The Post Ischaemic Stroke Cardiovascular Exercise Study: Protocol for a randomised controlled trial of fitness training for brain health

Short abstract

Introduction

Compared to healthy individuals, stroke patients have five times the rate of dementia diagnosis within three years. Aerobic exercise may induce neuroprotective mechanisms that help to preserve, and even increase, brain volume and cognition. We seek to determine whether aerobic fitness training helps to protect brain volume and cognitive function after stroke compared to an active, non-aerobic control.

Methods

In this Phase IIb, single blind, randomised controlled trial, 100 ischaemic stroke participants, recruited at two months post-stroke, will be randomly allocated to either the intervention (aerobic and strength exercise) or active control (stretching and balance training). Participants will attend one-hour, individualised exercise sessions, three days-per-week for eight weeks. Assessments at two months (baseline), four months (post-intervention), and one year (follow-up) post-stroke will measure brain volume, cognition, mood, cardiorespiratory fitness, physical activity, blood pressure and blood biomarkers.

Study outcome: Our primary outcome measure is hippocampal volume at four months after stroke. We hypothesise that participants who undertake the prescribed intervention will have preserved hippocampal volume at four months compared to the control group. We also hypothesise that this group will have preserved total brain volume and cognition, better mood, fitness, and higher levels of physical activity, than those receiving stretching and balance training.

Discussion

The promise of exercise training to prevent, or slow, the accelerated rates of brain atrophy and cognitive decline experienced by stroke survivors needs to be tested. Post Ischaemic Stroke Cardiovascular Exercise Study has the potential, if proven efficacious, to identify a new treatment that could be readily translated to the clinic.

Introduction

Worldwide, there are more than 46 million people with dementia, with this number expected to increase to 131.5 million by 2050.¹ Stroke is a major risk factor for dementia: 10% of survivors experience cognitive impairments at the time of stroke, 10% develop new dementia soon after a first stroke, and by three years post-stroke, 30% are cognitively impaired or demented.^2,3

Magnetic resonance imaging (MRI) indicates that focal brain atrophy both precedes and parallels cognitive decline.^4–7 Indeed, it appears that the rate of cognitive decline is driven by the rate of brain atrophy.^5,7,8 This suggests that brain volume changes are a sensitive proxy measure for predicting cognitive decline, with changes detectable over 6–12 months. Standard cognitive assessments, many of which suffer from floor- or ceiling-effects, are often not designed for serial testing over short time-frames and may not be so sensitive to change.

In the Cognition and Neocortical Volume after Stroke (CANVAS) study, a longitudinal study measuring cognitive performance and brain volume changes after ischaemic stroke, accelerated rates of structural brain aging, including total and regional brain atrophy, were observed in stroke survivors compared to healthy participants.^4,9 Brain volume loss may occur in stroke patients even prior to their events, possibly due to the deleterious effects of vascular risk factors.¹⁰ These findings support the concept of an insidious, covert, vascular neurodegeneration, manifesting both as stroke and brain structural integrity decline.¹¹ This corresponds with recent work emphasising dementia prevention, where the authors proposed that dementia is the terminal phase of a chronic, progressive, mid-life disease, caused in no small part by vascular risk factors.¹²

There is a complex relationship between vascular risk factors, physical inactivity, stroke and dementia. It has been estimated that potentially modifiable vascular risk factors account for 30% of all cases of Alzheimer’s disease (AD),¹³ and this percentage increases with age.¹⁴ The individual risk factors contributing most to the dementia burden are physical inactivity (8% of dementia burden), stroke (7%), and midlife hypertension (6%).¹⁴ Recurrent stroke, hypertension, and physical inactivity are risk factors for post-stroke cognitive decline.¹⁵ In the Framingham study, physical inactivity was associated with a higher risk for dementia in older adults.¹⁶ Physical inactivity is also associated with hippocampal atrophy and memory dysfunction.¹⁷ Regular, lifelong aerobic exercise reduces the risk of all-cause dementia,¹⁸ and is associated with greater brain volume.¹⁶ Aerobic exercise is associated with hippocampal neurogenesis in adults,¹⁹ and improved cognition in older adults with²⁰ and without mild cognitive impairment (MCI).²¹ Increased cortical thickness and greater cortical connectivity have also been associated with exercise.^19,22

