brainwaves newsletter summer 2013 - Brain Foundation by Brain Foundation

brainWAVES The Newsletter of the Brain Foundation

Summer 2013-2014

2013 Research Gift Results The Directors and Staff are very pleased to bring to you, our supporters, the 18 wonderful research projects funded in 2013 in this edition of BrainWaves. The calibre of the applicants is always very high and we certainly don’t envy our scientific committee who have the onerous task of making the final selection. These research gifts are made possible by your ongoing generosity and that of our corporate sponsors. Without your help, these projects researching the ‘most complicated organism in the universe’ would not be able to continue. We extend to you our sincere thanks and our very best wishes for the upcoming holiday season.

Headache Awareness Week – September 16 – 22 Brain, mind and spinal disorders have the greatest impact of all disease groups, and almost everybody knows someone who has a condition that affects the brain. But often when we think about these conditions, migraine or chronic headache is not the one that springs to mind. Very often, migraine sufferers are told “it’s just a headache, get over it” by people who don’t understand the impact that these debilitating conditions can have. Designated as a disability by WHO, sufferers are at risk of losing much of their work and social time and some who suffer very badly may not be able to work at all. Affecting

Sydney

as much as 20% of our population, this is a serious health issue and results in long term costs to our health care system. New treatment options are desperately needed. (See latest Headache News on page 10). This year Headache Australia, a division of the Brain Foundation, took to the streets of Sydney, Melbourne and Brisbane to raise awareness of these debilitating conditions and to encourage sufferers to join the Headache Register. The Headache Register aims to keep participants up to date with the latest research projects and inform them of new developments in treatments.

Headache Awareness Week gets a lot of support from pharmacies around the country and if you would like to support this very JOIN THE JOINNATIONAL THJO E IN NATH TIO E NA NALTIO REGISTER HEADAC HEA NAL HEDRE important event, HEADACHE GIS ACH ETER REGISTE 4 MILLION R 4 MILLION 4 MILLI ON please contact our office for the 1 51 5 1 5 2014 dates and to go on a list for a support pack. HEADACHE AND MIGRAINE WEEK HEA DAC HEHE AND ADMIGR ACHEAINE WEEK AND MI GRAINE WE

MORE THAN MORE THA MO N RE THAN AUSTRALIANS ARE AUSTRA AUAFFECTED LIAN ST S ARE RALIA AFF NSECT BY MIGRAINE AREED BY MIGOR BYCHRONIC RAIN MI E OR GRAI CHRONI AFFECTED HEADACHE HEADACHE HEADAC NE ORCCHRO NIC HE IN OIFNTHE EO SE NILELSLOSE F IW THE EO WTH ILLELOSE SLE WIL SIGNIFS ICIG ANITFIWORK K AND F SOCIAL GN CSAIN L LOSE T IWOR FICAN KTAWO N SOCIAL TIME DTUE HIEM IRE SUFFE RIND G RK IMTO T K ANLD EODT UE TO O TDH UE EIR TO OSU TFFERING SOCIAL Together wether can make a difference HEIR SUFF Toge Togcan eth we ERING er make we can a difference ma ke a dif

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1300 88613 660 1300 00660 886 886 66 0 headacheaustralia.org.au headache headaust acheralia .org. austr au alia.o rg.au Headache Australia is a division of the Headache Australia Foundation is a divisionHead of the ache Brain Foundation is a divisi Australia on Brain Foundof the ation

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Don’t they all look good in purple!

Brisbane

Melbourne

Would you like to support the Brain Foundation and get your money back too? Well, purchase an Oz Calendar for yourself, get one as a Christmas gift, and this could be you. See the enclosed flyer for more information or visit our web site.

Contact the Brain Foundation PO Box 579, Crows Nest NSW 1585 Telephone: 02 9437 5967 or 1300 886 660 Fax: 02 9437 5978 Email: info@brainfoundation.org.au Visit our websites brainfoundation.org.au and headacheaustralia.org.au

Fabulous Fundraisers For Dystonia Q: DYSTONIA: do you know what it is? A: A neurological movement disorder that causes muscles to contract and spasm involuntarily. This forces the body into repetitive and awkward, twisting postures. It can affect anyone at any time. There is no cure. This year, we have had a lot of fundraising activities to benefit research into this terrible disease.

The Brain Foundation goes to India Imagine a small, lime green brain, ‘tuk tuking’ its way across India. Can’t? Well, we have the pictures to prove it. This year we were lucky to have the support of three very intrepid fundraisers who spent two weeks and 3,500 kilometres crossing unknown territory in India - all to raise funds for research into Dystonia.

Julien Buttigieg, Andrew Nolan, Lee Pagan and Glen Gorton

Having watched his mother, Lee, suffer with this devastating neurological condition, Andrew Nolan, along with mates Julien Buttigieg and Glen Gorton, took on the 2013 Rickshaw Run. With no set route and no support crew, they painted their assigned ‘tuk tuk’ bright green – just like one or our ‘brainy’ caps, and set off on the adventure of a lifetime. Two weeks later, with many stories to tell of their adventures, they crossed the finish line.

Day 4 Dystonia And meanwhile, back in Australia, the Southport Rotary Club held Day 4 Dystonia to help Lee raise some extra funds for research too. With the money raised from this day added to that of the Rickshaw Boys, the total raised for Dystonia research is $11,000. Thank you so much Rickshaw Boys and Southport Rotary. 2014 anyone?

Walking for a Reason Recently diagnosed, Lisa McInnes and her family made the move from the southern states to sunny Queensland to enjoy some warmer weather. Wanting to contribute further funds, she and her family decided to hold their own ‘10k walkathon’. With family and friends supporting, Lisa has contributed $1,700.

