2014 Summer brainwaves Newsletter

brainWAVESThe Newsletter of the Brain Foundation Summer 2014-2015

Contact the Brain FoundationPO Box 579, Crows Nest NSW 1585

Telephone: 02 9437 5967 or 1300 886 660 Fax: 02 9437 5978Email: [email protected]

Visit our websites brainfoundation.org.au and headacheaustralia.org.au

Brain Foundation announces Major Research Gift

Headache disorders are among the most common disorders of the nervous system throughout the world. They are under estimated, under recognised and their impact on the public health system and in society is not widely acknowledged.

Is it any wonder then, that when Headache Australia (a division of Brain Foundation) takes to the streets of Sydney, Brisbane and Melbourne we attract a lot of attention. Somehow it seems wrong to say that we had a successful week, when so many of the population suffer with this terrible group of conditions, but we certainly raised some awareness of the impact of this condition.

We had a Cefaly device on display and this has resulted in many people purchasing a device and finding some relief from it. We also had information about new apps for managing migraine. Still in the developmental

stage, we were able to recruit ‘testers’ from our Headache Register, and their input has been invaluable.

This year, we were supported by Allergan, Aspen, Hydralyte, MSD and Reckitt Benckiser.

Headache Awareness Week gets a lot of support from pharmacies around the country and if you would like to support this very important event, please contact our office for the 2015 dates and to go on a list for a support pack.

The Directors and Staff are proud to present the 2014 Research Gifts. As always, Brain Foundation funding is highly sought after, and we have many more applications than we are able to fund. Australia really is the home of some very innovative research ideas and it is an unenviable position to have to choose the finalists from the submissions.

Your generous contributions make these awards possible year after year. We thank you for your support and wish you all a very happy holiday season.

2014 Research Gift Edition

Headache Awareness Week – September 2014

Caroline raising awareness

The Board of the Brain Foundation this year announced, for the very first time, a major research gift to the value of $300,000 over three years.

This grant will be in addition to our current research program of which all the 2014 award winners are in this newsletter along with an outline of their research for you to read. Our scientific advisory committee has a very difficult and time consuming task in selecting the best candidates for all our awards and this special award, showcasing the high standard of neurological research in Australia, is no different.

We will be pleased to announce the recipient of the Major Award in the next edition of BrainWaves!

MORE THAN 4 MILLIONAUSTRALIANS ARE AFFECTEDBY MIGRAINE OR CHRONIC HEADACHE

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JOIN THE NATIONAL HEADACHE REGISTER

HEADACHE AND MIGRAINE WEEK

1300 886 660 headacheaustralia.org.au

Funding Research Increasing Awareness

Together we can make a difference

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Headache Australia is a division of the

Brain Foundation








www.hydralyte.com

Headache Australia is a division of the Brain Foundation








www.hydralyte.com

Headache Australia is a division of the Brain Foundation

2 The Newsletter of the Brain Foundation

If you would like to visit site please go to http://australiandystoniasupportgroup.wordpress.com

Organised by Hariklia Nguyen and Lisa McInnes - of the Australian Dystonia Support Group – the month was supported by a Dystonia Awareness website, video and facebook page, which some group members provided photos and stories for. The awareness website had information on Dystonia, updates and events, stories of several

sufferers and links to further information and support groups. Group members joined in and helped spread the word and raise awareness.

A fabulous success, there were approximately 870 visits to the awareness website and 750 visits on the Awareness Facebook page. Altogether posts on the Facebook

page reached 5,021 people. A big thank you to ADSG group members and the community for helping to spread more Dystonia awareness.

Following on from this success, there have been quite a few requests to keep it running. So in response, a website for the Australian Dystonia Support

Group (ADSG) has been created. It is a first point of call for anyone interested to know a little more about the group. The website is somewhere that friends, family and the community can be referred to and understand a little more about the support offered. Also this site will help raise more awareness in the community.

Dystonia NewsDYSTONIA: Muscles Behaving BadlyDystonia is a terrible condition which causes muscles to contract and spasm involuntarily. The cause of this condition is unknown. The Dystonia supporters group is very active in raising awareness of the condition and funds for research.

For further information about Dystonia please email Lee Pagan at [email protected]

Fabulous Fundraiser For DystoniaIn our 2013 summer issue of Brainwaves, we featured little Karter. Only a toddler, Karter suffers from Dystonia. His mother Katherine has been actively raising awareness and funds for the cause, and this year Rentokil Initial along with Karter’s father Ashley, went into action.

The company organised a number of events from baking competitions, morning teas and bbq’s as well as auctions of sports memorabilia. Rentokil matched every dollar raised by the staff and we are the very happy recipients of just under $20,000 which will go towards Dystonia research.

Read all about the 2014 Dystonia research project later in the newsletter.

Parkinson’s Australia –Movement Disorder Conference, Adelaide May 27 – 29, 2015

For anyone who may be interested in attending, there will be sessions relating to Dystonia at this conference for both medical practitioners and patients. Please email [email protected] or contact Parkinson’s SA.

Successful first’ DYSTONIA AWARENESS MONTH’ – September 2014

My battle with dystoniaThe following article was written by Dystonia sufferer, Suzanne Bayliss for ABC Open projects. It may help our readers understand what it is like living with Dystonia.

“You may hear drills, I’m not sure. Although not unconscious, you are heavily sedated as we cut through your skull” said the anaesthetist. Okay, the Deep Brian Stimulation Surgery Admission Pack stated this. It is also what the anaesthetist told me in yesterday’s consultation. Surgery is finally under way.

