Translation in Stroke Research

Translation in Stroke Research

The Translational Research in Stroke laboratory is part of the Centre for Translational Neuroscience and Mental Health (CTNMH). We have a current strong focus in stroke neuroprotection, imaging and basic pathophysiology. We have active collaborations with several members of our own school, other schools within the University, with the clinical stroke research team based at the John Hunter Hospital.

Projects

Elevation of intracranial pressure (ICP) resulting in further neurological injury is a significant problem RAT MIDDLE CEREBRAL ARTERY THREAD-OCCLUSION STROKE MODELin stroke, and other forms of brain injury. Current therapies are often inadequate to control elevated ICP. Therapeutic hypothermia is the only non-perfusion neuroprotective therapy with proven benefit in human brain ischaemia (post cardiac arrest), and also lowers ICP. Clinical studies in a range of conditions have all used 12-24 hours or longer of hypothermia, and often encounter problems of rebound elevation of ICP during rewarming. However, recent experimental data from our laboratory demonstrated a dramatic benefit of 2.5 hours of mild-moderate hypothermia (32.5 0C) on ICP 24 hours later, with no evidence of rebound ICP elevation.

This project provides a unique opportunity to advance fundamental knowledge regarding regulation of intracranial pressure in neurological disease, and has the potential to revolutionise, simplify and extend the application of therapeutic hypothermia to treat a wider range of neurological diseases.

The major cerebral arteries are linked by small bypass channels over the surface of the brain (termed leptomenigeal collaterals). Patients with adequate collateral blood supply during stroke have smaller strokes and a higher rate of reperfusion with tissue plasminogen activator (tPA) leading to improved outcome. Despite convincing evidence of the benefit of good collaterals on stroke outcome there has been minimal investigation into interventions that improve collateral status. This experimental study will utilise our laboratories middle cerebral artery thread occlusion model combined with cerebral blood flow measurements to trial new therapeutics that enhance collateral flow and correlate this with perfusion of the ischaemic brain.

Stroke is a leading cause of morbidity and mortality worldwide. Although there have been major advances in the treatment of acute stroke, the most effective treatment when administered - dissolving blood clots with tissue plasminogen activator (tPA) - only dissolves half of the major clot blockages it targets. The use of enhancers for dissolving clot is now being explored and preliminary evidence suggests that standard ultrasound used to image the brain may significantly increase the effectiveness of tPA. This experimental study will use our laboratory's unique ability to measure brain blood flow in experimental stroke and test combinations of tPA and ultrasound for their potential impact on stroke recovery.

By the analysis of stroke patients and an animal model of stroke, this project will use proteomics to (i) identify novel biomarkers for the prognosis of hypothermia and re-warming response in stroke, and (ii) identify proteins involved in the molecular response to hypothermia and re-warming after a stroke.

This collaborative research effort involving both clinical and basic science researchers in Newcastle, Australia, and Harbin, China, will lead to the development of a clinically useful diagnostic for hypothermia outcome, as well as improve our understanding of the underlying mechanism of hypothermia-induced neuroprotection, leading to potential novel therapeutic targets.

Computed tomography perfusion (CTP) imaging is a relatively novel technique with huge potential to improve diagnosis and treatment in acute stroke patients worldwide. It uses widely available CT scanners, with imaging of tissue perfusion immediately following a bolus injection of an X-Ray visible dye into the veins (bolus tracking method). Recent major advances in scanner speed and coverage and perfusion imaging software have enabled development of this method. However, there are many unanswered questions regarding the tissue correlates of imaging findings, which can only be answered in animal models. Our pilot studies have determined that our rat stroke model is suitable for CTP imaging (McLeod et al. 2011).

Our aim is to correlate CTP imaging findings with the degree of subsequent tissue injury, assessed with histological methods. Findings from our future studies have the potential to improve the diagnosis and treatment of stroke patients and enable the development of targeted drug therapies to salvage threatened brain tissue, leading to improved patient health outcomes. Proof of principle of 'penumbral selection' of an enriched population of thrombolysis responders comes from the recent clinical trial of tenecteplase from our affiliated clinical research group (Parsons et al. 2012).