Thank you so much Dylan. Hope the blisters have settled down! 2

Lee with her family

Dystonia is a devastating condition at any age. Imagine then, if your little baby was affected.

Lisa McInnes and her family

Running for a Reason Using the Brain Foundation fundraising portal to advertise the cause close to his heart, Dylan Boone has contributed another $1,000 to the Dystonia research fund.

Lee with her team

Jaida looking gorgeous

Karter - what a cutie

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Joy for Jaida

Karter’s Fight

This is the case for little Jaida. Spending most of her time in a wheelchair, Jaida is very excited to now be at ‘big school’. In order to support her needs at school and to add some more funds for research into Dystonia, her extended family organised a family fun day – with jumping castles, raffles and lots of kids activities. More than 400 of Jaida’s friends came along and even though it was a very hot day, a lot of fun was had by all. The event raised $2,000 to go to a Dystonia Research project.

Another little cutie is Karter. Only 15 months old, his family are helping to raise awareness of Dystonia in the community and have been fundraising on our behalf through Everyday Hero. They have so far raised well over $6,000. You can support Karter’s fundraising effort through his Everyday Hero page. These wonderful fundraisers have contributed enough funds for a research project in 2014. Thank you everyone. For further information about Dystonia please email Lee Pagan at ADSG@live.com.au

Fabulous Fundraisers Some of the wonderful fundraising teams from 2012 had such a good time, they decided to come back and do it all again in 2013. And we are glad they did!

Team Steph Having braved the freezing cold conditions at the 2012 City to Surf, you would think that would have been enough. But no! Coming back bigger and better in 2013, Team Steph – who ran the City to Surf in memory of sister, Stephanie – more than doubled in size. And their fundraising also increased accordingly. So much so, that they have been able to fund one of the 2013 Research Gifts.

Team Steph – don’t they all look great!

Team Steph have contributed $28,000 to our Research Gift programme over the two years – an awesome effort of which we are very, very grateful. Thank you so much to the Ledonne family and all the members of Team Steph.

Caulfield Grammar – Run Against Brain Cancer In 2012, Rachael Stephens organised a fun run for her school community to raise funds for Brain Tumour research, and to remember her mother who lost a battle with the disease. Her school mates and friends agreed that it was a cause they wanted to support, and so they organised another Fun Run this year. Organised in conjunction with the Victorian Cross Country League, numbers for this event were also greater than last year – and that’s not counting the four legged friends who also came along. The extended school community has raised $6,000 to go toward a Brain Tumour research project. Thanks everyone!

The 2013 team of runners and walkers

Brisbane Fillies are the best in Melbourne Cup Once again Louisa Coote and Fiona Greenwood have put on a deluxe Melbourne Cup luncheon in aid of Brain Tumour research. Ably assisted by mum Nancy, the luncheon raised nearly $1,500 this year. The fillies all had a great afternoon and looked pretty stylish too. Thank you so much for your ongoing support.

Nancy and Louisa

Blue Hair – be gone! Someone who will probably think twice before fundraising again next year is Megan Dunbar who shaved off all her BLUE hair to raise funds for Brain Tumour research! Now proudly wearing a ‘brainy’ cap, having discovered it can be a bit cold without hair, Megan far exceeded her expectations and has raised over $2,600 – a fabulous effort that we would certainly be pleased to have again. Megan Dunbar

Zombies are Taking Over the Country... But Please Don’t Blame Us

Tamworth Fair Once again a big ‘thank you’ to Pip Warner and the hard working crew in Tamworth for another wonderful fundraising effort. The Tamworth Fair has been going for 10 years and is a valuable source of funds for our Research Programme.

Yes, it used to be only in Brisbane that the Australian Zombie hoard gathered. But, alas, these zombies have become a rather jet setting lot, and now gather all around Australia to recruit to their growing numbers. The Brain Foundation is very grateful to the organisers of these events, which are now in Brisbane, Perth, Sydney and Canberra, as well as in regional Queensland. It is no small feat to organise these events, with many permits required before the “undead can rise and take over the streets”. These walks are an important source of income for us... Because we all know that “zombies love braaaaainnnns”. And so do we.

Charity Challenge Golf Day Our golfing supporters hit the greens early again this year to help raise funds through the Charity Challenge. Run by Gary Dawson and Mathew Laverty of Bullant Sports, this has become an annual event on the Brain Foundation calendar. The support from all involved is greatly appreciated.

In Sydney, the Zombies love Cake

Charmaine and Gerald

Yes, the cake loving Zombie sisters are back in 2013 too. Thank you very much to Charmaine and Kimbly who have held two events this year raising over $1,000. With the help of Scott, Jackie, Diana, Leah and Brock, they held a Trash ‘n Treasure as well as their delicious cake stall. The cakes must be very good, ‘cause people don’t seem to mind buying them from a couple of blood soaked zombie sisters…… wooo, hahahahaha. Summer 2013-2014

2013 Research Gift Awards The Summer edition of BrainWaves is the showcase for our Research Gift Programme. Each year we receive many more outstanding applications than we are able to fund. And, it is with wise investment of funds, that we are able to allocate more funding for more projects each year. So it is with pleasure that we present to you the 18 successful projects for 2013. Our sincere thanks go to the members of the Scientific Committee who volunteer their time to assess the many applications, and also to the Governor of New South Wales, Her Excellency Professor Marie Bashir AC CVO, for her unwavering support and interest in these awards.

The Transmission of Parkinson’s Disease Pathology Chief Investigator: Dr Haydn Allbutt spread throughout the brain. Amongst the earliest detectable changes in the PD brain is the aggregation of a small protein of unknown function called alpha-synuclein (α-syn). The abnormal, aggregated form of this protein has become widely used as a marker for Parkinsonian pathology and has been used to characterise the parts of the brain that are affected by the disease.

