Divisions
Division
of Clinical Trials
Headed by Professor Geoffrey Donnan
The clinical trials divisioncontinues to expand with about
thirty trials being conducted at any one time. These
consist of investigator initiated studies as well as those
initiated by commercial interests. Investigator driven
trials such as ARCH in which patients in whom the
mechanism of ischaemic TIA or stroke is most likely due
to the presence of aortic arch atheroma are randomised
to receive either combination antiplatelet therapy or the
more traditional anticoagulant, warfarin. This continues
both here in Australia, France and new centres will be
opened in the UK, Switzerland and Portugal.
Our other main interest continues to be in acute stroke
therapy (neuroprotection and thrombolysis) as well as
secondary prevention. As part of our approach to the
former, the neuroimaging modalities are increasingly
being used (particularly MRI) to provide important “proof
of concept” information before embarking upon larger
clinical trials. The phase II MR based trial, EPITHET, cochaired
by Professor Stephen Davis and Geoffrey Donnan
has been completed and a new trial with MR based
imaging selection criteria is being planned (EXTEND).
Our other major focus is the A Very Early
Rehabilitation Trial (AVERT) wwhich is now in Phase III.
In this innovative study, the hypothesis that earlier
and more intensive mobilisation of stroke patients will
improve outcomes is being tested. In addition, the
cost effectiveness of the intervention will be
established. Associate Professor Julie Bernhardt is
Director of the Very Early Rehabilitation Research
Program and Associate Professor Helen Dewey leads
the cost effectiveness evaluation. In 2007, over 200
patients were recruited to the study from 11
Australian hospitals. We continue to expand the
number of participating sites and expect to have over
20 hospitals, including some international sites, by the
end of 2008. At completion, this trial will be the
world’s largest trial of early rehabilitation.
In the secondary prevention field, a large number of
studies are continuing to be conducted using
antiplatelet agents and anticoagulants as well as
agents designed to reduce the risk of surgical
procedures such as carotid endarterectomy. The latter
trial, Dextran in Carotid Endarterectomy (DICE) is one
of the largest of its type ever conducted and is now
nearing completion.
Any clinical trial is highly dependent upon collaborative
links with a large number of centres both within
Australia and internationally. In this regard, we are
particularly fortunate in having the Australian Stroke
Trials Network (ASTN) and well established international
linkages. A further initiative is the formation of
Neuroscience Trials Australia (NTA) which I co-chair
with my colleague Professor Stephen Davis at the
Royal Melbourne Hospital. Here, a series of nodes from
almost every neuroscience group (such as stroke,
epilepsy, migraine, movement disorders etc) form a
single organisation to attract more trials to Australia as
well as providing support for investigator driven
studies. The NTA Manager, Dr. Peter Keller, has already
been successful in attracting new initiatives on to the
Australian scene, an excellent sign for the future.
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Division
of Epidemiology
Headed by A/Prof Helen Dewey
The year of 2007 was one of major change within the
Epidemiology Division at NSRI. Dr Mandy Thrift,
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Associate Professor Helen Dewey
Epidemiology
previous Head of the Division, relocated to the Baker
Heart Research Institute and A/Professor Helen Dewey
assumed the role of Acting Head. The immense
contribution of Dr Thrift to the growth and
development of the NSRI during her 12 years of
association is gratefully acknowledged. Her leadership
within the Epidemiology Division has been pivotal to
the success of the world-renowned North East
Melbourne Stroke Incidence Study (NEMESIS) and she
will be sorely missed by her colleagues at NSRI.
The focus of the Epidemiology Division continues to
be on the impact of stroke on patients. In an ongoing
collaboration with Dr Thrift at the Baker Heart
Research Institute, long-term follow up of the more
than 1600 stroke patients recruited in the NEMESIS
has continued. During 2007, follow-up interviews
were completed with stroke patients surviving 7-10
years after stroke. These interviews assessed patient
disability status, management of risk factors for
stroke, quality of life and level of handicap as well as
determining whether or not patients had suffered
recurrent stroke. To date in this very large study,
more than 70% of the original cohort has died. The
cause of death has been determined in the majority
of these patients, with a few still to be investigated.
