Ramos Pereira, Renata Maria Silva Santos, Natalia Pessoa Rocha, Antônio Lúcio Teixeira, Paulo Pereira Christo, Victor Rodrigues Santos, Paula Luciana Scalzo.

  Studies have consistently reported a decreased level of brain derived neurotrophic factor (BDNF) in individuals with Parkinson's disease (PD). The benefits of exercise on BDNF levels are well-documented in humans, however, the effects of acute exercise are inconclusive in neurological disorders. In addition, there are no studies investigating a precursor molecule - proBDNF - and its comparison to patients with vs. without depression or fatigue. Thirty patients with PD were instructed to walk on a treadmill at light to moderate intensity for 30 minutes. Generalized Estimating Equation (GEE) showed a significant effect of time (pre- vs. post-exercise) when compared individuals with vs. without depression [Wald Chi Square (4.392), p = 0.036)] and with vs. without fatigue [Wald Chi Square (7.123), p = 0.008)] for mature BDNF (mBDNF) level. There was no effect of group, time, and group x time interaction for proBDNF level when compared individuals with vs. without depression or fatigue. The present study showed that a single bout of light to moderate-intensity exercise increases mBDNF serum levels in patients with PD regardless of depression and fatigue. Our finding is important because it is necessary investigate methods to enhance the gains made by rehabilitation, especially when considering a short period of rehabilitation in different health services. The increase in mBDNF level can lead to an enhancement of neuroplasticity and facilitate the improvement of motor performance. No effect on proBDNF level could be explained, as this precursor molecule is cleaved by intracellular or extracellular enzymes.

Keywords:  chronic disease; exercise; fatigue

DOI:  https://doi.org/10.1080/17461391.2021.1922505
J Int Neuropsychol Soc. 2021 May 06. 1-15

Exercise, Arterial Stiffness, and Cerebral Vascular Function: Potential Impact on Brain Health.

Jill N Barnes, Andrew G Pearson, Adam T Corkery, Nicole A Eisenmann, Kathleen B Miller.

  Exercise is associated with higher cognitive function and is a promising intervention to reduce the risk of dementia. With advancing age, there are changes in the vasculature that have important clinical implications for brain health and cognition. Primary aging and vascular risk factors are associated with increases in arterial stiffness and pulse pressure, and reductions in peripheral vascular function.
OBJECTIVE: The purpose is to discuss the epidemiological, observational, and mechanistic evidence regarding the link between age-related changes in vascular health and brain health.
METHODS: We performed a literature review and integrated with our published data.
RESULTS: Epidemiological evidence suggests a link between age-related increases in arterial stiffness and lower cognitive function, which may be mediated by cerebral vascular function, including cerebral vasoreactivity and cerebral pulsatility. Age-associated impairments in central arterial stiffness and peripheral vascular function have been attenuated or reversed through lifestyle behaviors such as exercise. Greater volumes of habitual exercise and higher cardiorespiratory fitness are associated with beneficial effects on both peripheral vascular health and cognition. Yet, the extent to which exercise directly influences cerebral vascular function and brain health, as well as the associated mechanisms remains unclear.
CONCLUSION: Although there is evidence that exercise positively impacts cerebral vascular function, more research is necessary in humans to optimize experimental protocols and address methodological limitations and physiological considerations. Understanding the impact of exercise on cerebral vascular function is important for understanding the association between exercise and brain health and may inform future intervention studies that seek to improve cognition.

Keywords:  Aging; Cardiorespiratory fitness; Cerebral blood flow; Cognitive function; Endothelial function; Imaging; Pulsatility

DOI:  https://doi.org/10.1017/S1355617721000394
Acta Neurobiol Exp (Wars). 2021 ;81(1): 58-68

Neurobiological effects of forced swim exercise on the rodent hippocampus: a systematic review.

Rodrigo Freire Oliveira, Karina Maia Paiva, Gabriel Sousa da Rocha, Marco Aurélio de Moura Freire, Dayane Pessoa de Araújo, Lucídio Cleberson de Oliveira, Fausto Pierdoná Guzen, Paulo Leonardo Araújo de Gois Morais, José Rodolfo Lopes de Paiva Cavalcanti.