Our research is looking to confirm the mechanism by which the pathologies underlying Parkinson’s disease (PD)

In recent years, a promising new mechanism has been proposed in which it is the misfolded α-syn itself which is responsible for transmitting the pathology from cell to cell. It has been shown that

α-syn is secreted by cells in the normal brain and that it is also taken up by both neuronal and non-neuronal cells. The abnormal, misfolded form of α-syn can also be secreted and taken up by cells. In addition the abnormal form is capable of inducing the normal form to misfold. Thus the disease pathology appears to spread throughout the brain via the transmission of misfolded α-syn between anatomically connected cells. We are examining this by creating misfolded α-syn and then injecting it into the brain and seeing if it is transported to regions distant to the injection site

as opposed to simply diffusing through the tissue. Once at the target site we will investigate whether degenerative changes are subsequently induced in the new site, thereby confirming how the disease is spread. In addition, it is believed that one possible route of entry for misfolded α-syn into the brain is from the gut to the brain stem via the vagus nerve. We will examine this by feeding misfolded α-syn to rats and examining the α-syn positive cells of the gut and the brain stem to see if the abnormal pathology has been transmitted.

Gambling and impulsivity in Parkinson’s Disease Chief Investigator: Dr Richard Blazé Co Investigators: Professor Malcolm Horne and Dr Andrew Evans

Approximately 20% of patients with Parkinson’s disease (PD) will develop impulsive and compulsive behaviours (ICBs) during the course of the disease. ICBs range from mild obsessions and hobbyism to disruptive behaviours that include compulsive buying, compulsive eating, hypersexuality, punding, and pathological gambling. In turn, ICBs often lead to financial burden, disruption of relationships, and occasionally criminal offence. Specific classes of drugs used to treat PD are thought to be the main contributors to the development of ICBs. However it is suspected that there may be several contributing factors including the direct effects of PD on cognition and motivation.

Indeed, there may be more than one type of ICB in PD. Recently we undertook investigations using the Parkinson Kinetigraph (PKG), a device worn on the wrist of PD patients that measures and records movement. The device also vibrates to remind patients when to take their medications, and patients acknowledge having taken them by pressing a button. Some patients were found to respond excessively to medication reminders. The extent of the excessive response was found to correlate closely with presence and severity of an ICB. Another much smaller subset of patients with ICBs did not demonstrate excessive responding and these patients differed from most

ICB patients by generating high apathy scores and by the absence of involuntary movements known as dyskinesias. Our hypothesis is that the two groups represent two different types of ICBs We plan to further examine the relationship between the development of ICBs, excessive response using the PKG and the effects of changing medications. We also plan to establish whether the two ICB groups differ according to the brain regions activated during ICB activity using functional MRI. Understanding the mechanisms that drive ICBs will inform better detection and management of this common and disabling feature of Parkinson’s Disease.

Short Glossary of Terms Novel –

Referring to that which is new, and/or original.

In Vitro – means in the glass. The experiment is carried out in a test tube or petri dish. In Vivo – means in life. The experiment is carried out using a living organism. 4

The Newsletter of the Brain Foundation

Hyper – means over, excessive or more than normal ie hyperglycaemia = high blood sugar. Hypo – means under, defective or inadequate ie hypoglycaemia = low blood sugar.

The impact of environment and behaviour on dopamine Chief Investigator: Dr Tim Aumann Co Investigators: Malcolm Horne and Henri Prijanto We are interested in how the adult brain adapts to changes in our environment to bring about behavioural changes. About 50 years ago it was discovered that new neurones are generated in the adult brain (‘neurogenesis’) and 40 years ago it was discovered that connections between neurones or synapses change (‘synaptic plasticity’). Recently, we and our collaborators have obtained evidence of another form of adaptation involving neurones changing the amount of dopamine they make and use to

communicate with other neurones (‘dopamine neurotransmitter plasticity’). We have so far shown that neurones in two different parts of the brain (the hypothalamus and the midbrain) exhibit dopamine neurotransmitter plasticity, they do this in response to environmental stimuli, and this leads to altered behaviour in adult mice and rats[1, 2]. Dopamine is strongly associated with rewarding outcomes of behaviour, movement control, and regulating hormones. Also, abnormal dopamine levels are associated with several important human diseases and disorders including depression, Parkinson’s disease, schizophrenia, ADHD and drug addiction. Many of these

diseases and disorders are treated with drugs that restore dopamine levels towards normal, however these drugs also produce serious side-effects because they alter dopamine levels throughout the brain, even in areas where dopamine is otherwise normal, and they change dopamine levels in artificial ways. Our research into dopamine neurotransmitter plasticity indicates we might be able to better treat these diseases and disorders by placing patients into environments that increase or decrease the amount of dopamine made by neurones in only those areas of brain that are affected. However, to progress along this line we first need to determine whether the environment

Dementia

stop working properly and eventually die. One protein that has been identified to do this is the transactive response DNAbinding protein 43 (TDP-43). The function of the protein is unknown. Understanding its function could provide clues as to what is causing FTD. There is now evidence from our laboratory and others that TDP43 is involved in maintaining connections or synapses between brain cells.

relay information to the neuron’s cell body, these synapses are present on small protrusions known as dendritic spines. TDP-43 has been shown to affect the number and maturation of spines. Therefor, it is feasible that an early disease-causing event in FTD may be changes to synapses. We will determine how TDP-43 changes lead to dendritic spine alterations in ‘real time’ through a unique mouse model and sophisticated imaging techniques, coupled with post mortem human FTD brain investigation. This novel research program addresses an important gap in the current understanding of how synaptic changes

