START is a large multi-centre research study which utilises state of the art neuroimaging to study acute stroke therapy, its prevention and its impact. It comprises two major studies; EXTEND (Extending The Time for Thrombolysis in Emergency Neurological Deficit) and PrePARE (Prediction and Prevention to Achieve Optimal Recovery Endpoints after Stroke).
EXTEND is a randomised, multicentre, double blinded, placebo controlled phase 3 trial. The objective is to test the hypothesis that ischaemic stroke patients of similar age and stroke severity selected with significant penumbral mismatch at 4.5 – 9 hours post onset of stroke will have improved clinical outcomes when given intravenous tPA compared to placebo. Secondary objectives are to collect biomarkers, lifestyle and dietary factors which may influence the function outcome and risk of hemorrhage.
Patients randomised to treatment will be stratified for time of randomisation after stroke into one of three groups:
- greater than 4.5 hours (or 3 hours depending on local practice) and up to 3 hour
- greater than 6 hours and up to 9 hours
- patients who wake with symptoms of stroke where the time difference between the mid-point of going to sleep without symptoms and waking up with symptoms is less than or equal to 9 hours
The unique feature of EXTEND is the utilisation of state-of-the-art neuroimaging to identify patients who may benefit from thrombolytic therapy in this extend therapeutic time window.
PrePARE involves advanced MRI studies and clinical assessments to investigate the relationship between changes in the brain, thinking and movement abilities, and their impact on mood and the ability to maintain participation in everyday activities. It will help identify brain ‘markers’ that are linked with recovery. 75 stroke survivors will be tested at 3 and 12 months.
1) Terms of Reference
Within the context of the START program, to address issues related to:
- depression outcomes
- functional outcomes, including cognition and activity participation
- diet as a predictor of depression and functional outcome (including cognition)
- lifestyle as a predictor of depression and functional outcome
2) Aim & Hypothesis
Our overall aim is to identify predictors of depression and functional outcome following stroke based on putative biochemical, genetic and imaging biomarkers. In particular we aim to:
- Identify early, stroke survivors ‘at risk’ of depression and recurrent stroke through use of novel imaging approaches and well established biomarkers.
- Investigate the association between post-stroke depression with functional outcomes, recurrent stroke and participation in daily activities.
- Explore if thrombolysis, an acute treatment known to be effective in reducing disability, is associated with a reduced prevalence of depression and
recurrent stroke and increased participation in daily activities.
It is hypothesised that: candidate biochemical and genetic markers related to stress and inflammation will predict presence of post-stroke depression; novel imaging measures of brain morphometry and resting state function will be associated with depression and functional outcome; and lifestyle factors related to diet, activity levels, participation in daily activities and known cardiovascular risk factors will be associated with post-stroke depression, recurrent stroke and functional outcome.
Figure 1: Overview of the relationship between predictive markers and clinical endpoints post-stroke. Predictive markers to be investigated are based on: novel brain imaging markers of brain morphometry (cortical thickness, hippocampal volume), functional resting state brain activity, and lesion location (as it impacts on brain networks); and on biochemical and genetic markers related to stress and inflammation. Lifestyle factors related to diet and change in levels of activity participation post-stroke will be explored for expected associations. Important clinical endpoints to be assessed are: mortality and recurrent stroke; depression and emotional well-being; neurological, cognitive and functional status; participation in household, social/educational and leisure activities; return to work and productive occupations; and quality of life.
3) Clinical Measures
Patients will be clinically assessed for depressive symptoms and depressive disorder using structure interview and the Montgomery-Asberg Depression Rating Scale (MADRS), a quantitative, standardised measure of depression (Williams and Kobak, 2008). Anxiety: Anxiety and stress will be assessed using the Depression Anxiety Stress Scales (DASS).
Functional independence in activities of daily living will be assessed using the modified Rankin Scale (mRS) (Bonita and Beaglehole, 1988); Barthel questionnaire (Mahoney and Barthel, 1965) and instrumental activity of daily living scale. Neurological status will be assessed using the National Institute of Health Stroke Scale (NIHSS) (Brott et al., 1989).
The Montreal Cognitive Assessment will assess speed, vigilance and executive function (Nasreddine et al., 2005). The PrePARE subgroup will also be tested on Digit span, Stroop test, Trails B and Mini-Mental State Examination (MMSE). Sensorimotor (subgroup only): Upper limb function will be assessed using the Action Research Arm Test (Van der Lee et al., 2001) and the Tactile Discrimination Test (Carey et al., 1997). Mobility will be assessed using the Timed Up and Go test (Podsiadlo and Richardson, 1991). Background visual and sensory functions will be screened for.
Quality of Life
Qaulity of life will be assessed using the Stroke Impact Scale (short version) (Duncan et al., 1999). Medication and prior history: All medications, including antidepressants will be recorded at hospital admission and 3 and 12 month follow ups. Prior history of depression or mood disorders will be obtained from medical history and patient interview. Recurrent stroke will be monitored throughout the study.