APPLICATION OF CBF INFARCT CORE AND PENUMBRA THRESHOLDS TO A PERMANENT MCAO ANIMAL OVER TIME.

Raised intracranial pressure (ICP) is a serious complication of ischaemic stroke, known to occur in both rats and humans. Recent studies in our laboratory have shown that ICP increases following mild-moderate stroke in an animal model. Increase in intracranial volume will cause an increase in pressure within the cranial compartment resulting from increased volume of one of the intracranial components (brain/oedema, blood or CSF).

Cerebrospinal fluid (CSF) aqueduct volume and flow were investigated using a novel contrast-enhanced CT scanning method to quantify changes in CSF production following ischaemic stroke and determine whether this is a possible contributor to the observed ICP elevation.

CONTRAST-ENHANCED CT IMAGES OF RAT CSF SYSTEM

CaMKII is an important regulatory molecule in the brain, where it plays an essential role in certain forms of learning and memory and in the appropriate development and maturation of neural pathways.  It also undergoes specific changes in animal models of brain ischaemia (local deficiency in blood supply) and epilepsy. 

Recent evidence has shown that in nerve cells, the regulation and role of CaMKII is more complicated than previously thought, and that it differs in brain regions that exhibit differing sensitivities to stroke. 

This project investigates the roles of a new control mechanism in regulating the function of CaMKII in nerve cells.  This will provide a more complete understanding of how CaMKII influences brain function and allow assessment of whether CaMKII regulation might be a suitable target for drugs aimed at protecting against the damaging effects of brain injury following stroke or heart attack.

STROKE PATIENTS IN AN ENVIRONMENTALLY ENRICHED SETTING.Stroke is the leading cause of adult disability in Australia. What are clearly needed are better stroke recovery therapies to aid in rehabilitation after stroke. Increased activity is the basis of all proven recovery therapies, but most are therapist-driven and prohibitively expensive.

Environmental enrichment (EE) consists of modifying the environment by provision of facilities and equipment to stimulate physical, social and cognitive activity. It shows great promise as a low-cost means to increase activity outside therapy times.

ENVIRONMENTALLY ENRICHED RAT CAGE.Indeed, there is strong experimental data showing better functional recovery, coupled with clear evidence of neurobiological effects (Janssen et al. 2010). Interestingly, the different components used in EE (physical, social and cognitive) appear to result in some quite distinct neurobiological effects. However, essential gaps in our knowledge of EE remain and addressing these gaps will be essential to optimise EE for stroke patients.

Lab Members and Affiliates

Lab members:
Dr Neil Spratt - Senior Lecturer, Senior Staff Specialist Neurology
Dr Damian McLeod - Postdoctoral Researcher
Miss Debbie-Gai Pepperall - Research Assistant
Ms Lucy Murtha - PhD Student
Mr Daniel Beard - PhD Student
Ms Amelia Tomkins - PhD Student
Affiliated Researchers:
Mrs Heidi Janssen - Clinical PhD Student
Prof. Chris Levi - Neurologist HNELHD, School of Medicine and Public Health
Ms Di Marsden - Clinical PhD Student
A/Prof. Mark Parsons - Neurologist HNELHD, School of Medicine and Public Health
Prof. Michael Nilsson - HMRI Director
Prof. John Rostas - Medical Biochemistry
Dr Rohan Walker - Brain Repair and Rehabilitation
Prof Robin Callister - Human Physiology Laboratory
Dr Mark Baker - Proteomics, School of Life Sciences
Dr Nikki Verrils - Medical Biochemistry
Dr Kathryn Skelding - Medical Biochemistry
Mrs Janine Johnston - Brain and Mental Health

For more information contact:
Dr Neil Spratt - Senior Lecturer, Senior Staff Specialist Neurology