Chief Investigator: Dr Catherine Blizzard Co-Investigator: Associate Professor Tracey Dickson Frontotemporal dementia (FTD) is a devastating disease affecting primarily the frontal and temporal part of the brain. It is the second most common form of dementia in people under the age of 65. In FTD proteins than play important functional roles in neurons inappropriately aggregate in the neuronal cytoplasm. This causes the neurons to

Synapses are specialised structures that allow neurons to communicate with each other. Changes in synapses can have serious effects on neurons and if not controlled can cause neuron death. In dendrites, the large structures that

triggers dopamine neurotransmitter plasticity in the humans as it does in mice and rats. Our recent Research Gift Award from the Brain Foundation enables us to proceed with some of these exciting experiments. 1. Aumann, T.D., D. Tomas, and M.K. Horne, Environmental and behavioral modulation of the number of substantia nigra dopamine neurons in adult mice. Brain and Behavior, 2013. Sep 7(doi:10.1002/brb3.163). 2. Dulcis, D., et al., Neurotransmitter switching in the adult brain regulates behavior. Science, 2013. 340(6131): p. 449-53.

can lead to neuron death in FTD and may open up a new target for drug intervention in this devastating disease.

The impact of brain stimulation on language functions in stroke patients

Chief Investigator: Dr Marcus Meinzer Co Investigators: Dr AmyRodriguez and Dr David Copland

Aphasia following stroke results from damage to the neural networks that underpin language processing and can impact all communication functions that utilize language. About 30% of all stroke patients suffer from aphasia and in a large percentage of these patients the condition persists more than one year after stroke. These chronic language impairments are among the most devastating consequences of stroke, by affecting vocational re-integration, social life and psychological well-being on the individual level and placing major burdens on the health care system. Due to the increasing pressure to provide more efficient rehabilitation services, there is an urgent need to explore new strategies to enhance treatment efficacy. In an

exciting recent development, non-invasive transcranial direct current stimulation (tDCS) has shown promise in improving language function in post-stroke aphasia. Yet the neural mechanisms underpinning language facilitation by this new approach are not known. This study aims to exploit recent developments in brain stimulation paired with neuroimaging technology, to address the neural underpinnings of improved language functions in post-stroke aphasia induced by tDCS. This will be accomplished in a placebo (“sham”) stimulation controlled cross-over functional magnetic resonance imaging (fMRI) study with simultaneous (intrascanner) tDCS. The design allows assessing in parallel the impact of the stimulation on language

production and functional brain activity and connectivity. We hypothesise that improved language processing during atDCS compared to placebo-stimulation will result in enhanced neural efficiency in stimulated language-related networks as assessed during fMRI. This study will help to optimize the effectiveness of future clinical trials that administer speech therapy in combination with brain stimulation in aphasia, to provide more efficient rehabilitation services. Improving outcomes for individuals with post-stroke aphasia would have a major impact on the community, given the significant negative social and economic effects of this common condition on the individual and their family.

Summer 2013-2014

2013 Research Gift Awards Glioblastoma stem cell – derived microvesicles Chief Investigator: A/Professor Michael Buckland Co Investigators: A/Professor Catherine Suter, Mr Edwin Lau and Professor Gilles Guillemin very rapidly (weeks to months) and are almost invariably fatal. According to a recent Victorian study, the average survival for GBM patients was only 8.1 months.

Glioblastomas (GBMs) are the most common and most malignant primary tumours of the brain. Most GBMs arise

GBM cells often exist and thrive in environment relatively low in oxygen and/ or blood flow. This environment seems to promote “tumour stem cells”, which are often considered as being the drivers of GBM growth, recurrence, and resistance to modern therapies. Currently the mechanisms by which GBMs manipulate their environment to promote tumour growth are still poorly understood. However there is growing interest in

the fact that many GBM cells release numerous small particles (microvesicles) filled with proteins RNA and DNA, which are able to deliver their cargo to other cells nearby, and even to distant parts of the body. This has been dubbed the biological equivalent “tweeting”, in that these information-rich particles allow continuous real-time communication between cells. In this project, we hypothesised that these small particles mediate much of the properties of GBM stem cells, in that they drive GBM tumour growth and mould the brain landscape to facilitate tumour infiltration and resistance to treatment.

We plan to harvest these microvesicles from GBM stem cells in culture, examine their cargo, and examine the effects they have when added to other brain cells in culture. We are particularly interested in the small non-coding RNAs, as our previous work has shown that microvesicles are enriched in unusual and novel noncoding RNAs. We believe that understanding how these microvesicles function in brain tumours will uncover new targets for brain tumour therapies in the future, and also point to potential new blood tests for the diagnosis or monitoring of brain tumours.

Improving brain tumour care on-line Chief Investigator: A/Professor Kate Drummond Co Investigators: A/Professor Lynette Joubert, Professor Fetnando Martin-Sanchez, Ms Heidi McAlpine, Mr Mark Merolli a multidisciplinary outpatient clinic, at regular appointments. Distance, disability, and the inability to drive due to seizures can make this episodic and centralised approach to care inadequate. Similarly, attendance at patient support groups and the ability to share experiences, may be difficult.

The specialised care of brain tumour patients is generally undertaken at tertiary, centralised hospitals, often in

We aim to build an online therapeutic community to overcome these barriers, allowing people with brain tumours to connect with their treating team, other patients and educational resources. Elements of the platform will include online access to the treating team, including for advice and remote appointments and

the ability to connect with other patients for support through social media. In the first part of this project, we reviewed the literature to assess the evidence for benefit from on-line interventions for people with cancer. We found surprisingly little information despite many described platforms and in some cases evaluation had shown the platform to be of no benefit, or even harmful. Therefore, a second phase is planned, made possible by the generous support of The Brain Foundation. We will undertake a detailed needs assessment survey of hundreds of people with brain tumours through The Royal Melbourne Hospital, linking it to

quality of life measures to allow rational design of our planned platform. This will be an important and unique approach, as most on-line resources for cancer patients are developed without their input. With this valuable information, we will seek further funding to build the online community and rigorously assess its benefit in a randomised trial. We aim to help people with brain tumours enjoy a better quality of life, by bringing them closer and more conveniently to their treating team, their fellow travelers on the journey and quality information.

