Stroke

Stroke-Group copy

Group Members
Neil Spratt – Group Leader
Damian McLeod – Postdoctoral Researcher
Debbie-Gai Pepperall – Research Assistant
Amelia Tomkins – PhD Student
Lucy Murtha – PhD Student
Daniel Beard – PhD Student
Rebecca Hood – PhD Student
Caitlin Logan – PhD Student
Kirby Warren- Honours Student
Mr Naseer Abdul – B. Med. Sci. Student

Research Focus
The Translational Research in Stroke laboratory have a current strong focus on stroke pathophysiology, imaging and in the regulation of intracranial pressure and cerebrospinal fluid production and drainage after neurological injury. 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 (of which Dr Spratt is a member), and with national and international researchers.

Projects

1. Short duration hypothermia to prevent subsequent intracranial pressure rise
Elevation of intracranial pressure (ICP) resulting in further neurological injury is a significant problem in stroke, and other forms of brain injury. Our recent data suggests that dramatic but transient (4-6 hours) ICP elevation may occur after even minor stroke. Experimental studies with collaborators in Glasgow (Prof. Mhairi MacRae and team) using in vivo MRI and other techniques indicate that this ICP rise is not related to oedema, which peaks later post-stroke. 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 studies from our laboratory demonstrated a dramatic benefit of 2.5 hours of mild-moderate hypothermia (32.5 or 35.0°C) on ICP 24 hours later, with no evidence of rebound ICP elevation. Interestingly, the ICP rise. 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.
2. Increasing perfusion to the ischaemic brain via leptomeningial collaterals
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 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. Our group have recently developed a technique to accurately quantify blood flow through collateral vessels in experimental stroke, and have used this to show the dramatic changes in collateral flow during occlusion and reperfusion of the middle cerebral artery. Recent studies also indicate that intracranial pressure is a powerful regulator of blood flow through collateral vessels.
3. Testing stroke sonothrombolysis using an improved experimental model of thromboembolic stroke
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.
4. The China-Australia Therapeutic Hypothermia in Stroke (CATHS) research program
By the analysis of stroke patients and an animal model of stroke, this project will use mass spectrometry to (i) identify novel biomarkers for the prognosis of hypothermia and re-warming response in stroke, particularly regarding our recently identified role for hypothermia in the prevention of intracranial pressure elevation, and (ii) identify the molecules involved in this response. 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.
5. CT imaging of cerebrospinal fluid (CSF) flow in rats
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.
6. Functional characterisation of a new regulatory for CAMKII at synapses
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.
7. The use of enriched environment post stroke: translation from bench to bedside
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. Indeed, there is strong experimental data showing better functional recovery, coupled with clear evidence of neurobiological effects (Janssen et al. 2010). A recently completed pilot clinical study by members of the affiliated clinical research team has shown that comprehensive environmental enrichment analogous to that used in experimental stroke (but using stimuli appropriate to humans) results in significantly greater activity of stroke patients in a rehabilitation ward. In collaboration with the Florey Neurosciences Institute (A. Prof. J. Bernhardt), Dr Heidi Janssen and Dr Spratt are currently conducting a phase II multicentre trial of enriched environment, enrolling 208 patients in 4 rehabilitation hospitals in NSW and Victoria.
8. FiTIST – Fitness Training in Stroke Trial
With Prof. Robin Callister and PhD students Di Marsden and Ashlee Dunn we are studying fitness training in stroke survivors. Cardiovascular fitness and regular exercise prevent stroke and improve wellbeing. In survivors of heart attack, promotion of cardiovascular fitness is a key goal of cardiac rehabilitation. Despite the shared pathophysiology and risk factors, fitness has largely been neglected in stroke patients, with rehabilitation focussed on functional tasks. However fatigue may be function-limiting in many stroke patients and improving cardiovascular fitness may not only reduce risk of another stroke (or of heart attack) but also improve the ability to function in the community. We have already found that fitness is largely leg fatigue limited in stroke survivors (rather than limited by breathlessness), however using a program of interval circuit training stroke patients can achieve excellent duration and intensity of cardiovascular fitness training. We are currently completing data collection on the effectiveness of a community-based fitness training program to promote cardiovascular fitness.

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