In work completed by Dominique Cadilhac as part of her
PhD thesis, new estimates of the long-term costs and
burden of stroke in Australia have been made, using
patient level data obtained from the NEMESIS cohort.
Economic modeling was used to estimate the costs and
burden associated with stroke in Australia. The presentvalue
of total costs of ischaemic and haemorrhagic
stroke in Australia was over $2 billion dollars.
In a separate study designed to investigate the
responses of patients, family members, other
bystanders and the Melbourne Metropolitan
Ambulance Service to the symptoms and signs of
stroke, a total of 198 patients with stroke and TIA
were included. This work, completed by Ian Mosley
as a PhD project, has yielded some interesting
findings. Patients with knowledge of two or more
stroke symptoms were more likely to recognise stroke
when it occurred. However, the effects of the stroke
appeared to severely limit the ability of patients to
rapidly seek ambulance care. Only 1% of the patient
group recognised their symptoms as due to stroke
and, because of this recognition, went on to call for
an ambulance. This finding indicates that the onus
for rapid response to stroke symptoms must rest
with family members and other bystanders who
witness stroke symptoms and signs. In addition,
consultation with a general practitioner prior to
a call for ambulance assistance resulted in
considerable delay in arrival to hospital. Clearly, the
best response for people who experience or observe
stroke symptoms in others is to call an ambulance.
Dr Wen Wen Zhang commenced her PhD project
within the Epidemiology Division during 2007. Her
research will focus on 24 hour blood pressure
patterns after TIA and stroke in a post-acute
ambulatory setting, the incidence of autonomic
dysfunction among stroke and TIA patients and the
relationship between blood pressure patterns and
subtype and topography of stroke.
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Division
of Ultrasound
Headed by A/Professor Brian Chambers
The current focus is investigating the clinical
significance of a newly appreciated ultrasound sign,
referred to as “small vessel knock”. The NSRI is
collaborating with Compumedics DWL, a Melbourne based
transcranial Doppler ultrasound company, to
determine whether knock is useful in the diagnosis of
stroke. Compumedics sponsored a visit from Dr Paul
Syme, a Scottish physician who discovered knock, to
describe his research and train our sonographers. Dr
Chesda Udommongkol, a stroke research fellow from
Bangkok, has commenced his PhD study of knock, due
for completion in 2008.
Dr Syme has a series of stroke patients with knock, in
whom continuous insonation of the point where
knock was observed, has resulted in disappearance of
knock and improved clinical outcome. If our studies
validate small vessel knock as a useful sign, the next
phase will be to investigate the therapeutic potential
of continuous insonation of knock, a novel treatment
for stroke with exciting potential.
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Division
of Neuroimaging
Headed by Professor Geoffrey Donnan
The ischaemic penumbra continues to be an
important focus of our research. This is brain tissue
which, while damaged, continues to live after the
onset of the stroke process. The duration of this is
uncertain in humans although we now have the
ability to create images of its behaviour using
positron emission tomography (PET) and magnetic
resonance imaging (MRI).
Using PET, the Institute has pioneered the use of
18F-Fluromisonidazole, a hypoxic marker which has
been particularly useful in providing a direct image
of the ischaemic penumbra. This approach to
imaging the penumbra is now being taken up by a
number of other centres around the world. The PET
technique is also being used to develop new
compounds which may be of use in imaging various
neurochemical processes which occur within the
ischaemic penumbra. Much of this work is going on
in collaboration with our basic science division.
We have developed several new initiatives using
positron emission tomography (PET). One of these is
to use the ligand PK-11195 as a marker of
inflammation post-ischaemic stroke. There is intense
interest in this area but great uncertainty about its
influence on stroke outcome. This project is being led
by Dr. Jorge Zavala. The second PET initiative involves
the use of the radio-ligand C11-PIB which binds to
amyloid plaque, the main pathological change in
Alzheimer’s disease. There is considerable evidence
that this pathological change may predispose to
intracerebral haemorrhage and the cognitive change
seen after stroke. Dr. John Ly is leading this
investigation to test as to whether these ideas are
supported in clinical cases of stroke.