Human neural stem cells in the development of medulloblastoma Chief Investigator: Dr Jacqueline McGlade. Co Investigators: Dr nicholas Gottordo, Dr Peter Dallas and Dr Raelene Endersby the most significant cause of childhood medulloblastomas may look the same transform normal human neural stem cancer-related death. down a microscope, when examined cells into cancer-causing cells by altering more closely at the genetic level, they specific genes that are implicated in If we are to improve the outcomes of are not all the same and in fact there medulloblastoma. Not only will this children with these cancers it is imperative are at least four distinct subgroups of research inform us as to how a normal that we have a good understanding of these tumours, each arising when certain cell can become a cancerous cell, but what drives tumour growth, which will subsets of genes malfunction in specific these cells will become critical tools allow us to design better treatments. cells within the brain. for future work. With these models we We have known for a long time that some can understand what genes are directly Previous laboratory studies have shown patients with medulloblastoma respond involved in medulloblastoma formation, that mimicking these genetic changes in well to treatment, but others do not and which will enable us to select and test mouse neural stem cells can cause these are likely to die from their disease. In the specific, targeted drugs in order to find cells to behave like medulloblastoma, past we haven’t had enough information more effective therapies with reduced Medulloblastoma is the most common to understand why this is, but recent however this has never been shown side effects for children with this disease. malignant brain tumour in children and research has revealed that although in human cells. In my study, I aim to 6

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Multiple System Atrophy MSA-specific α-synuclein gene (SNCA) expression seems to play a fundamental role in the induction and persistence of the α-synuclein accumulation in MSA.

Chief Investigator: Dr Michael Janitz Multiple system atrophy (MSA) is a sporadic and rapidly progressive neurodegenerative disorder that presents clinically with autonomic failure in combination with Parkinsonism or cerebellar ataxia. The pathology of MSA is the presence of misfolded, fibrillar α-synuclein in oligodendroglial cytoplasmic inclusions. The cause of MSA is unknown: no specific risk factors have been identified, and there is no cure or effective treatment. Therefore, urgent efforts are required to properly understand this disease in order to develop appropriate treatments. Although clinically well-defined, the molecular pathophysiology of MSA has barely been investigated. In particular, there have been no systematic studies of the perturbation of the brain transcriptome during the onset and persistence of this disease.

Clean Traumatic Brain Injury Chief Investigator: Dr Justin Moore Co-Investigators: Profesor Jeffrey Rosenfeld, Dr Piers Thomas, Dr Dashiell Gantner, Dr Owen Roodenburg, Mr Nicholas Maarents and A/Profssor Allen Cheng Traumatic brain injury is a major health care burden world-wide. Approximately 108-332 case of head injury per 100,000 population are admitted to hospital each year. Of those with severe head injury (generally arriving in a coma) up to 40% of these die per year and

Comparative α-synuclein protein characterization between MSA and Parkinson’s disease (PD) strongly suggests the presence of a unique alternative splicing pattern for SNCA which leads to accelerated translation of α-synuclein in the MSA brain. Moreover, evidence from our own research suggests that this posttranscriptional process is accompanied by MSA-specific down-regulation of the β-synuclein gene (SNCB), which has been recently identified to inhibit aggregation of α-synuclein. We therefore propose a hypothesis that, compared with PD, MSA has a fundamental dysregulation of transcription causing increased expression of the α-synuclein protein. In this project, to be funded by the Brain Foundation, we will determine the pathomechanism which leads to the perturbation of α-synuclein expression and its aggregation in oligodendroglia using next-generation sequencing analysis of MSA brain transcriptome followed by validation studies on the mRNA level. This project is significant to a resolution of the pathogenesis of the clinically similar MSA and PD α-synucelinopathies. Through identification of transcriptional isoforms which are specific to MSA, this project will deliver potential molecular markers and targets for pharmacological intervention.

60% have severe disability. External ventricular drain (EVD) catheters are integral to the management of patients with severe traumatic brain injury (TBI), both for monitoring of intracranial pressure (ICP) and therapeutic diversion of cerebro-spinal fluid (CSF). As with other interventions the possible benefits must be weighed against the possible complications. A common and potentially devastating complication of EVD insertion is catheter-associated infection, with reported rates of 3-22% in heterogenous neurosurgical populations. Development of ventriculitis causes significant morbidity and can worsen long terml outcome of patients, and is associated with significantly increased health care costs as a result of increased medical interventions, increased intensive care unit (ICU) and hospital lengths of stay,

The effect of infrared light in Parkinson’s Disease tissue, inducing self-repair of damaged cells, but we have recently shown that the brain is also protected by irradiation of remote tissue, such as the dorsum of the body.

