Stroke research why does it matter?

Transcription

1 Stroke research why does it matter? Dr Brad Sutherland Radcliffe Department of Medicine Wednesday 23 September 2015

2 1660 s Oxford

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5 Sobering stroke statistics 85% of all strokes ischaemic, 15% haemorrhagic 5 th largest cause of death and leading cause of disability in the UK ~152,000 people suffer a stroke in the UK per annum Of these, 1/3 die Costs the UK economy > 7billion per year National Stroke Strategy allows rapid screening for rtpa treatment But costs the UK 2/citizen/year Only 11.6% of patients have access to rtpa treatment (due to timing and geography)

6 Aim is to salvage penumbra

7 Infarct core expands with time

8 Endovascular action of tpa tpa Plasmin Plasminogen rtpa only FDA approved treatment for acute ischaemic stroke within 4.5 hours 3-8% incidence of haemorrhagic transformation ~40% clots not recanalise Fibrin FDPs 10-15% of all ischaemic stroke patients eligible for treatment

9 Infarct core expansion prevented with treatment

10 Benefit of rtpa gone by 5h post-stroke Number-neededto-treat for benefit with rtpa 3.6 before 90mins 5.9 at 3h-4.5h Emberson et al., Lancet 2014

11 Patient stratification Use scoring systems with CT/MRI scans to assess degree of stroke damage and likeliness of haemorrhage Reduce the risk of adverse effects Maximise benefit Diffusion Penumbra

12 Ischaemic cascade Sutherland et al Int J Stroke

13 Failure of neuroprotection

14 Translational problems? Animal models Human population Highly controlled, homogeneous population Younger animals Limited comorbidities Induced onset of stroke Ischaemic territory usually MCA Controlled occlusion duration & severity Wide scope for dose optimisation Infarct volume as predominant outcome Variable, heterogeneous population Older patients Numerous comorbidities Spontaneous onset of stroke Ischaemic territory variable Variable occlusion duration & severity Reduced scope for dose optimisation Function as predominant outcome

15 Blood flow is depleted during ischaemia Blood flow measurements on the surface of the brain Pre-MCAO During MCAO MRI measurements of whole brain Z-Score

16 Endovascular thrombectomy Sutherland et al., JCBFM 2015 In Press Balami et al., Int J Stroke 2015

17 Implementing endovascular thrombectomy Requires substantial investment into infrastructure Training of interventional radiologists Upgrading catheter-lab facilities This may increase the National Stroke Strategy cost to 4 / citizen / year

18 Stroke Research in Oxford Stroke Prevention Research Unit (led by Prof Peter Rothwell) Acute Stroke Programme (led by Prof Alastair Buchan)

19 Founded in 2000 Increase the understanding of cerebrovascular disease and improve the prevention of stroke Oxford Vascular Study (OXVASC) Population-based study of all acute vascular events (e.g. TIA, stroke) in a population of nearly 100,000 people in Oxfordshire Clinical, imaging and blood data Oxford Vascular Cognitive Impairment Cohort (OXVIC) Focus on cognitive function in vascular disease Oxford Plaque Project (OPP) Clinical and plaque data following carotid endarterectomy

20 Phase 1 = slow fax referral to TIA clinic for treatment Phase 2 = quick immediate referral to TIA clinic for treatment Rothwell et al 2007 Lancet Treatment with aspirin and/or antiplatelet therapy can reduce the risk of recurrent stroke Investigation of biomarkers of TIA or large artery stroke Investigation of the genetic basis of stroke

21 Acute Stroke Programme Founded in 2005 Understand the key mechanisms contributing to brain cell death following stroke and attempting to prevent this Pre-clinical development of novel drug targets and therapies for ischaemic stroke Clinical development of penumbra assessment and patient stratification

22 Hamartin as a target ATP DNA damage Hypoxia Growth factors AMPK REDD1 PI3K TSC1 Hamartin TSC2 Tuberin ATG/LC3 Autophagy S6K mtor Protein synthesis Cell proliferation Cytoskeleton Hamartin/mTOR pathway Papadakis et al 2013 Nat Med

23 Pericytes are a target O Farrell & Attwell 2014 Nat Rev Cardiol Hall et al 2014 Nature

24 Purpose-designed Clinical Research Centre embedded in an NHS-hospital environment Has a fully-equipped interventional angiography suite, functionally conjoined to a 3T MRI scanner by a mechanised rapid transfer system.

25 ph-weighted Brain Imaging Harston et al 2015 Brain

26 Conclusions Stroke is a big and costly problem Exciting new therapies but Only a minority of patients eligible Costly Stroke research in Oxford at the forefront for determining Prevention strategies Treatment strategies Patient selection for treatment