In a resting state functional MRI study, we previously demonstrated a positive association between the percentage of the day spent active with increased connectivity in the dorsal attention network. This, in turn, was associated with better attention.²³ However, these findings were observational, and the influence of exercise on cognition post-stroke is uncertain. In a small randomised controlled trial (RCT) comparing the effects of six-month high- and low-intensity exercise programs on cognition post-stroke, exercise was not beneficial in improving cognition,²⁴ although this was not a primary endpoint. In contrast, a randomised study found that people with a diagnosis of subcortical ischaemic vascular cognitive impairment receiving a six-month progressive aerobic exercise training program had significantly improved cognitive performance compared with the usual care group.²⁵ A pilot study demonstrated that a 12-week training program combining aerobic exercise and lower limb muscle strengthening improved selective measures of executive function after stroke.²⁶ Furthermore, a meta-analysis showed that physical activity (PA) training conferred small, but significant, cognitive benefits after stroke.²⁷ Notably, a combined aerobic and strength training intervention may optimally improve cognition post-stroke.²⁷

Whilst the collective evidence suggests potential links between exercise, cognition and brain volume and function, the longitudinal relationship between post-stroke brain volume, cognitive performance, and prescribed exercise remains unexplored in a RCT. Here, we describe Post Ischaemic Stroke Cardiovascular Exercise Study (PISCES), a Phase IIb, single-blind, safety, feasibility and pilot-efficacy RCT to examine whether an eight-week fitness training intervention, combining aerobic exercise and resistance training, implemented at two months post-stroke, preserves brain volume better than a stretch and balance active control.

Study objective

To test the hypothesis that stroke survivors receiving an aerobic fitness training intervention will experience a slower rate of decline in hippocampal volume at four months post-stroke compared to stroke survivors receiving stretching and balance training (non-aerobic, active control).

Study design

The training intervention is modelled on cardiac rehabilitation, which includes a professionally supervised, 6–10-week exercise training program²⁸ and has been shown to improve multiple cognitive domains, including memory, attention and global cognition in people with cardiovascular disease.²⁹ Participants will be assessed immediately before and after the exercise intervention, and again at one year post-stroke, to determine if the potential benefits are sustained. The trial will be reported according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines (Table 1)³⁰ and the Template for Intervention Description and Replication (TIDieR).³¹ The first participant was recruited in November 2016 and recruitment is ongoing (see Supplementary Figure 1 for the Consolidated Standard of Reporting Trials [CONSORT] flow diagram).³²

Table 1.

Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) diagram of the study procedures for the PISCES trial.

	Study period
	Enrolment	Pre-allocation	Post-allocation	Follow-up
Time point	−t1	t1	t2	t3
Enrolment
Eligibility screen	X
Informed consent	X
Randomisation		X
Intervention
Aerobic exercise
Stretching and balance training
Assessment
Clinical scales
National Institutes of Health Stroke Scale		X	X	X
Modified Rankin Scale		X	X	X
Brain MRI		X	X	X
Demographic interview		X	X	X
Cognitiona		X	X	X
Mood and quality of lifea		X	X	X
Physical activity monitor		X	X	X
Cardiorespiratory fitness assessment		X	X	X
24-hour ambulatory blood pressure monitoring		X	X	X
Cardiac function		X	X	X
Blood biomarkers
BDNF		X	X	X
HbA1c		X	X	X
APOE ε4 genotyping		X
PASE scale		Administered at 2-, 4-, 6-, 8-, 10- and 12-months post-stroke

PISCES: Post Ischaemic Stroke Cardiovascular Exercise Study; MRI: magnetic resonance imaging; PASE: physical activity scale for the elderly; BDNF: brain-derived neurotrophic factor: HbA1C: haemoglobin A1c; APOE ε4: apolipoprotein E ε4.

Following enrolment, participants are randomised to either the aerobic exercise intervention or the stretching and balance intervention (control). All assessments are carried out before (two months post-stroke) and after (four months post-stroke) the eight-week intervention, and at one-year post-stroke (except APOE ε4, which will be measured at one time point only, and the PASE scale, which will be administered at 2-month intervals in between baseline and the 12-month follow-up assessment).