Chief Investigator: Dr Dan Johnstone Co Investigators: Professor Jonathan Stone and Professor John Mitrofanis Current therapies for Parkinson’s disease (PD) relieve the clinical signs and symptoms of disease but do not prevent or even slow disease progression. Thus there is an urgent need for safe, readily administered treatments capable of preventing disease progress. Our research using animal models of PD has shown that irradiation of tissue with low-energy near infrared light (NIr) can protect the brain against the damage associated with PD and partially restore normal movement. Yet it is unclear exactly how this treatment has its protective effects. Most previous work has assumed that NIr acts directly on the damaged

and post-acute care costs. Antibioticimpregnated EVDs are of uncertain benefit. Antibiotic-impregnated EVDs have been trialed with variable success; however previous trials did not include representative TBI populations, and it remains unknown whether their use in TBI patients can improve outcomes and reduce health care costs. Additionally, the rate of EVD-associated ventriculitis occurring in Australian patients with TBI has not been established. As a result of these uncertainties, considerable practice variation currently exists with both antibiotic-impregnated and non-impregnated EVDs being used. Independent, investigator-initiated randomised evidence is needed to guide local practice. This study seeks to enhance an established process of care. This will be a prospective, randomised

This project will investigate how NIr protects the brain, addressing the central question of whether treatment must directly target the damaged tissue or whether instead it remains effective when targeted at remote tissues. Specifically, we will test the novel idea that NIr-induced neuroprotection is mediated by stem cells that are released from the bone marrow, circulate in the blood stream, congregate in sites of damage and induce repair of damaged nerve cells. This research has important implications for translating NIr therapy into a treatment. While NIr has shown great promise in animal models, there has been skepticism about its usefulness for humans, stemming from the assumption that light would need to penetrate the thick human skull and large brain of humans to reach the deep sites affected in PD. If the indirect neuroprotective actions of NIr are confirmed, the problem of reaching deeply embedded sites in the brain becomes irrelevant. We strongly believe this work has the potential to open novel therapeutic avenues for PD and other CNS degenerations that currently lack effective treatment.

controlled trial comparing the effect of antibiotic-impregnated EVDs on incidence of ventriculitis when compared with standard EVDs. The results will help improve the care and outcome of patients suffering TBI, as well as optimizing health care resource allocation.

Summer 2013-2014

2013 Research Gift Awards Investigating intrabody-mediated The diagnosis of vestibular migraine targeting of pathogenic tau as a novel therapy for who seldom experience headaches find it impossible to believe that their vertigo Alzheimer’s disease results from “migraine”.

Chief investigator: Dr Rebecca Nisbet Co-investigator: Professor Jürgen Götz There are over 300,000 people in Australia currently living with dementia and this number is expected to double by 2030 if there continues to be no effective treatment. Alzheimer’s disease is the most common cause of dementia, accounting for approximately 70% of all dementia cases. One of the main pathological hallmarks of the disease is the formation of large protein tangles, composed of the aggregated protein tau, within neurons. The normal function of tau is to stabilise the cells transport system. In Alzheimer’s disease, however, tau becomes modified by a process known as phosphorylation.

This causes tau to aggregate into tangles and results in neuronal degeneration through a mechanism that is still relatively unclear. Ongoing work by our group at the Clem Jones Centre for Ageing Dementia Research aims to develop Alzheimer’s disease therapeutics, which prevent tau phosphorylation and its formation into tangles. The greatest challenge, however, is to generate molecules that are also capable of entering the neuron where tau is predominately localised. A novel mechanism to achieve this is to use small, intracellular, antibody fragments called intrabodies. We are currently developing intrabodies, highly specific for phosphorylated tau, which are localised within neurons. These intrabodies are engineerd to not only prevent the aggregation of tau but also promote its clearance by taking advantage of the cells protein degradation machinery. The funding we receive from the Brain Foundation will enable us to test the efficacy of the novel intrabodies in clearing phosphorylated tau and delaying the onset of disease in transgenic mouse models. We envision that this work will provide a strong foundation for progression of these intrabodies into human clinical trials.

Chief Investigator: Dr Sally Rosengren Co Investigator: Dr Miriam Welgampola This project aims to improve the diagnosis of patients with vestibular migraine, a common and treatable cause of episodic vertigo. Vertigo is the illusion of movement and is a debilitating symptom of inner ear vestibular (balance) dysfunction. Vestibular migraine is a form of migraine in which patients experience recurring episodes of vertigo, which sometimes coincide with a migraine headache, an aura or sensitivity to sound or light. The diagnosis is seldom straightforward since episodes of vertigo can sometimes occur without an accompanying headache. Episodes can vary in character from true spinning, rocking or tilting sensations to light-headedness; symptom duration can range from seconds to days! Patients

The duration of vertigo attacks can also vary greatly between other vestibular diseases. This means that depending on the duration of vertigo episodes, vestibular migraine can mimic several different inner ear disorders. For example, very short episodes lasting seconds can be difficult to distinguish from benign positioning vertigo, intermediate episodes lasting hours are similar to Meniere’s Disease and prolonged episodes lasting days can be confused with vestibular neuritis. In this project, we will recruit patients with vestibular migraine based on the duration of their attacks and compare their vestibular function test results to those of the closest mimic. By using new, non-invasive tests of vestibular function that test all five parts of the vestibular system we will build a diagnostic profile that will help identify vestibular migraine by the pattern of clinical features and test results. This research will reveal the commonalities and differences between vestibular migraine and other common vestibular diseases. Measurement of the function of each vestibular end-organ will provide a disease profile to enable easier recognition by clinicians and facilitate early initiation of treatment.

Reducing scar formation after stroke to promote brain repair Chief Investigator: Dr Carli Roulston Co Investigators: Professor Phil Beart A/ Professor Chris Williams, Professor Greg Dusting With an incidence of 50,000 strokes in Australia each year, and a mortality rate of approximately one third, stroke is the second most common cause of death and disability world-wide. Although many patients experience some recovery without therapeutic intervention, significant functional loss often ensues due to a failure of nerve cells to re-grow across the injury site. Nevertheless, a slow but consistent recovery can be observed in a cross section of patients

during rehabilitation, and damage to the brain has now been shown to trigger brain remodelling and the generation of new stem cells. Despite this response to injury, very few stem cells convert into nerves for replacing damaged circuitry, most likely due to critical events such as inflammation and toxic signalling. Indeed studies in our laboratory now show that many stem cells generated in response to injury contribute to extensive glial scar formation that acts as a physical barrier to re-modelling and brain regeneration (figure 1). A more supportive environment devoid of scar tissue is required to facilitate brain repair Our research currently focuses on the

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use of two new treatment strategies to manipulate the brain environment after stroke to support brain remodelling. The first involves delayed treatment with an enzyme inhibitor that has the potential to reduce scar formation in the weeks after stroke, and at the same time promote nerve regeneration. The second approach involves the use of non-invasive electrical brain stimulation to promote the growth of new blood vessels across the damaged tissue as well as stimulate nerve reorganisation. By breaking down the scar and stimulating the damaged brain to rewire, we hope that this approach will improve and accelerate functional recovery. Importantly these treatment strategies are already approved

for individual clinical use in other models of neurological disease. Any positive results obtained from these studies might therefore be fast-tracked for use in human stroke.