After 24 years living with dystonia, a rare incurable neurological movement disorder, there is hope. With muscles feeling like sailor’s knotted ropes twisting against the force of cyclonic seas, there were months of preparation before genetic testing cleared me for brain surgery. I do not have the troublesome gene preventing successful surgery.

This may end travelling from Cairns to Brisbane every three months for botulinum toxin (Botox) injections into many muscles; vocal chord muscles tightly spasmed together, making speech harsh and effortful; muscles twisting my head back and to the right; spasming muscles at the base of skull; eyelid muscles spasming eyes shut; muscles inshoulders and lower back twisting me with strong spasms; muscles

continues page 11

3Summer 2014-2015

DHE / Dihydroergotamine – Now available in BrisbaneThey say that if you want something done, you ask a busy person.

Well, if you want to get a drug that has been ‘discontinued’ then ask someone who needs it.

Thanks to one of our valuable headache supporters up north, this drug is now available in Brisbane.

Please contact Monique at The Wesley Pharmacy, Level 2, Sandford Jackson Building, 30 Chasley Street, Auchenflower, 4066. Phone (07) 3371 1754. They will ship Australia wide.

Don’t forget, you can also access this drug from Green Dispensary Pharmacy, S.A. on (08) 8363 7322.

Want to try Botox but don’t know where to go? With the recent listing of Botox on our Pharmaceutical Benefits Scheme, for sufferers who meet the criteria, practitioners need to be registered with Medicare to administer it. If you are thinking of trying this treatment you can now go to chronicmigrainehelp.com.au, enter your postcode, and list of registered practitioners nearby will be emailed to you.

At least that is one headache solved!

Headache Week SuccessAs reported on the front cover, Headache Awareness Week always draws a lot of interest from the public. There are a lot of sufferers of Migraine and chronic headaches – probably as much as 20% of the population – so never think that you are alone in your suffering.

This year we had a Cefaly device on display and this resulted in a lot of interest and an increase in sales at Headache Australia. Cefaly is not for everyone, some people just cannot tolerate it, but you won’t know this until you try it. Of the people who have purchased a device some have reported much better sleep (and lack of sleep can be a big trigger for migraines) others have reported a much reduced incidence of headache and yet others have reported an almost cessation of their headaches. Some sufferers use Cefaly to help them reduce their drugs. Overall, we have had very positive feedback from purchasers of the product. If you would like to make further enquiries about Cefaly, then call or email our office. You do need to use the device for at least a month to guage the benefit for you.

Better Migraine Management! That would make you ‘AppyAs more and more of us are using smart phones you can get ‘an app for nearly everything’, and migraine health is no different. If you wish to take a more active role in your migraine management, then check out these two apps. They may be ‘just what the doctor ordered!’

Headache Australia

Are you on the Headache Register? Our register members receive regular email updates of current information as we receive it. Don’t miss out, join now! headacheaustralia.org.au All donations made by members of the Headache Register will go towards headache and migraine research.

The Brain Foundation cannot offer medical advice and we must stress the importance of discussing any issues you have with your medical practitioner.

iManage Migraine App – re invented

Many of our supporters will remember the iManage Migraine App which was launched a few years ago. Well, that App has been redeveloped and improved by MSD in conjunction with Headache Australia and now includes a lot more features. Nearing completion, it should be available for both iPhone and Android users early 2015.

MigrainePal

This smart diary gives you individual reports and feedback to better manage your condition. Developed by a migraine sufferer in conjunction with neurologists and Headache Australia it makes it easier for you to uncover your triggers, and develop a migraine management plan. This App is also still under development but you can learn more at migrainepal.com

Both of these Applications will require your input and active management of your condition.


Rare Diseases touch more than just the patient. The conditions impact families, friends, caregivers, physicians and society as a whole. Globally, about 7000 rare diseases have been identified and many of these, of course, affect the brain. Compared to widespread conditions, most of the rare diseases receive little attention and lack interest amongst the general public as they only affect thousands, or maybe only hundreds, of patients worldwide.

Recently, we have had some wonderful support for some of the rarer brain disorders.

Brain Tumour Research

Rare Diseases

DebHey Dan, looks good! Stu, striking a pose

Esther and Joe

What is it that makes our wonderful young people shave off all their hair? There must be easier ways to raise a buck!

Fabulous Fundraisers

Having recently been diagnosed with a Tumour, Dan Warner decided he would ‘go wild’ and shave his head in preparation for surgery and raise some funds in the process. Joined by his mother, Deb and some intrepid work colleagues, they raised $1000 for Brain Tumour research.

Using Everyday Hero, Stu Johns wanted to raise funds for Tumour Research to remember his good friend, Tristan Eddy. Having tried his luck in life with a wonderful ‘mullet’ haircut, it was time to move with the times. All his friends must have been very happy to see the mullet go, as Stu raised $18,000. I cannot believe a mullet is worth this much. An impressive effort for which we are very grateful.

Brain Injury ResearchSeveral years ago, Esther Nolan suffered a traumatic brain injury. Needing 15 months of rehab just to be able to walk again, not being diagnosed correctly extended this period of suffering. “I believe that if we know more about the brain and diagnoses, rehabilitation would be more effective” says Esther. Joined by her ever supportive brother, Joe, they ‘shaved it all off’ in August this year and raised $900. Just as well they live in Brisbane: it can be pretty cold without hair.

What is Susac’s syndrome?

Susac’s syndrome is an autoimmune disease first described in 1979. “Autoimmune” means that the person’s immune system mistakenly attacks the person’s own tissues.

