Quick Project Snapshot

Post-Stroke Longitudinal Imaging & Behavioural Change in Rodent Models

Background:

  • Dementia and cognitive impairment are becoming increasingly recognised as major complications occurring in patients post-stroke and are associated with higher rates of mortality, institutionalisation and greater healthcare costs.
  • This project, which forms part of a larger collaboration between leading Florey neuroscientists and clinicians, aims to characterise the trajectory and mechanisms of post-stroke cognitive dysfunction
  • Using rodent models of the stroke, and cutting edge technologies, our goal is to develop new therapies for this devastating that will improve quality of life in stroke survivors.

Aims:

In post-stroke animal models:

  • Examine the trajectory of cognitive dysfunction and corresponding changes in brain volume occurring in rodents subjected to stroke.
  • Quantify protein accumulation occurring at sites of remote volume change post-stroke

Methods: 

We will employ two complementary approaches to model ischaemic stroke in rats and mice (Jackman Meth Mol Biol, 2010). In C57Bl/6 mice, transient occlusion of the proximal MCA (MCAO) will be induced using the intraluminal filament technique, while the endothelin-1 (ET-1) model of stroke will be used in Wistar rats to induce localised lesions in specific regions of the brain. The degree of acute cerebral infarction, as well as progressive changes in regional brain volume and the development of selective neuronal degeneration in remote brain regions will be evaluated using MRI at various time points up to twelve months post-stroke. Immunohistological techniques will also be employed to assess selective neuronal degeneration in more depth, as well as the spatiotemporal profile of various dementia-related proteins (e.g. Tau, TDP-43). To assess cognitive function post-stroke, both rats and mice subjected to experimental stroke will be assessed using the rodent touchscreen cognitive assays (Bussey et al., Neuropharmacology, 2012; Nithianantharajah et al., Nat Neurosci, 2013) – a recently developed innovative method for modelling complex higher order cognitive functions in rodent models.

Progress:

  • Middle cerebral artery occlusion (MCAO) stroke surgeries in mice, including MRI scans commenced July 2016.
  • Focal cortical endothelin-1 (ET-1) stroke surgery in rats and MRI scans will commence in early November 2016.
  • Evaluation of post-stroke cognitive deficits using touchscreen technology will commence in October 2016.

Vascular Neurodegeneration Research Laboratory

In 2016, Associate Professor Amy Brodtmann and co-investigators were awarded a Dementia Research Team Grant (DRTG).  The NHMRC offered this $6.5 million grant to only a select few exceptional teams undertaking dementia research, with the aim to provide support in undertaking high quality dementia research over a five year period.  The grants were designed to promote the effective collaboration of research spanning from discovery research through to clinical treatment trials.

As a clinical stroke and cognitive neurologist with a PhD in cognitive neuroscience, Associate Professor Brodtmann founded her career on merging these two areas of expertise. Her interest is exploring the mechanisms by which vascular risk factors and brain ischemia drive and determine neurodegeneration and cognitive decline All late-onset dementia syndromes, especially Alzheimer’s disease (AD), are driven or exacerbated by vascular brain burden. In this series of connected projects we ask, not whether, but how does vascular burden and injury cause dementia and neurodegeneration?  With the financial support of the DRTG grant, Associate Professor Brodtmann and her team of international leaders in their fields aim to identify these mechanisms, with a view to prevent late-life cognitive decline via targeted risk management, as well as the development of treatments to prevent dementia.  Dr Emilio Werden, a research neuropsychologist, is the Project Manager and oversees the operational aspects of projects conducted under the DRTG.

As CIA of the project, Associate Professor Brodtmann formed a multidisciplinary team of world-leading researchers,  including Professor Charles DeCarli of University of California Davis, a world leader in vascular dementia and expert in translating research into clinical settings and public policy, Professor Vladimir Hachinski, arguably the world’s leading expert on vascular dementia, Professor John McNeil, an Australian luminary in translational research and Public Health, Professor Geoffrey Donnan, Director of The Florey institute of Neuroscience and Mental Health and a pioneer in stroke research, Professor Louise Burrell, Professor Martin Dichgans, Professor Leonid Churilov, Associate Professor David Darby, Dr Toby Cumming, Dr Marco Duering, Dr Katherine Jackman, Dr Jess Nithianantharajah, and Dr Lachlan Thompson.  Working with these, and other local and international, collaborators on the project, Associate Professor Brodtmann has several studies currently in progress. 

One of the keystone projects is the Cognition And Neocortical Volume After Stroke (CANVAS) Study, originally started in 2011 with funding from the Brain Foundation.   The DRTG has enabled the project to continue on to five years. 

In another exciting study, the Diabetes and Dementia (D2) team intensively documents the cardiovascular status of patients with T2DM.  Participants are recruited with T2DM, upon which we integrate transthoracic echocardiography, neuroimaging, circulating and genetic biomarkers and neuropsychology tools to establish the relationship between T2DM and brain atrophy and cognitive decline in a cohort of 168 individuals with and without LVH.   Baseline testing includes structural neuroimaging with MRI to assess global brain volume, regional cortical thickness and hippocampal volume, an echocardiogram to assess the absence or presence of LVH, a carotid ultrasound to assess vascular disease, 24-hour ambulatory blood pressure and ECG monitoring, cognitive assessment, and APOE gene risk assessment. After the baseline evaluation, a follow-up assessment will be repeated at the 24-month interval.

All Projects by this Lab

Diabetes and Dementia (D2)Post-Stroke Longitudinal Imaging & Behavioural Change in Rodent ModelsCognition And Neocortical Volume After Stroke (CANVAS)

Behavioural Neuroscience

The Division of Behavioural Neuroscience focuses on the use and development of models that reflect aspects of human disorders such as addiction, anxiety, depression, schizophrenia, autism and neurodegenerative conditions such as Huntington’s disease. The Cognitive Neuroscience group additionally studies cognitive disorders caused by diseases such as stroke (cerebrovascular disease), Alzheimer's disease and other dementias from a clinical perspective.

All Labs that operate in this Division

Addiction Neuroscience LaboratoryClinical Cognitive Neuroscience LaboratoryDevelopmental Psychobiology LaboratoryEpigenetics and Neural Plasticity LaboratoryGenes Environment and Behaviour LaboratoryInhalant Addiction LaboratoryMidbrain Dopamine Plasticity LaboratorySynapse Biology and Cognition LaboratoryVascular Neurodegeneration Research Laboratory