^aRefer to Supplementary Table 1 for detailed cognitive functioning, mood and quality of life assessments.

Patient population

Adult, ischaemic stroke patients will be eligible. A pre-study screening questionnaire will be used to ensure that participants have no contraindications for MRI, do not have pre-existing dementia, or other exclusions (Table 2). Consent will be obtained for the individual as per our ethics approval.

Table 2.

PISCES inclusion and exclusion criteria.

Inclusion criteria	Exclusion criteria
Ischaemic stroke Cardiac function sufficient for participation in exercise training Premorbid mRS of ≤3 Able to give consent or have next-of-kin/caregiver who can consent by proxy (e.g. for patients with severe aphasia) Aged >18 years	Significant medical co-morbidities precluding participation in an exercise intervention (e.g. severe cardiac disease), or making survival for 12 months unlikely Contraindications for MRI (e.g. implanted metal, severe claustrophobia) Pre-existing dementia

PISCES: Post Ischaemic Stroke Cardiovascular Exercise Study; mRS: modified Rankin Scale; MRI: magnetic resonance imaging.

Baseline assessment

Demographic and medical information including age, gender, medication status, medical and vascular risk factor history, side and site of stroke, admission stroke severity (National Institutes of Health Stroke Scale, NIHSS) and functional status (Modified Rankin Scale, mRS) will be obtained by trained health-care professionals. Total brain volume will be derived from the baseline (two months post-stroke) 3T MRI scan for randomisation (see below).

Randomisation

Participants will be randomly allocated into two groups using a computer-generated schedule with permuted blocks of various sizes, stratified by baseline function (grouped into mRS 0–1, 2–3) and by baseline total brain volume (grouped into high or low total brain volume based on the median two-month total brain volume derived from the CANVAS dataset). Randomisation will take place after the baseline assessment.

Intervention group

Participants will perform a combination of progressive aerobic exercise and resistance training three times per week for eight weeks at a prescribed intensity range based on their heart rate reserve (HRR)³³ for the aerobic exercise, and their three-repetition maximum (3-RM) for the resistance training. Each exercise training session will begin and end with a five-minute warm-up and cool-down at 30% of the participants HRR.

Aerobic exercise. The participants will complete up to 30 minutes of aerobic exercise on a treadmill, stepper or cycle ergometer (pending participant preference and functional capacity) in each exercise session. Each participant will complete two moderate-high-intensity, interval-based aerobic exercise sessions per week, and one steady-state, aerobic exercise session per week. In each exercise session, the exercise intensity will be adjusted according to the participant’s physiological response until they reach their target heart rate (HR) range, but will not exceed the upper portion of the target range. The development of the aerobic exercise component of the intervention is based on a model of aerobic exercise training for cardiovascular health in subacute stroke.³⁴ The intensity or duration of the exercise will be modified from session-to-session following developed guidelines.

Resistance training. The participants will also complete two, 10-minute bouts of moderate intensity strength training (70–80% of their 3-RM) on the same days as the aerobic interval training. Strength training exercises will focus on improving muscle strength bilaterally in upper and lower limbs, torso and back. The participants will be familiarised with the exercises and muscle actions and their 3-RM will be assessed during the first week of the intervention. Following this, participants will be invited to choose resistance exercise options to train select muscle groups in week one. Between training sets, participants will passively rest for 15–30 seconds, and for one-minute between exercises. Exercise progression, or regression, will be based on participant tolerance, with the aim being for the participants to maintain a rating of perceived exertion (RPE)³⁵ of 15–18.

Control group

Balance and stretching exercise. The participants in the stretching and balance training group (active, non-aerobic control) will complete 30 minutes of light stretching, followed by 20 minutes of balance-challenging tasks. The stretching program will consist of both upper and lower body static stretches involving all the major joint complexes. The participants will be asked to maintain a muscle tension at a level that induces a feeling of ‘stretch’. The balance program will include balance-challenging tasks, such as heel-toe walking and reaching tasks. All stretches and balance tasks will be held for 30 seconds each, repeated three times with a 30-second passive rest interval between each repetition, and a one-minute rest between each muscle group/task. To maintain interest, new exercises will be introduced every two weeks. Each active, non-aerobic control session will begin and end with a five-minute walk at 30% of the participant’s HRR as a warm-up and cool-down, respectively.