MRI is also proving to be an extremely useful tool. Not
only in helping us understand the dynamics of the
ischaemic penumbra better but providing a “surrogate”
marker in some of our early clinical trials. By using MR
images of the penumbra (diffusion weighted imaging and
perfusion weighted imaging mismatch) smaller numbers
of subjects are required to determine the potential
efficacy of new compounds which may help minimise the
damage from stroke. Other studies to determine the
duration and nature of the ischaemic penumbra continue
using MR as the primary imaging tool. Dr Henry Ma leads
this aspect of penumbral research.
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Division
of Public Health
Headed by Dominique
Cadilhac
The research activities of the Public Health Division for 2007 have included a range of projects related
to clinical management of stroke and improved
disease prevention.
Stroke care in acute public hospitals
Ongoing audit of hospitals in both metropolitan and
rural New South Wales have continued. The use of time
series auditing has demonstrated important changes in
clinical practice associated with investment in stroke
services in NSW. Furthermore, audit reports provided for
individual hospitals have informed clinical teams of areas
to focus further clinical practice improvement activities.
National Stroke Audit
The Public Health team have been involved in the
development and data analysis of the National Stroke
Audit undertaken this year by the National Stroke
Foundation. This audit has resulted in two reports
that were launched in 2007. The National Stroke
Audit of Acute Hospitals will occur biannually.
Results of this audit are used to inform the planning
of better health service delivery in stroke.
Determining Differences in Stroke Unit Care:
Melbourne versus Trondheim
This project, being undertaken for a Master of
Physiotherapy, aims to examine in what way processes
of care differ between stroke units at Austin Health
and St Olavs Hospital in Trondheim, Norway (gold
standard care). The study design involves a mixed
methods approach. Quantitative data from
retrospective medical record audits of 50 consecutive
stroke patients per hospital will be used. This audit
tool includes newly developed early rehabilitation
process of care indicators. In addition, qualitative
information will be obtained from hospital staff
working in these units. Semi-structured interviews
with clinicians will be conducted to gain perceptions
on how the service is organised and the way in which
it operates. In turn, qualitative and audit data from
both countries will be analysed to determine how
stroke care delivery differs between the sites. Our
objective is to identify factors that might be associated
with better stroke outcomes, particularly in relation to
early rehabilitation practices. This information may be
used to help improve care in existing stroke units, or
inform the development of new stroke units.
Economic evaluation of blood pressure lowering
interventions for stroke
The project was completed as a PhD. The aims of this
study were to estimate the current cost-of-illness
and disease burden of ischaemic stroke and
intracerebral haemorrhage (ICH); and the costeffectiveness
of BP lowering interventions as a
prevention strategy for stroke in Australia. Existing
economic models for ischaemic stroke and ICH were
updated (from 1997 to 2004) and developed using
new long-term costs and outcome data. The
economic evaluation was an assessment of an
‘organised care’ system to improve the control of BP
for both primary and secondary prevention of stroke.
This entailed technical (cost-effectiveness) analysis
and use of a reference committee, for both the
selection of interventions and consideration of issues
related to implementation. The intervention was
incrementally assessed against current practice (the
usual care of high BP in Australia). A novel aspect of
this analysis was adapting the intervention to fit
within current general practice prevention policy
initiatives available in Australia.
National Blood Pressure Awareness Program
In 2007, the National Stroke Foundation ran the first
‘Blood Pressure Awareness Program’ for stroke. This
included over 100 community-based venues
conducting blood pressure measurements and
providing information packages about stroke and
blood pressure. Staff of the Public Health Division
contributed to the design of the program, as well as
the evaluation. A sample of participants will
complete a 3-month follow-up survey in 2008. All
data are being processed and analysed at the NSRI.
Chronic Disease Self-Management Program
This Divison has been involved in the design of a
Phase II, multicentred, single blind randomised
controlled trial of the ‘Stroke self-management
program’ versus standard care to be conducted in
South Australia. This study is being coordinated by
the National Stroke Foundation.