Forced swimming is a common exercise method used for its low cost and easy management, as seen in studies with the hippocampus. Since it is applied for varied research purposes many protocols are available with diverse aspects of physical intensity, time and periodicity, which produces variable outcomes. In the present study, we performed a systematic review to stress the neurobiological effects of forced swim exercise on the rodent hippocampus. Behavior, antioxidant levels, neurotrophins and inflammatory markers were the main topics examined upon the swimming effects. Better results among these analyses were associated with forced exercise at moderate intensity with an adaptation period and the opposite for continuous exhausting exercises with no adaptation. On further consideration, a standard swimming protocol is necessary to reduce variability of results for each scenario investigated about the impact of the forced swimming on the hippocampus.
Forced swimming is a common exercise method used for its low cost and easy management, as seen in studies with the hippocampus. Since it is applied for varied research purposes many protocols are available with diverse aspects of physical intensity, time and periodicity, which produces variable outcomes. In the present study, we performed a systematic review to stress the neurobiological effects of forced swim exercise on the rodent hippocampus. Behavior, antioxidant levels, neurotrophins and inflammatory markers were the main topics examined upon the swimming effects. Better results among these analyses were associated with forced exercise at moderate intensity with an adaptation period and the opposite for continuous exhausting exercises with no adaptation. On further consideration, a standard swimming protocol is necessary to reduce variability of results for each scenario investigated about the impact of the forced swimming on the hippocampus.

DOI: https://doi.org/10.21307/ane-2021-007
Front Aging Neurosci. 2021 ;13 643809

The Benefits of High-Intensity Interval Training on Cognition and Blood Pressure in Older Adults With Hypertension and Subjective Cognitive Decline: Results From the Heart & Mind Study.

Narlon C Boa Sorte Silva, Andrea F M Petrella, Nathan Christopher, Catherine F S Marriott, Dawn P Gill, Adrian M Owen, Robert J Petrella.

  Background: The impact of exercise on cognition in older adults with hypertension and subjective cognitive decline (SCD) is unclear. Objectives: We determined the influence of high-intensity interval training (HIIT) combined with mind-motor training on cognition and systolic blood pressure (BP) in older adults with hypertension and SCD. Methods: We randomized 128 community-dwelling older adults [age mean (SD): 71.1 (6.7), 47.7% females] with history of hypertension and SCD to either HIIT or a moderate-intensity continuous training (MCT) group. Both groups received 15 min of mind-motor training followed by 45 min of either HIIT or MCT. Participants exercised in total 60 min/day, 3 days/week for 6 months. We assessed changes in global cognitive functioning (GCF), Trail-Making Test (TMT), systolic and diastolic BP, and cardiorespiratory fitness. Results: Participants in both groups improved diastolic BP [F (1, 87.32) = 4.392, p = 0.039], with greatest effect within the HIIT group [estimated mean change (95% CI): -2.64 mmHg, (-4.79 to -0.48), p = 0.017], but no between-group differences were noted (p = 0.17). Both groups also improved cardiorespiratory fitness [F (1, 69) = 34.795, p < 0.001], and TMT A [F (1, 81.51) = 26.871, p < 0.001] and B [F (1, 79.49) = 23.107, p < 0.001]. There were, however, no within- or between-group differences in GCF and systolic BP at follow-up. Conclusion: Despite improvements in cardiorespiratory fitness, exercise of high- or moderate-intensity, combined with mind-motor training, did not improve GCF or systolic BP in individuals with hypertension and SCD. Clinical Trial Registration: ClinicalTrials.gov (NCT03545958).

Keywords:  aging; cardiovascular risk; elderly; exercise; memory impairment

DOI:  https://doi.org/10.3389/fnagi.2021.643809
Dement Geriatr Cogn Disord. 2021 May 06. 1-8

The Effects of Aerobic Exercise in Patients with Early-Onset Dementia: A Scoping Review.

Tine Roman de Mettelinge, Patrick Calders, Dirk Cambier.