Participants will train at the campus of a metropolitan health service and will be supervised by trained exercise physiologists or physiotherapists.

Monitoring

In both groups, HR and RPE will be monitored throughout each exercise training bout. Blood pressure (BP) will be assessed before and after each training bout. In the absence of dose-limiting events (e.g. a participant exceeds pre-exercise session safety limits or experiences an adverse event during a session), participants will progress through the intervention as per the PISCES protocol. If a participant experiences a dose-limiting event, pre-defined rules are in place to regress the exercise training to encourage continued participation and adaptation within the limits of safety. Participants will also complete exercise diaries over the course of the 8-week exercise program.

Primary outcome

The between-group (intervention versus control) difference in hippocampal volume change between baseline and four months post-stroke.

Imaging overview. A 3T Siemens Skyra MRI scanner (Siemens, Munich, Germany) will be used to acquire 1 mm isotropic 3-dimensional (3-D) magnetisation prepared rapid acquisition gradient echo (MP-RAGE), fluid-attenuated inversion recovery (FLAIR) and T2 images for structural analyses of the participants.

Hippocampal volume. Hippocampal volume will be estimated using FreeSurfer.³⁶

Secondary outcomes

• Between-group difference in hippocampal and total brain volume change between baseline and one year post-stroke.

• Between-group difference in executive function change between baseline and one year post-stroke.

• Relationship between brain volume and executive function at one year post-stroke.

Total brain volume. Following image acquisition, the FreeSurfer software package,³⁷ which has previously been demonstrated to be reliable and accurate in stroke populations,³⁸ will be used to measure total brain volume using default processing settings.

Cognition. The main outcome of interest is executive function, as measured by the Trail-Making-Test Part B. This test is part of the neuropsychological battery developed for CANVAS⁹ that will be used to assess cognitive function in this study. The test battery is designed to assess global cognition and seven cognitive domains (processing speed, attention, working memory, memory, executive function, language, and visuospatial ability) (Supplementary Table 1). Performance on individual cognitive tests will be standardised using established norms, and domain scores will be calculated by averaging the standardised scores from each contributing test.⁹

Tertiary outcomes

The change in cardiorespiratory fitness (CRF), PA, mood, quality of life (QoL) and level of fatigue from baseline to one year post-stroke, and the relationship between these variables and brain volume and cognition.

Cardiorespiratory fitness. A supervised, graded exercise test (GXT) on a total body recumbent stepper (TBRS) (NuStep, T5XR, NuStep, Inc., Ann Arbor, MI), will be conducted to measure CRF. Participants will be asked to abstain from consuming food and caffeine three hours prior to the scheduled test. Expired respiratory gases will be collected through a breath-by-breath (BxB) pneumotach system connected to gas analysers calibrated immediately before each test as per the manufacturer’s instructions. Participants will be instructed to step at a cadence of 80 steps per minute, beginning with an initial resistance of 25 Watts (W), and increasing by 15 W every two minutes until set end-points are reached. This protocol is based on a previously validated maximal, incremental TBRS protocol for stroke survivors.³⁹ The BxB data will be integrated for each 5-second interval. Ventilatory gas analysis, RPE, HR, BP, and symptomatic assessment will be monitored throughout the GXT to ensure safety. Intake of beta-blocker medication will be recorded. The GXT will be terminated if the participant reaches volitional exhaustion or they demonstrate absolute test termination criteria according to the American College of Sports Medicine exercise test guidelines.⁴⁰ Peak volume of oxygen consumption (VO_2peak), as measured by averaging the last 30 seconds VO₂ uptake data from the GXT, will be used in the analyses.

Physical activity. To monitor incidental PA, a SenseWear Pro Armband (BodyMedia Inc., Pittsburgh, US) will be given to the participants to wear for seven-days after each testing time-point.⁴¹ Activity and sedentary behaviour data will be extracted for each participant to obtain mean percentage of the day spent performing sedentary (<1.5 metabolic equivalents [METs]), light (≥1.5 to ≤3 METs), moderate (>3 to ≤4.5 METs), and vigorous (>4.5 METs) activities. The percentage of waking time spent active will be calculated by dividing the time spent active (≥1.5 METs) by the duration of armband wear-time minus the time spent asleep measured over the entire duration of armband recording.