Minimally Invasive Deep Brain Stimulation Chief Investigator: Dr Thomas James Oxley Co Investigator: Dr Nicholas Lachlan Opie Deep brain stimulation involves the implantation of electrodes into deep brain structures with millimetre precision. It has led to a significant improvement in the lives of patients with a range of neurological disorders including Parkinsonâ&#x20AC;&#x2122;s Disease.

Dystonia is a poorly understood medical condition that leads to sustained muscle contraction. This condition can be extremely disabling for patients, who persistently maintain abnormal posture. There are medications available that aim to reduce muscle contraction, but no cure is available.

We are investigating methods of delivering deep brain stimulation from within a blood vessel in the brain. This method is analogous to the method used to deposit stents to treat heart attacks. We enter the brain via a blood vessel in the groin, with no invasive brain operation, or craniotomy, necessary.

Deep brain stimulation has proven to be successful for some people with Dystonia and can lead a significant improvement in their quality of life.

We hope to be able to one day expand the use of deep brain stimulation using a safer and cheaper method, that will enable a broader range of patients access to this promising technology.

Understanding energy requirements in Duchenne muscular dystrophy

Chief Investigator: A/Professor Monique Ryan Co Investigators: Dr Zoe Davidson, Professor Helen Truby and A/Professor Andrew Kornberg

Duchenne muscular dystrophy (DMD) is the most common and severe muscular dystrophy of childhood. Affecting 1 in 3,500 boys, the natural history of the disorder is characterised by relentlessly progressive muscle weakness that usually first manifests in boys ~3 to 7 years old. The last decade has seen considerable developments in treatment for males with DMD, including the virtually universal use of corticosteroids. Despite these recent advances, the nutritional issues associated with DMD are complex and remain poorly understood. Many boys with DMD experience excessive weight gain from as early as seven years of age; and this is often a cause of great parental concern.

The effects of increased weight can be extremely debilitating. Obesity can contribute to the progression of the disease by exerting extra force on already weak muscle groups, decreasing mobility. Our own data demonstrate that 50% of Australian 10 year old boys with DMD are obese. This is an alarming statistic when compared to Australian population data; 7% of boys aged 9-13 years old are obese. Understanding energy metabolism in DMD is fundamental to the provision of appropriate nutrition counselling to prevent or manage obesity, but the relationship between energy expenditure and body composition remains unclear. This project aims to investigate

how energy requirements and body composition change over time in males with DMD, and to determine if a reduction in energy needs is related to weight gain in these children. Specifically, this prospective cohort study will recruit 20 boys with DMD aged 7-9 years. Energy expenditure will be measured using gold standard methodology (doubly labelled water) together with body composition from DXA at four points over a three year period. Results from this study will be used to inform the creation of specialised dietary protocols for weight management in DMD.

Using cells derived from teeth to promote functional recovery following a stroke

Chief Investigator: Professor Neil Sims Co Investigator: Professor Simon Koblar

Many stroke patients show improvements in their symptoms during the first few months after the disease develops. The improvements result in part from changes in surviving nerve cells around the area of damage in the brain. These nerve cells take on functions of cells that were lost during the stroke. There is growing interest in producing treatments that can promote changes in the nerve cells and enhance recovery. Such treatments have the major advantage that they can improve outcomes for patients when initiated many hours to days after stroke onset. The studies will bring together expertise from two groups of researchers with interests in the processes associated with

recovery following a stroke. Professor Simon Koblar and his colleagues at Adelaide University have been investigating the possibility of treating stroke using cells known as stem cells derived from the pulp of impacted teeth removed from young adult humans. Injection of these cells into the brain of rats following an experimental stroke improves functional recovery. Research led by Professor Neil Sims at Flinders University is characterizing alterations in support cells, known as glial cells, in the brain and investigating the involvement of these cells in limiting recovery from stroke.

whether the positive effects arise, at least in part, by modifying the glial cells in ways that can promote recovery of nerve cell function. The studies will also test whether the stem cell treatment is effective in a second stroke model that better mimics some aspects of this disorder in humans. The studies have good potential to identify new targets for treatments that can be used alone or in combination with stem cells to improve recovery following a stroke.