Policy advice and expert review
Input into various national and state based activities
related to reducing the burden of stroke has been
provided. In 2007, we contributed to clinical guidelines
including the updated Acute Stroke Clinical Guidelines
produced by the National Stroke Foundation and the
Evidenced-Based Practice Guidelines for the Assessment
Ms. Dominique Cadilhac
Public Health
14
3. Divisions
National Stroke Research Institute
15
Professor Leeanne Carey
Neurorehabilitation and Recovery
of Absolute Cardiovascular Disease Risk currently being
finalised as part of work undertaken by the National
Vascular Disease Prevention Alliance. In addition, a
special report “Tobacco use and Stroke: Estimates for
New South Wales” was produced for the Cancer
Institute of New South Wales, and the results used in
a media campaign about smoking cessation and stroke
during QUIT week.
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Division
of Neurorehabilitation and Recovery
Headed
by Professor Leeanne Carey
Novel insights into how the brain adapts with
recovery and experience, together with advances in
learning theory, provide a strong foundation for the
development of rehabilitation approaches that aim to
restore lost capacity and improve clinical outcome.
Within the division of Neurorehabilitation and
Recovery our aim is to conduct and disseminate
internationally-competitive research focussed on
investigation of the scientific foundations of
neurological rehabilitation post-stroke. In particular
our studies focus on the investigation of neural
processes underlying spontaneous and traininginduced
recovery, and effectiveness of approaches
to improving sensation and movement in the upper
limb post-stroke.
Researchers and clinicians from multiple disciplines,
including occupational therapy, physiotherapy,
neurospychology, neurology, physics and
experimental psychology are involved in the research.
Currently there are 5 research officers in the division
as well as 6 PhD, 2 Clinical doctorate, 2 masters and
1 honours students. We welcome Louise Bannister,
Kate Noonan and Rebecca Avery who have
commenced studies in 2007.
An important feature of our program is the collaborative
links with researchers and centres locally and
internationally, including the Brain Research Institute;
Faculty of Health Sciences and School of Psychological
Sciences, LaTrobe University; Howard Florey Institute;
The Oxford Centre for Enablement, UK; Center for
Advanced Imaging, West Virginia, USA; Neurology and
Neuroimaging, Düsseldorf University, Germany; and with
clinical centres in Australia including Austin Health,
Northern Health, Southern Health, Melbourne Health,
Barwon Health, Eastern Health and Donvale Hospital.
During 2007 Professor Seitz, a neurologist from
Germany visited as a Distinguished International
Fellow for 4 months. This provided a great
opportunity for intensive collaboration, discussion
with students, dissemination of results and
development of new projects. Prof Carey travelled
to Washington University in St. Louis to visit and
discuss collaborative opportunities with Prof Carolyn
Baum and the Cognitive Rehabilitation Research
Group. Finally Prof Carey was supported by the
James S. McDonnell Foundation to attend and chair
the rehabilitation section of a workshop on Touch,
Space and Body Awareness held in Boston, with the
outcome a textbook for clinicians on the Cognitive
Neuroscience of Rehabilitation.
Our current research projects span three major
research areas.
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Mechanisms of recovery: Investigations of neural
processes associated with spontaneous and traininginduced
recovery of touch sensation (Carey, Abbott,
Puce, Seitz), limb position sense (Ben-Shabat, Carey,
Matyas, Brodtmann) and movement (Carey, Abbott,
Jackson, Egan, Donnan) are being conducted using
functional imaging studies of the brain. Identification
of brain regions correlated with good recovery at
different times in the recovery process (1 and 6
months post-stroke) provides direction for the
development of new therapies (Carey et al, 2005).
New evidence of reemergence of activation in
sensory regions associated with good recovery and
specific sensory retraining strengthens the
neuroscientific foundations of rehabilitation (Carey
& -Seitz, 2007).
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Restorative approaches to rehabilitation: The
effectiveness of training sensation in the hand after
stroke is being conducted using a randomised
controlled trial (Carey, Matyas, Macdonell, Wade).
We have completed recruitment to the study, with
some positive outcomes from our preliminary
analyses. Both task specific and generalisation
enhanced approaches to training have been
developed and tested in order to maximise outcome.
Influence of touch sensation and its retraining on
finger grip after stroke (Carey, Matyas) and use of
botulinum toxin and modified constraint induced
movement therapy in the treatment of the upper
limb in children with spastic hemiplegic cerebral
palsy (Hoare, Imms, Carey) are also being
investigated.