A rare disorder characterized by three main problems: impaired brain function (encephalopathy), partial or complete blockage (occlusion) of the arteries that supply blood to the retina (branch retinal artery occlusion, or BRAO), and inner ear disease (hearing loss, most notably). It is not necessary for all three components of the disease to appear at the same time. Any one of the above symptoms may be the first sign of Susac’s syndrome. It may take weeks, months, or even years for all three parts to show up. Some patients never have more than two of the components.

Although considered very rare, Susac's syndrome is being recognized more often worldwide and its true frequency in the general population is unknown.

When the going gets tough, the tough hop on their bikes ... and ride from Melbourne to the Sunshine Coast. Really!

When Kristy McGrath was asked to be Godmother to beautiful baby Eliie, it was a very happy time. But just 6 short months later, Ellie was diagnosed with Tay-Sachs disease. This rare, inherited disorder is progressive and life limiting and life has changed a lot for everyone.

To raise awareness of this terrible disease and funds for research and support, Kristy hopped on her bike. The response to her efforts over the nearly 1800kms has been overwhelming and she has collected more than $10,000 along the way. That’s about $5.80 for each kilometre!

Thank you Kristy, we think you are amazing.

Also using Everyday Hero was David Paterson who, like Stu, was having a ‘hair style crisis’. David had been growing ‘dreads’ and had become quite attached to them. But supporting a good friend, Gus, through Susac Syndrome, David decided these dreads could be put to good use. Many thanks for your support and the $5,500 to go to our Cerebral area of research.

5Summer 2014-2015

Going Purple for Chiari awarenessDiagnosed 18 months ago with Arnold Chiari (kee-are-ee) Malformation, Syringomyelia and Tethered Spinal Cord Syndrome, Tammy Koch found that these conditions are not very well known at all. Having already had surgery and with the likelihood of more, and, living with the crazy symptoms and constant pain, Tammy was inspired by her beautiful daughter Chloe to raise some awareness for the syndrome and some funds for research as well.

Wanting to hang on to their beautiful long hair, Chloe came up with the idea of “Go Purple for Chiari Awareness”. Tammy held a morning tea with lots of donated raffle items and Chloe engaged her school community at Harristown State School.

Together they have added $3,500 to the research fund and raised a lot of awareness along the way. A very big “Thank you” to all who supported Tammy and Chloe. And next time you see crazy purple people………think Chiari!

Team Eat Brains

Tammy, Chloe and school friends

Sarah, Pip and Gerald Edmunds

Chloe and Tammy

Chloe

Fabulous Fundraisers

A Chiari Malformation means that the lower parts of your brain have been pushed downwards towards your spinal cord, so they are below the entrance to your skull.

Most people will have a type 1 Chiari malformation, the least serious form of the disease. This is where the lowest part of the back of the brain (the cerebellar tonsils) drops down into the top of the spinal canal.

Types 2 and 3 Chiari malformations are less common and more serious. They are associated with spina bifida (a birth defect involving problems with spinal development), and adults will also have hydrocephalus (a build-up of fluid in the brain).

The exact cause of Chiari malformation is unknown; however, it is believed that problems during foetal development may cause abnormal brain function.

Tay-Sachs disease is a rare inherited disorder that progressively destroys nerve cells (neurons) in the brain and spinal cord.

The most common form of Tay-Sachs disease becomes apparent in infancy. Infants with this disorder typically appear normal until the age of 3 to 6 months, when their development slows and muscles used for movement weaken. Affected infants lose motor skills such as turning over, sitting, and crawling. They also develop an exaggerated startle reaction to loud noises. As the disease progresses, children with Tay-Sachs disease experience seizures, vision and hearing loss, intellectual disability, and paralysis. An eye abnormality called a cherry-red spot, which can be identified with an eye examination, is characteristic of this disorder. Children with this severe infantile form of Tay-Sachs disease usually live only into early childhood.

A very big thank you to Charmaine and Team Eat Brains for another wonderful cake stall fundraising effort. The team has raised $3000 over the last couple of years. We know that the Zombies have become very popular of late but who would have thought that Zombie cakes would be so sought after.

Charmaine and her boys at the Sydney Zombie Walk

Tamworth Fair 2014One of our wonderful regular fundraisers won’t make the production cut off, so we would like to send our thanks to the indefatigable Pip Warner and her team in Tamworth who are holding the Annual Christmas Fair in late November. Here’s hoping for another successful weekend!


Chief Investigator: Associate Professor Stephen Bowden

Co-Investigator: Professor Steven Collins, Dr Catherine Meade and Mr Simon Vogrin

Despite dramatic advances in technologies, accurate diagnosis of dementia remains a scientific challenge, particularly in the early stages of disease. The clinical diagnosis in a person suspected of suffering dementia still relies on observation of changes in behaviour, particularly changes in cognitive functions such as memory and reasoning abilities. Accurate diagnosis assists in patient care and lifestyle planning, as well as allowing more effective targeting of therapeutic agents that may slow the worsening of symptoms.

With the aim of improving the diagnosis of dementia, we plan to evaluate a diagnostic strategy that combines high-quality cognitive assessment with automated, quantitative neuroimaging. Despite enormous

research interest, the cognitive assessments used to diagnose dementias often compromise on quality, trading-off diagnostic accuracy in the belief that brief assessments retain sufficient sensitivity to measure the effects of dementia.

In addition, quantitative neuroimaging has excellent potential to identify certain types of disease processes in the brain, but the best available techniques are labour intensive and require highly skilled technicians to manually trace target brain structures using the operator’s expert knowledge of neuroanatomy. Using such techniques, it has been hypothesised that volume loss in medial temporal-lobe structures may be an early warning sign of deterioration into Alzheimer’s disease. Advances in automated,

quantitative neuroimaging promise high accuracy and inexpensive investigations, but accuracy that is yet to be proven against the best manual techniques.