The studies will build on the exciting finding with dental pulp stem cells by investigating

Summer 2013-2014

Research Grants – Progress Reports Nerve and Muscle Excitability in Inclusion Body Myositis Chief Invesigator: Dr Jessica Sylvester Co Investigator: Dr Karl Ng Sporadic inclusion body myositis (sIBM) is the most common form of acquired myopathy in people over the age of 50 years. It has been estimated that it affects more than 1 in every 20,000 Australians. This disease is more common in men than women and causes weakness of limb muscles as well as swallowing difficulties. sIBM is a slowly progressive disease and in more severe cases affected people may become wheelchair bound. The cause of this disease is poorly

understood. It causes degeneration and inflammation of the muscles, but what sets this off is unknown. It appears to involve both dysfunction of the immune system and abnormal protein accumulation inside the muscle cells. There is no known effective treatment for sIBM. Recently developed computerized neurophysiological techniques allow the study nerve and muscle excitability, which is an indirect measure of cell membrane function. Electrical dysfunction of the cell membrane can occur under several circumstances and these studies give clues as to where the problem is occurring. This includes dysfunction

of ion channels and pumps in the cell membrane as well as problems with energy supply to the cell, which can result from problems with the blood supply or mitochondria, which are the energy generators within each cell. This project will use these recently developed techniques to characterize the change in nerve and muscle excitability in patients with sIBM. We hope to shed light on whether electrical dysfunction of nerve and muscle cells in sIBM plays a role in the development of symptoms and this may in turn lead to development of more effective therapies through a better understanding of the mechanisms of disease.

Headache News For those supporters who are not on our HEADACHE REGISTER, we have had some great news on the drug front for chronic headache and migraine sufferers.

BOTOX® Botox has now been approved by the PBS for use on adult patients with chronic migraine. Chronic migraine is defined as headache on at least 15 days per month, with migraine on at least 8 of those days. You will need to consult with your neurologist for this treatment and they can advise eligibility and treatment options.

DHE / Dihydroergotamine Now Available In Australia Following the discontinuation of this drug, many of our Headache supporters were dismayed by the lack of effective options available for them. Well, we are very pleased to advise that there is now a manufacturing pharmacy in Adelaide, who can supply this drug on prescription. They will ship around Australia. Please contact Green Dispensary Pharmacy, S.A. on (08) 8363 7322 for further information.

Genetic Testing Still Available Phase 3 trials are proceeding for the treatment of migraine using B group vitamins and there is some hope that this treatment may be on the market towards the end of 2014. In the meantime, if you would like to obtain your own diagnostic test, please see http://www.genomicsresearchcentre.org/flash/contact/htm for further information.

Professor Lectures About Latest Advances Headache Australia was pleased to bring Prof. Paul Rolan to Sydney for a talk to Register Members on headache and migraine best practices and latest advances in treatment. Held at the Kolling Centre in RNSH during Headache Awareness Week, our supporters gained some valuable insight into treatment options and new drug research.

Understanding & Treating Headache Symposium, Sydney In October, many of Australia’s leading Headache and Migraine specialists attended this symposium to explore the best clinical practices in understanding and treating headaches. Organised by the Pain Management Research Institute, they explored many treatment options and some new approaches. We hope that this may lead to some new option for the many sufferers of chronic headache and migraine. We will keep you posted.

A special thank you to Hydralyte for their support during Headache and Migrane week.

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

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Exercise your brain Remember all brainiacs... an active brain is a healthy brain! Try this intriguing puzzle for size, and remember, you can receive puzzles like this one for free via e-mail by signing up to the Brain Food Factory. Now that is good value!

Summer 2013-2014

Get Involved Cerebral Lupus – A Patient’s Perspective Just over two years ago, supporter Venette Hedges contacted us to let us know she was writing this book about her journey with Cerebral Lupus. A debilitating auto-immune disease, Cerebral Lupus attacks the brain. Venette has written about her experiences with this terrible condition, from diagnosis to today, and we are pleased to now have her book available for sale to anyone who may be affected or have a relative or friend diagnosed with the condition. Please contact our office or Lupus NSW for a copy.

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In Memorium The Brain Foundation would like to extend our very sincere thanks to the families of the following who supported us in a time of great sadness and loss. Jayne SHORT Ben CHUWEN Mark PAYTON Michael PROWSE Tristan EDDY

Supporting Brain Research – treatments for the future! Our Research Gift programme is highly sought after by our country’s best and brightest researchers with many more applications received at the Brain Foundation than we are able to fund. Please help us increase our annual amount provided to these researchers by fundraising on our behalf. You can organise your own event, as some people in this edition have done, or you can join in a public event. Everyone has a brain! No one can live without one! Please see: www.gofundraise.com.au, www.everydayhero.com.au, www.mycause.com.au Our thanks go to the following people who have used these sites to raise funds on our behalf: Go Fundraise: Lisa McInnes, Dylan Boone, Charmaine & Kimbly Hollywood, Megan Dunbar. Everyday Hero: Brett Pedler, Megan Kitely, Rachael Bode, Scott Clayton, Georgina Cross, Dimi Rigas, Kate Muldowney, Elise Wright, Alexandra Sady, Kirrali Doecke, Bethany Richards, Veronika Andrijanic, Scott Williams, David Spurling, Gab Kane, Brad Nicol, Martin Nicol. My Cause: To the Brisbane Zombie Walk and supporters who raised over $5,800 and the Perth Zombie Walk and supporters who raised $7,400 our most grateful thanks.

Regular Giving: If you would rather make a donation than join an event, it may be worth thinking about making a monthly or quarterly donation. Contact our office or download a form and send it in; we will do the rest for you.

Workplace Giving:

Roma June SPENCER Neil HOILE Claire DOONAN Lilian ALLEN Sean MC MULLEN Lorraine DONALDSON Christine MURPHY Mario SPRALJA Daroslav SPRALJA

Bequests Thank you to the Estate of Nancy Ann Geraty for generously donating to our Brain Research Programme.

In Celebration Congratulations go to Meaghan Davies and Anthony O’Donohue who have raised funds on our behalf to celebrate their Engagement.

Thanks to the following companies for their support:

Alternatively you may have the option of Workplace giving. Your employer can organise this for you and no further paperwork is required. Speak with Gerald if you would like more information.

Estate Planning and Bequests: Our benefactor, Australian Executor Trustees is pleased to offer reduced fees on their Estate Planning Service for Brain Foundation supporters. If you would like more information or a booklet, please call Gerald in our office.

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