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Nature of impairment and impact on function: Our
group is also involved in development of quantitative
measures of sensation in the upper limb after stroke.
This has included: the Tactile Discrimination Test
(Carey, Oke, Matyas); Wrist Position Sense Test (Carey,
Matyas, Oke); Functional Tactile Object Recognition
Test (Carey, LeBlanc, Harvey, Nankervis) and
Multijoint Limb Position Sense Test (Carey, Ben-
Shabat, Eickmeyer, Goh). Congratulations to Jannette
Blennerhassett who has successfully completed her
PhD on the relationship between touch sensation,
motor function and pinch grip after stroke. These
findings (Blennerhassett, Matyas, Carey) have
advanced our understanding of the nature of
impairment after stroke and will inform therapy.
The Melbourne Assessment of Unilateral Upper Limb
Function, developed for children with neurological
impairment, is also being modified and tested for its
validity (Randall, Imms, Carey).
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Division
of Basic Science
Headed by Associate Professor David Howells
We have expanded our analysis of the literature
supporting a role for neuroprotection as a treatment for
stroke. This work (conducted in collaboration with
Malcolm McLeod, Emily Sena, Jenifer Lees and Philip
Bath in the UK) has identified a significant impact of
bias in the animal literature that has led to an overestimation
of the efficacy of many drugs. Failures of
randomisation and blinding have the greatest impact
while publication bias has a modest effect. It is also clear
that, with the exception of tPA, there has been a
systematic failure to conduct human trials within the
time window that works in animals. These factors very
likely explain the failure to successfully introduce such
drugs into the clinic.
In addition to identifying where things may be going
wrong in the conduct of stroke research this analysis
also allows us to generate hypotheses to test in the lab.
For example, from Victoria O’Collins landmark review of
the animal neuroprotection data (Annals of Neurology
2006; 59: 467-477) indicated that a combined treatment
with Magnesium, Melatonin and Minocyclin to target
the processes of excitotoxicity, oxidative stress and
inflammation might provide an effective therapy that
was not constrained by intellectual property issues.
However when it was tested with statistical rigour in the
lab the combination was found to have no discernable
effect in young or old animals with hypertension, the
co-morbidity most common in stroke patients. By
contrast, hypothermia which gave the most robust
effect in all of our meta-analyses did prove highly
effective when tested with appropriate statistical power
in hypertensive rats with moderate sized strokes but was
less effective in rats with larger strokes.
A highly topical analysis conducted in collaboration with
Malcolm McLeod (UK) and Simon Koblar (Adelaide) has
started to define the limits of efficacy of stem cell based
therapies for stroke (as well as spinal cord injury and
traumatic brain injury) and strongly suggests that their
strength may lie in promotion of long term plasticity
and reorganisation of the brain rather than acute effects
on infarct volume. As a consequence we are conducting
an extensive review of the data on promotion of
regeneration and rehabilitation in animal models of
stroke with the assistance of our local experts (Julie
Bernhardt and Leeanne Cary) and Neil Spratt (recently
returned to Newcastle, NSW) and our collaborators in
Edinburgh and Gothenburg.
In the past our laboratory has relied heavily on the
thread occlusion model of stroke. Since this model does
not permit a realistic assessment of the interaction
between neuroprotection and thrombolysis Sarah Rewell
(PhD Student) and Dr Michelle Porritt (Research Fellow)
have made extensive visits to the laboratories of Marc
Fisher and Eng Lo (Boston, USA) and Michael Nilsson
(Gothenburg, Sweden) to learn about autologous clot
and photo-thrombotic models of stroke induction which
have now been established in our laboratory. Emily Sena,
Sarah Rewell and Michelle Porritt are currently using the
autologous clot method to explore the interaction
between tPA based thrombolysis and hypothermia in
hypertensive rats.