In this study we will compare the accuracy of the newest automated neuroimaging techniques against the established manual techniques. Both quantitative techniques will be combined with high sensitivity cognitive assessments to measure change prospectively in people with an early diagnosis of Alzheimer’s. If the automated approach to quantitative neuroimaging proves to be as accurate as the manual approach, we will have an inexpensive, efficient and readily available technique to improve the early diagnosis of dementia.

Chief Investigator: Dr Mark Graham

Co Investigator: Dr Kasper Engholm-Keller

Alpha(α)-synuclein is a key protein in Parkinson’s Disease (PD). It is the predominant component of Lewy bodies, which are a hallmark of the pathology of PD and related neurodegenerative disorders. Thus, something must be going wrong with α-synuclein, but it has been difficult to determine its role in PD because aspects of its normal function in nerve cells remains unknown. An intriguing early observation was that α-synuclein is involved in

the control of birdsong in zebra finches. The gene for α-synuclein is switched on in the song control circuit of the brain during the period of juvenile development and learning in these finches. This implies that in humans α-synuclein also has a normal role in learning and memory. But until now there has been no explanation or mechanism for this α-synuclein role.

We screened proteins in neurons to determine if they are involved in the cellular signalling that occurs during neurotransmission. Specifically, we looked at phosphorylation, a chemical modification of proteins, involved

in rapid cellular signalling that switches protein function on/off. We identified a novel site of phosphorylation on α-synuclein that related to neurotransmission. This phosphorylation site had a profile similar to other proteins involved in synaptic plasticity. Synaptic plasticity is how neurons adapt based on environmental and electrical stimulation and is the basis of learning and memory. This phosphorylation site is in a crucial part of α-synuclein and adjacent to a cluster of sites of genetic mutation associated with PD. We propose that phosphorylation of this site acts as a switch to regulate the sub-

cellular localisation of α-synuclein and has a role in synaptic plasticity by influencing neurotransmitter release. In this pilot project, we aim to link adaptive brain activity, like in the zebra finch, to α-synuclein function, to facilitate a broader study of how dys-regulation of normal function relates to toxicity in models of PD.

2014 Research Gift AwardsEvery year the Brain Foundation receives many outstanding applications for research into all areas of brain disease and disorder. The quality of researchers and projects in this country is outstanding and it is disappointing that so many great ideas go without funding.

As the slogan goes …’from little things big things grow’ and many of the projects the Brain Foundation has funded have gone on to further government funding or clinical trials. It would be wonderful if we were able to fund them all. It is certainly a difficult decision for our panel of eminent practitioners who decide on the recipients and we thank them for their ongoing dedication to this task.

It is with pleasure that we present the winners for 2014.

Function of Parkinson’s disease protein synuclein

Automating the analysis of brain scans to improve the diagnosis of Alzheimer’s disease in clinical practice

7Summer 2014-2015

Chief Investigator: Dr Katherine Jackman

Co Investigators: Associate Professor David Howells

The aim of this project is explore the therapeutic potential of progranulin - a secreted protein that has recently been linked to dementia - for the acute treatment of stroke. We hypothesise that treatment with progranulin will reduce brain damage and improve outcome when given intravenously after stroke.

In order to evaluate the therapeutic potential of progranulin, animal models will be subjected to an experimental model of stroke by blocking one of the main blood vessels supplying blood to the

brain. Then, at clinically relevant time points (i.e. 0 – 24 hrs), the models will subsequently be treated with progranulin. Three days after induction of stroke, both the health of the animal models and the degree of brain damage will be quantified. In addition, we will evaluate the influence of progranulin on the leakiness of brain blood vessels using specialised dyes, as we predict that this plays a key mechanistic role in progranulin’s protective effects.

Once we have determined the influence of progranulin on acute stroke outcome and vessel leakiness, we will explore the mechanisms by which it achieves this. This component of the study will focus on the very tight associations between endothelial cells – cells that line blood vessels and prevent leakiness - and examine the changes that progranulin induces in both their structure and function. Knowledge gained from this study will determine the potential for the use of progranulin and related compounds as novel therapeutic agents for the treatment of stroke.

Chief Investigator: Dr Stephanie Rainey-Smith

Co Investigator: Professor Ralph Martins

Alzheimer’s disease (AD) is a progressive degenerative condition which develops over several decades. Symptoms include decline in memory and

thinking (cognitive) abilities which are sufficient to interfere with everyday activities. The greatest known risk factor for AD is advancing age.

The world’s population is growing older due to improved healthcare and nutrition. Consequently, AD prevalence will increase in the coming decades, resulting in a worldwide epidemic requiring billions of dollars of government funding for the care and treatment of individuals with this devastating disease. Currently, no cure for AD exists, thus it is essential that effective preventative approaches to delay the onset of decline in cognitive abilities leading to AD are developed.

Attention has consequently turned to identifying lifestyle factors that may influence disease course. While much research has focused on diet and exercise, sleep characteristics (i.e. quantity and quality) in relation to disease course have been inadequately studied.

Emerging research suggests sleep may be an important contributor to AD pathology, with poor sleep acting as a risk factor both for developing AD and for increased disease severity. Furthermore, a recent study of community dwelling older adults at one time point described an association between self-reported shorter sleep duration and poorer sleep quality and greater brain

amyloid levels (a hallmark of AD pathology). However, additional studies over multiple time points, using unbiased devices that measure sleep, are needed to determine whether sleep disturbance causes or accelerates AD-related pathology. Our study aims to address this important gap in our understanding of the impact of sleep on memory and thinking abilities and AD-related biological markers in the brain, blood and spinal fluid. It is hoped that the data collected through our study will contribute to the development of preventative public health strategies to delay or prevent AD onset.