   BACKGROUND: Early-onset dementia (EOD) defines all dementia related conditions with an onset before the age of 65 years. EOD places a large and distressing psychological, emotional and financial burden on the individuals themselves and their caregivers. For various reasons, diagnostic and treatment strategies for EOD are very challenging. There is a general agreement that not only the human body but also the mind benefits from physical activity and/or exercise. Especially aerobic exercise has shown to have favorable effects on cognitive functions in healthy older adults, as well as in patients with MCI and dementia. However, there are major differences in age, physical fitness level and clinical presentation between EOD and late-onset dementia. Therefore, one cannot just assume that the same type and intensity of exercise will lead to similar effects in the former population. By conducting this scoping review, the authors aimed to identify the evidence on the effectiveness of aerobic exercise on physical and mental health outcomes in individuals with EOD, display gaps in this context, and formulate related directions for future research.
SUMMARY: There are a number of reasons to assume that aerobic exercise might be extremely valuable within individuals with EOD. However, this scoping review led to the surprising and striking finding that not a single study so far has investigated the effects of physical exercise on cognition, physical performance and feelings of well-being and quality of life in EOD. Although nowadays the disease is increasingly recognized, coping and (non-pharmacological) treatment strategies for EOD are virtually non-existent. Key Messages: Exercise intervention studies in EOD are lacking. With this scoping review the authors hope to inspire researchers in the field for related directions for future research. The potential beneficial effects of aerobic exercise in individuals with EOD should be explored and assessed extensively. Secondarily, decent guidelines for non-pharmacological treatment and coping strategies should be developed, with the aim of supporting people with EOD and their caregivers.

Keywords:  Early-onset dementia; Exercise; Health outcome; Intervention

DOI:  https://doi.org/10.1159/000516231
Aging Ment Health. 2020 Dec 16. 1-12

Resistance training improves cognitive function in older adults with different cognitive status: a systematic review and Meta-analysis.

Helio Coelho-Junior, Emanuele Marzetti, Riccardo Calvani, Anna Picca, Hidenori Arai, Marco Uchida.

  The present study investigated the impact of resistance training (RT) on cognitive function in older adults with different cognitive status by conducting a systematic review and meta-analysis of intervention studies. We performed a literature search with no restriction on publication year in MEDLINE, Embase, CINAHL, SPORTDiscus, and AgeLine from inception up to August 2020. Experimental studies investigating the impact of RT on the cognitive function of cognitively healthy (CH) and cognitively impaired (CI) older adults (≥60 years) were included for analysis. Eighteen studies were included in the final analysis, of which ten studies investigated CH community-dwelling older adult, seven studies investigated CI older adults, and one study investigated both. RT significantly improved overall cognitive function in both CH (SMD = 0.54; 95% CI = 0.00 to 1.08, P = 0.047) and CI (SMD = 0.60; 95% CI = 0.21 to 1.16, P = 0.005) older adults. However, short-term memory was only improved in CH older adults (MD = -0.20; 95% CI = -0.25 to -0.15, P < 0.00001). In conclusion, RT improved overall cognitive function in CH and CI older adults, whereas short-term memory, assessed by the digit span of the WAIS III, was only significantly improved in CH older adults.

Keywords:  Physical exercise; dementia; frailty; strength training

DOI:  https://doi.org/10.1080/13607863.2020.1857691
Brain Res. 2021 May 04. pii: S0006-8993(21)00369-3. [Epub ahead of print] 147512

The Effect of Exercise on the Total Number of BrdU+ Cell Counts in Rats' Hippocampal Dentate Gyrus: A Meta-Analysis Study.

Ayşegül Burçin Yildirim.

DOI: https://doi.org/10.1016/j.brainres.2021.147512
Stroke. 2021 May 06. STROKEAHA121034557

How to Address Physical Activity Participation After Stroke in Research and Clinical Practice.

Natalie A Fini, Julie Bernhardt, Catherine M Said, Sandra A Billinger.



Keywords:  cardiovascular disease; exercise; physical activity; risk factors; secondary prevention; stroke

DOI:  https://doi.org/10.1161/STROKEAHA.121.034557