A new avenue of research that has also started in
response to the failure of translation of effective animal
neuroprotectants into effective human drugs is the
establishment of a tissue culture screening program to
initially evaluate agents in cultures of human neurons
and glia derived from commercially available stem cell
preparations under conditions of hypoxia and glucose
deprivation and then to screen them for efficacy in
similarly stressed slice cultures of normal human cortex
obtained during the course of neurosurgery. At present
Ana Antonic (PhD student) is gaining experience with
animal cell lines before transferring the expertise to the
more costly human program. This work is inspired by the
observation that despite the similarities between the
genes expressed in rodents and man there are also many
differences. Since the size and complexity of our brains
appears to be our most characteristic feature as a
species of mammal these differences may have
significant consequences for our understanding of
3. Divisions
National Stroke Research Institute
Associate Professor David Howells
Basic Science
10
Professor Geoffrey Donnan
Clinical Trials & Neuroimaging
neuroprotection and brain repair.
With interesting new observations of increased binding
of the PET tracer PIB in the brains of people with stroke,
a laboratory program is being developed to determine
whether we can model and thus extend our
understanding of the role of this novel imaging agent
for stroke.
A major new collaboration started with CSIRO and
Monash University will focus on imaging and aging of
clots and atherosclerotic plagues, development of X-ray
phase contrast imaging modalities for high resolution
visualisation of blood vessels and blood flow and use of
ultrasound to enhance thrombolysis.
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Division
of Statistics and Decision Support
Headed by A/Prof Leonid Churilov
The objective of the Division of Statistics and
Decision Support within the NSRI is to provide
expertise in data, quantitative, and statistical aspects
of research projects carried out in the divisions of
the NSRI. An important source of that expertise is
our own research in a number of areas of modelling
methodology of relevance for promoting the use of
high-standard, rigorous quantitative methods to
support decision making in the disciplines making up
our institutional environment. Since advanced
statistical methodology is of little use for real
applications without the availability of appropriate
computational and modelling tools, adapting,
extending and validating complex statistical and
decision modelling software is another basic task for
our Division. The Division serves as a hub for
collaboration within Florey Neuroscience Institutes
and with other Australian and international research
institutions in the areas of statistical, data, and
decision modelling. The Division has responsibility for
the local data network (LAN) of the NSRI as a whole.
Click to the research section of the Statistics and Decision Support mini website.
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Neurosciences
Trials Australia (NTA)
Neuroscience Trials Australia (NTA) was established in 2001 as the clinical trials
platform of the National Neuroscience Facility (NNF), building on
the established goodwill and cooperation between Australian investigators
to develop a clinical trials network across the nation. The general
aims are to raise the profile of Australian clinical trial capabilities,
secure a larger share of the international clinical trials market,
and provide a range of services to the benefit of both industry and
researchers for sponsored clinical trials and local investigator driven
studies, respectively. NTA was established to assist the emerging
disease specific clinical trial interests groups in the neurosciences,
to provide support and services to formalise those networks and to
facilitate interactions with biotechnology and pharmaceutical sponsors
of clinical research. Not just enhancing the capabilities of the existing
trials networks, NTA has provided the impetus to establish, support,
and promote additional networks across disease specific interests
groups within the neurosciences, and has interacted with similar organisations
in other therapeutic areas.
Our
core business at NTA is to facilitate neuroscience clinical trials
for investigators and sponsors. We offer a range of clinical trial
support services and our collaborative structure provides us with
the ability to access target patient populations using state of the
art facilities across multiple centres. NTA is led by two co-platform
leaders, Professors Geoff Donnan and Stephen Davis, and managed by
a small administrative team based at the coordinating centres, the
NSRI and Department of Neurology Melbourne Health. Governance is provided
by a Platform Management Board made up of representatives of the nine
disease groups and a leading neuropharmacologist, Professor Frank
Vajda (Monash University). The disease groups are:
- The Dementias
- Epilepsy
- Migraine
- Movement Disorders
- Multiple Sclerosis
- Neuromuscular Disorders
- Neurosurgery
- Pain
- Stroke
NTA is ideally placed to play a key role in the translation of novel
and effective treatments and therapies into clinical practice with
resultant benefits in the health of all Australians. Ultimately, the
facilitation and expansion of investigator-driven and Australian-led
neuroscience trials of international importance will be the benchmark
of success for the network.
For further information, please see our web site www.neurotrialsaustralia.com
National Stroke Research Institute