Modelling Alzheimer’s disease in patient-derived neurons

Chief Investigator: Lezanne Ooi

Co Investigator: Dr Greg Sutherland

Alzheimer’s disease is the most common form of dementia and its prevalence in Australia is increasing at a rapid rate. By 2050, Alzheimer’s disease is predicted to be the most costly health problem in the country. This imminent epidemic can only be prevented with the development of novel treatments.

One of the problems with trying to work out how to treat Alzheimer’s disease is that the brain of animal models is a particularly poor substitute for the

complexity of the human brain. Recently, with the advent of stem cell technology, it has become possible to convert skin cells from Alzheimer’s disease patients into neurons in the laboratory. These neurons show many of the deficits that we see in Alzheimer’s disease brains. In addition, one interesting clue we have about the cause of Alzheimer’s disease is that diabetes increases the risk of developing the disease. In the proposed work we intend to manipulate the insulin signaling pathway to try and rescue the neurons from patients so that they behave exactly like those from a person without Alzheimer’s disease or any other brain disease.

In so doing we hope to uncover novel targets for a future cure to this devastating disease.

Determining the influence of sleep quantity and quality on memory, thinking and biological markers of Alzheimer’s Disease

Progranulin, blood brain barrier integrity and ischaemic stroke

Glossary of Terms

Novel – Referring to that which is new, and/or original


Chief Investigator: Dr Renée Turner

A common, life-threatening complication of stroke is cerebral oedema (brain swelling) and subsequent elevated intracranial pressure (ICP). Stroke patients suffering this condition are more likely to die or be left permanently disabled as a result. Despite this, current treatments for cerebral oedema and elevated ICP are largely ineffective in treating this life threatening condition, given that they simply treat the symptoms rather than address the cause of the swelling. Pharmacological treatments aim to pull water out of the brain to decrease the swelling whilst decompressive surgery aims to accommodate the swollen brain and although life saving, it is highly invasive and potentially risky. As a result, alternate treatments for brain swelling that address the cause of the

swelling and stop it in its tracks are urgently required in order to improve survival and long-term outcomes for stroke patients.

To address this the Neurological Diseases laboratory at the University of Adelaide has identified a novel therapy to treat brain swelling following stroke that targets the action of substance P and blocks its receptor (NK1 tachykinin receptor). Levels of substance P are increased in the brain following stroke, causing an increase in the permeability of blood vessels, movement of water into the brain, cerebral oedema and poor outcomes. Results to date show that NK1 tachykinin receptor antagonist treatment completely prevents blood vessel permeability changes, brain swelling, elevated ICP and mortality following stroke. The next stage is to assess long-term efficacy, as it is essential that patients not only survive an episode of brain swelling but also have meaningful function. Using a novel pre-clinical stroke model that we have developed we will determine the long-term effects of NK1 tachykinin receptor antagonist treatment on functional outcome following stroke. Results from these studies provide compelling evidence for the use of NK1 tachykinin receptor antagonists for the treatment of brain swelling following stroke.

2014 Research Gift Awards

Targeting brain swelling to improve long-term outcome following stroke

Chief Investigator: Dr Andrew Gogos

Co Investigator: Dr Andrew Morokoff

Glioblastoma multiforme (GBM) is the most common and most deadly form of primary brain cancer. Most patients survive only 12 months from diagnosis, often with significant disability. Despite a huge volume of research into the disease, only two drugs have shown significant benefit in clinical trials. A possible reason for this translational gulf is that most therapies focus on the bulk group of cell composing the tumour. In contrast, we study glioma ‘stem’ cells: a subpopulation of the tumour that may be responsible for initiating the tumour, and for tumour regrowth after existing treatments fail.

Specifically, we are investigating the role of the ‘YAP pathway’. This is an intracellular signalling system that is involved in cell growth, proliferation and differentiation during development. In the normal brain the pathway is active during development but not in mature neurons or supporting cells. We and other research groups have noted that the pathway is highly active in GBM cells, specifically in the glioma stem cells. It appears the tumour has co-opted a normal developmental system for its own abnormal grothh. The YAP pathways high activity within the tumour, but not normal brain, makes it an ideal potential therapeutic target.

With the help of the brain foundation we aim to investigate the effects of blocking the activity of the YAP pathway and confirm that it is a viable target for brain cancer therapies. We also aim to investigate the efficacy of some existing drugs acting on this pathway.

Our long term goal is to develop novel therapies for GBM and improve the survival and quality of life of patients with brain tumors.

Targeting the YAP pathway in glioblastoma stem cells

Return of memory after Traumatic Brain InjuryChief Investigator: Dr Gershon Spitz

Co-Investigator: Professor Jennie Ponsford, Dr Matthew Mundy

Traumatic brain injury (TBI) remains one of the leading causes of death, disability, and hospitalization worldwide. TBI has a significant burden of disease within Australia, with TBI-related costs estimated to total $8.6 billion, annually. These costs include rehabilitation services, loss of productivity, and

requirements for long-term care.

Moderate and severe TBI accounts for 30% of injuries, often resulting in ongoing adverse cognitive, behavioural and psychiatric outcomes. Following their injury, these individuals initially experience a transient period of post traumatic amnesia (PTA).

This period is characterised by an inability to form new memories, but also includes confusion and disorientation. Importantly, the length of time individuals remain in PTA, which may last from minutes to months, has emerged as one of the strongest predictors of the severity of injury as well as long-term functional outcome.