The Physical Activity Scale for the Elderly (PASE)⁴² will be administered via a telephone call to the participant at 6-, 8-, and 10-months post-stroke to monitor the participants’ engagement in PA between the post-intervention (4-month) and final (12-month) MRI scans. This is in addition to its administration at the 2-, 4-, and 12-month assessment sessions. The PASE scores will be used in the exploratory analysis.

Mood, fatigue and QoL. The Generalised Anxiety Disorder-7 (GAD-7),⁴³ the Patient Health Questionnaire (PHQ-9),⁴⁴ the Fatigue Assessment Scale (FAS),⁴⁵ and the Assessment Quality of Life (AQoL)⁴⁶ will be administered.

Exploratory outcomes

The relationship between CRF and PA, 24-hour ambulatory BP, recurrent stroke, pre-specified growth factors and APOE ε4 allele status will be investigated (see Supplementary information).

Blinding. The assessors conducting the post-intervention cognitive testing, MRI analysis, CRF testing and the mood, fatigue and QoL assessments will be blinded to participant group. Participants will be aware of their group allocation based on the exercise-training program they are administered. To avoid contamination, the exercise sessions for the two groups will be conducted at different times throughout the day, with at least one hour between the end of one session and the beginning of another.

Sample size estimates. A total sample size of 100 participants (50 per group) will yield 80% power to detect a difference in hippocampal volume between groups corresponding to a medium-to-large effect size (d = 0.6), assuming the standard settings of two-tailed significance and alpha = 0.05. In CANVAS, we find hippocampal volume loss of −3% over four months after stroke, in contrast to the −0.4% change in the stroke-free control group (unpublished data). This gives a total 45 patients per group. We have increased the sample size by 10% to account for attrition over the 12-month period and the possibility of non-evaluable scans.

Statistical analysis. The primary outcome will be analysed on an intention-to-treat basis. The difference in hippocampal volume from baseline to four months will be compared using an ANCOVA model, with group as a factor (intervention versus control) and baseline total brain volume and functional status (mRS 0–1 versus mRS 2–3) as co-variates.

Separate ANCOVAs, with groups as a factor and baseline total brain volume and functional status as co-variates, will be used to analyse the difference in hippocampal volume, total brain volume and executive function from baseline to one year. A repeated measures random effect regression model will be used to determine the relationship between hippocampal and total brain volume and executive function.

The tertiary and exploratory outcomes will be analysed according to standard statistical principles for comparisons of change between groups and associations between variables.

Study organisation. All study procedures will follow Good Clinical Practice guidelines. A Data Safety Committee will monitor trial performance, protocol violations, data quality and unblinded serious adverse events for trial safety bi-annually. An Operations Committee and a Steering Committee consisting of members of the investigating team and other trial staff will convene at regular intervals.

Summary and conclusion

Stroke survivors experience accelerated rates of brain atrophy and cognitive decline.^4,9 This study builds on our previous exploration in CANVAS of post-stroke changes in brain volume and cognitive function,⁹ in which we demonstrated a positive association between PA, cognition and brain volume. This research is robust and novel in its inclusion of an established neuropsychological test battery and advanced imaging techniques and analysis. It includes an intervention that is supported by recent recommendations for optimising cognitive function after stroke, and a 12-month follow-up that will indicate the longitudinal effects of fitness training post-stroke. Critically, the study is powered to detect change in the primary outcome – hippocampal volume at four months post-stroke. If we demonstrate safety and feasibility with promising signs of efficacy, the study design is immediately translatable into a Phase 3 trial.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work is supported by the Heart Foundation Future Leader Fellowship for AB (grant number: 100784).

Ethical approval

The ethics committee of Austin Health Human Research Ethics Committee approved this study (reference number: HREC/16/Austin/45).

Informed consent

Written informed consent will be obtained from all participants before enrolment.

Trial registration

Australian New Zealand Clinical Trials Registry: 12616000942459.

Guarantor

AB.

Contributorship

AB researched literature and conceived the study. All authors were involved in protocol development and gaining ethical approval. LJ wrote the first draft of the manuscript. All authors reviewed and edited the manuscript and approved the final version of the manuscript.