Although PTA is used worldwide for diagnosis and prognosis following

TBI, the guidelines regarding the management and expectations of individuals within this period are largely based on clinical experience. Systematic research studies are lacking that detail the cognitive or neuropsychological impairments presented during period. There has been no explicit investigation of the mechanisms responsible for initial memory disturbance or the mechanisms responsible for the resumption of normal memory processes following TBI.

Treatments during PTA comprise only essential monitoring of depth of PTA, physiotherapy, and speech therapy input regarding feeding and swallowing. The viability of other behavioural, occupational,

or cognitive interventions in this period is limited as it is not known to what extent patients can process and remember new information. In this project, we propose a world-first study to add critical information through a novel prospective fMRI investigation of individuals in PTA and their recovery of function following this period.

9Summer 2014-2015

Can expression of the NFI genes in glioblastoma stop tumour growth?

Chief Investigator: Dr Jens Bunt

Co Investigators: Professor Linda Richards

Glioblastoma (GBM) is a devastating primary brain cancer that affects around 800 Australians annually. Despite surgery, radiotherapy and chemotherapy, 1 in 2 people diagnosed with GBM will not survive for more than 14 months. The short life expectancy

among patients highlights the need for novel therapies. One possible therapeutic strategy, to complement the current treatment, may be to focus on the glial origin of GBM. Glial cells are essential for normal brain development and function, as they play important roles in regulating synapse formation and function as well as supplying nutrients to neurons. GBM tumours originate from these cells. If we can reactivate the glial differentiation program that normally drives the production of glial cells in the brain, we can potentially induce the differentiation of cancer cells and prevent further tumour growth.

One family of genes required for normal glial biology is the Nuclear Factor One (NFI) transcription

factor family. Transcription factors are master regulators of gene expression, thereby coordinating the expression of other genes during processes such as proliferation and differentiation. In GBM, these genes are commonly deleted or mutated. As the NFI genes drive the differentiation of glial cells during brain development, they may act as tumour suppressors in GBM. NFI expression directly correlates with clinical outcome (less NFI = shorter patient survival) and for the gene NFIB, decreased gene copy number is associated with adverse disease progression and clinical outcome. We found that re-introducing NFI in GBM cells stops cancer cell division and promotes the transition of these cells into normal glial cells, effectively reversing the cancer.

Here, we propose that activating the NFI pathway may provides a novel complementary strategy for treating GBM.

In this proposal, we will test the hypothesis that activating NFI in primary GBM tumours both stops their growth and reverses the cancer. Briefly, primary tumours resected from human patients will be grown in mice. Grafted tumours will be treated using NFI-expressing DNA constructs. The effect of the treatment will be analysed by staining the tumour cells with suitable differentiative and proliferative markers and comparing them to control tumour cells. Together, these experiments, in a pre-clinical mouse model, will determine if targeting NFI gene family is suitable for the treatment of GBM.

Chief Investigator: Dr Susan Tomlinson

Both neuropathic pain and epilepsy are common chronic disorders which result in significant morbidity to the sufferer, and have a major impact on health resources. Severe chronic pain costs the Australian economy $34 billion per year, and may carry a global health impact equivalent to that of heart disease or severe mental illness. Chronic pain suffers attend to primary care physicians five times more frequently than those without pain.

There is a critical need for better understanding and management of chronic pain. Epilepsy affects 1- 3% of the adult population, and morbidity associated with epilepsy is associated with injury related to seizure, loss of license, the cost of life-long need for medication, and the side effects associated with anticonvulsants. While vastly different in their clinical manifestations, abnormal nerve excitability is implicated in the pathogenesis of both neuropathic pain and epilepsy. Therefore, we aim to study these conditions in tandem to evaluate the mechanism by which abnormal nerve excitability results in symptoms.

Nerve cell membranes are electrically active. Ion channels are membrane-bound proteins which allow the passage of charged particles (ions) across the membrane of nerve cells. Dysfunction of ion channels (genetic or acquired) can result

in abnormal nerve excitability. Neurological features caused by ion channel dysfunction include seizures, ataxia, migraine, pain, epilepsy and stroke-like symptoms. Assessment of ion channel dysfunction previously relied on in vitro expression of single channels. This cannot factor in the complex cascade of interactions that occur in vivo, therefore a tool to sensitively measure ion channel function in vivo is critically needed in order to define pathophysiology, aid diagnosis, monitor progress and assess treatment outcomes. The TROND protocol of nerve excitability studies is a non-invasive test performed in a similar fashion to nerve conduction studies. It provides information regarding channel function in peripheral nerve. While the central nervous system cannot be directly interrogated, peripheral nerves carry many similarities and can provide a surrogate marker of

channel function in the CNS.

This project seeks to define how specific channel currents (including Ih, due to HCN channel activity) result in aberrant nerve excitability and pacemaker misfire, and play an important role in generation of neuropathic pain AND seizures. The project has 2 arms with similar study design. One arm will study patients with neuropathic pain and the other arm will study patients with seizures/epilepsy. Subjects will undergo clinical assessment and nerve excitability studies annually for 3-5 years. It is anticipated that peripheral nerve excitability studies will be contribute to defining the mechanism of disease, and potentially predict outcome and response to treatment. Hence, the role of nerve excitability studies as an aid to diagnosis and management in these cohorts will be explored and defined.

Channelling into mechanisms of neurological disease: An in-depth study of abnormal nerve excitability in neurological disorders (epilepsy and chronic neuropathic pain)


2014 Progress Reports

Both neuropathic pain and epilepsy are common chronic disorders which result in significant morbidity to the sufferer, and have a major impact on health resources. Severe chronic pain costs the Australian economy $34 billion per year, and may carry a global health impact equivalent to that of heart disease or severe mental illness. Chronic pain suffers attend to primary care physicians five times more frequently than those without pain. There is a critical need for better understanding and management of chronic pain. Epilepsy affects 1- 3% of the adult population, and morbidity associated with epilepsy is associated with injury related to seizure, loss of license, the cost of life-long need for medication, and the side effects associated with anticonvulsants. While vastly different in their clinical manifestations, abnormal nerve excitability is implicated in the pathogenesis of both neuropathic pain and epilepsy. Therefore, we aim to study these conditions in tandem to evaluate the mechanism by which abnormal nerve excitability results

in symptoms.

Nerve cell membranes are electrically active. Ion channels are membrane-bound proteins which allow the passage of charged particles (ions) across the membrane of nerve cells. Dysfunction of ion channels (genetic or acquired) can result in abnormal nerve excitability. Neurological features caused by ion channel dysfunction include seizures, ataxia, migraine, pain, epilepsy and stroke-like symptoms. Assessment of ion channel dysfunction previously relied on in vitro expression of single channels. This cannot factor in the complex cascade of interactions that occur in vivo, therefore a tool to sensitively measure ion channel function in vivo is critically needed in order to define pathophysiology, aid diagnosis, monitor progress and assess treatment outcomes. The TROND protocol of nerve excitability studies is a non-invasive test performed in a similar fashion to nerve conduction studies. It provides information regarding channel function in

peripheral nerve. While the central nervous system cannot be directly interrogated, peripheral nerves carry many similarities and can provide a surrogate marker of channel function in the CNS.

This project seeks to define how specific channel currents (including Ih, due to HCN channel activity) result in aberrant nerve excitability and pacemaker misfire, and play an important role in generation of neuropathic pain AND seizures. The project has 2 arms with similar study design. One arm will study patients with neuropathic pain and the other arm will study patients with seizures/epilepsy. Subjects will undergo clinical assessment and nerve excitability studies annually for 3-5 years. It is anticipated that peripheral nerve excitability studies will be contribute to defining the mechanism of disease, and potentially predict outcome and response to treatment. Hence, the role of nerve excitability studies as an aid to diagnosis and management in these cohorts will be explored and defined.

The Biennial Elizabeth Penfold Simpson PrizeThis prize is awarded to the authors of the best original research published in the last two years. The research must have been conducted wholly or substantially in South Australia.

Human Adult Dental Pulp stem cells enhance poststroke functional recovery through non-neural replacement mechanisms

Is dystonia due to a fundamental defect in movement or postural control?Chief Investigator: Dr Florence Chang

Co Investigators: Associate Professor Victor Fung and Associate Professor Steve Vucic

Dystonia is a disabling neurological condition that is relatively common. Primary dystonia has a prevalence of greater that 3/1000 people. This extrapolates to 70.000 people in Australia. Dystonia secondary to other neurological disease such as stroke or neurodegenerative disease is probably even more common. Patients with dystonia suffer involuntary muscles spasms that typically occur

during attempted activity, and interfere with function. Onset can be at any age, and therefore dystonia often results in significant physical and social losses. A limited understanding of its cause restricts the current treatment of dystonia.

There are two main controls of human movement. There is posture, which is like the crane portion of the cherry picker. Then there’s fine motor movement, which is the part of the cherry picker that picks cherries. Recent animal studies found a separate system of brain cells that control posture in the movement part of the brain. Our project propose that

dystonia is due to abnormality in this area of the brain, leading to abnormal postures and relatively preserved fine motor movement. We will use techniques like surface muscle electrode recordings, magnetic stimulation recordings and functional brain imaging to examine patients with dystonia compared to normal subjects. We want to see if during postural control tasks, patients with dystonia have increased muscle and brain activity, compared to fine motor movements. We measure if previously proven therapies for dystonia like botulinum toxin can reduce excess muscle and brain activity during posture control

tasks. We hope by understanding the cause of dystonia better, we can produce more effective and long lasting treatment for this condition.

Chief Investigator: Dr Karlea Kremer

On behalf of: Wai Khay Leong, Tanya Henshall, Agnes Arthur, Karlea Kremer, Martin Lewis, Stephen Helps, John Field, Monica Hamilton-Bruce, Scott Warming, Jim Manavis, Robert Vink, Stan Gronthos, Simon Koblar

11Summer 2014-2015

Exercise your brainRemember all brainiacs... an active brain is a healthy brain!

The 7 Day Memory Test

For this test, you will need a small notebook or pad, and a pen.

Below you will see five objects and five words. On the morning of Day 1, sit quietly for fifteen minutes and commit them to memory and then don't look at them again. Once you have done this, label seven sheets of paper Day 1, Day 2 etc up to Day 7. Each night before going to bed, write down the words and the objects that you remember on the daily sheet of paper, then put it away. When you complete Day 7 bring out all the sheets including this one and compare your results.

If you have managed to remember all the words and objects by Day 7 your memory is excellent, forgetting one to four would be normal. If you have forgotten more, then you should start doing some memory training exercises.

Remember, subscription to the puzzles from Brain Food Factory is free. brainfoodfactory.com

Following the success of the 7 day memory test in our last edition of Brainwaves, why reinvent the wheel? Here is new lot of memories for you to create!

Apps – for the young at heart not just the young!We all know that exercise and a good diet will make a difference to us in our lives, but one thing universally sought, is to be mentally alert and have a good memory into old age.

Active Memory is a new App launched by ABC Commercial (yes, the broadcaster) last year. It uses a process known as “progressive mastery” to help users boost their cognitive skills. Offering a series of five-minute training blocks that test different functions, players can choose which to play or have a personalised training session. They are then given scores and an ongoing record for the next time they log on. An algorithm allows the App to adapt the level of challenge to the individual user. A key reason why people don’t engage in cognitive activities is because they begin with a crossword or a puzzle which is too difficult. A key to success is high levels of engagement and continuous playing. Three 20 minute sessions per week are recommended.

But you don’t need to be a senior citizen to play. The age range is 11 to 92 – and it’s a good way to fill in time. Even if does not help your cognitive function, it will help you to use your existing abilities much better.

So, what’s stopping you? Check it out: activememory.com

turning feet inward so toes pull down and soles of feet face each other.

It started in 1990. First appearing as though vocal chords alone were affected. In 2004 I was sent to Brisbane for a second opinion by a neurologist specialising in movement disorders such as essential tremor, Parkinson’s disease and dystonia. Diagnosed with laryngeal dystonia, also known as (aka) spasmodic dysphonia, I began Botox injections through the front of my neck into vocal chord muscles, thus allowing those muscles to relax. Glorious exaltation! Although my voice became very soft and high pitched, I could speak!

Soon, I succumbed to other forms of dystonia. My head pulling back and to the right, impossible to see where I was stepping, nor what was in front of me. Now diagnosed with cervical dystonia aka retro spasmodic torticollis. This rapidly progressed to lower back dystonia quickly followed by eyelid spasms aka blepharospasm dystonia, then lower limb dystonia.

Unbeknown to me, cousins were diagnosed with various forms of dystonia. One of my deceased maternal aunts had been diagnosed

with cervical dystonia. My mother, also deceased, had symptoms of laryngeal and cervical dystonia although, not diagnosed. This is understandable. Very few people have been diagnosed correctly until recent time. Two of my adult children experienced episodes of cervical dystonia. One progressed to lower limb dystonia. My diagnosis now? Progressive familial multi-segmental dystonia!

Finally the anaesthetist said, “We are putting you to sleep now. Time to put leads from your brain between skull and scalp, down to chest attaching them to an internal neuro-stimulator.” Almost over. Hooray!

Twenty-four hours in intensive care before returning to the ward. Discharged five days later. Staples in top of skull, eyes open, walking upright, head straight, feet in order, good voice. I still have the incurable neurological disease. However, successful deep brain stimulation surgery means smooth ripples of obedience to neurotransmitters from my brain to muscles.

The constant nightmare of living with painful symptoms of dystonia ends!

My battle with dystonia continued. . .

Thank you for supporting brain research through the Brain FoundationTo make a donation please visit our website brainfoundation.org.au/donate or use the donation form on the letter enclosed.

We would welcome your contribution!As you can see, there are many ways you can become involved. You can organise your own event or join a public event, such as a fun run, shave your head or dress up in your favourite colour.

Please help us to increase our funds provided to the research grant programme by going to: gofundraise.com.au, everydayhero.com.au, mycause.com.au

Our thanks go to the following people who have used these sites to raise funds on our behalf:

GoFundraise: Team Brainiacs in the Pub to Pub Fun Run, Christina Cardillo-Zalio 18th Birthday, Virginia Scott and Nelson Summerhouse Tea Cosies, Samantha Timms and Rebecca Reddie running in half marathons, Mel Hanger Great Hair Chop

Everyday Hero: Sharna Montgomerie for brain tumour research, Hannah Agnew-Elliott for Myasthenia Gravis, a neuromuscular condition, Dani Stevens for epilepsy, and all our City 2 Surf fun runners, Sunday Mail Suncorp fun runners and Sunday Mail City to Bay fun runners.

My Cause: Simon Lumsden for brain tumours, Kristy Justice for Chiari, Brisbane, Sydney and Canberra Zombies.

Everyone has a brain! No one can live without one! Research will benefit us all.

Regular Giving Would making small, regular donations suit you better than one bigger donation per year?

Perhaps you should think about making a regular monthly or quarterly donation. Contact our office or download a form and we will do the rest for you.

Workplace Giving is an easy alternative and your company may even match your donation. Speak to your paymaster for further information.

Estate Planning and Bequests: Our benefactor, Australian Executor Trustees offers reduced rates for Brain Foundation supporters. For more information, please call Gerald in our office on 1300 886 660.

As we go into production, it is Zombie time of the year againGood luck and thanks to the hoards in Sydney, Canberra, Cairns, Gladstone and Townsville and a big thank you to the ever growing Brisbane hoard, who had to walk early this year because of the G20. You just never know what a Zombie will have in his ‘pocket’!

Find us on Facebook. Like us today!Get Involved

In MemoriumThe Brain Foundation would like to extend a very sincere thank you to the families of the following who supported us in a time of great sadness and loss.

Andrew RIVETT

Maurie PERROTT

Mark LANGFORD

Robert Gary STEVENS

Reg GASNIER

Neil HOILE

David BIRTWISTLE

Mark PAYTON

Shirley HUDSON

Marion Marcia COOK

Maurice James SHOARD

Joyce WILLIS

Jennifer Nicola HUNT

Len GILBERTSON

Mrs H MARTIN

Gwen JUKES

Pete MAY

Ken McDONALD

Terri-Anne BANNON – Heaven Address

Rhona McKERRAS – Heaven Address

Leland MALIN

Matthew BULLOCK

Zane HARTWIG

In CelebrationWe would like to congratulate Ms Jodi Mosca and Mr Erik Andersen on their recent wedding and wish them all the very best.

Thanks to the following companies for their support:

Documents

2014 Summer brainwaves Newsletter