2017 summer brainwaves newsletter

brainWAVES The Newsletter of the Brain Foundation

Summer 2017-2018

Brains, pains and migraines How well do you know yours?

Imagine for a moment that you were diagnosed with diabetes. Would you listen to your doctor’s advice and follow a treatment plan? Or, would you leave the surgery thinking that you could look after your own health?

Asthma can be life threatening. It requires careful treatment and constant care. If your child was diagnosed with Asthma, wouldn’t you treat them medically as you were advised? Would you think that you didn’t need the doctor’s help to keep your child healthy?

Now, think about being diagnosed with Migraine. Many of you are – as much as 15% of the population – or possibly even higher. (Exact figures in Australia have not been ascertained). Yet, only 2% of people diagnosed with migraine used a preventative in the last year. Only 5% who suffer chronic migraine have an adequate diagnosis and treatment. Now, that would mean a large number of people diagnosed – DO NOT FOLLOW A MEDICAL PLAN! They are going it alone and treating themselves, and this can lead to chronic medication overuse headaches as well as the migraines.

Does that sound like a plan? Maybe not a very good one.

Migraine is not a trivial problem and is often not recognised as a neurological disorder. It is more common than diabetes and asthma combined and has similarities to epilepsy.

It is really important is that you get a proper assessment, diagnosis and management plan. There can be a few physiological reasons for migraine and it is important that you get as accurate as possible diagnosis as this then affects the treatments offered.

Remember that you often don’t get things right the first time and the first medication offered may not be the one which treats you the best.

Improve your health literacy – seek treatment, seek control!

To help raise awareness, we encourage all sufferers to join our Headache Register. It is free and you get access to wonderful information and webinars from leading practitioners in Australia.

Our thanks to A/Prof Susan Tomlinson, from whose presentation during Headache Week, these statistics have been taken. To see the full discussion via the webinar, e-mail for more details.

Summer 2017 Edition Welcome to our Research Gift Awards edition. We hope you enjoy reading about the projects being undertaken by these enthusiastic researchers.

The Directors and Staff of the Brain Foundation would like to take this opportunity to sincerely thank all of our supporters, donors, fundraisers and corporate sponsors and the many neurologists and neurosurgeons who are available to help and advise us. Without you, we could not do the work that we do.

Only 2% of

people diagnosed with

migraine used

a preventative

in the last year.

Only who suffer

5%

chronic

migraine adequate

have an

diagnosis

and treatment.

We wish everyone a very happy, relaxing and enjoyable Christmas and holiday period.

The Brain Foundation office will be closing over the Christmas and New Year period. Your receipts will be issued in January 2018.

Thank you for your understanding.

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

Fabulous Fundraisers Team Steph – breaking more than City 2 Surf records In Memory of Stephanie 1986 - 2007 Named after their much loved daughter and sister, Team Steph first began running and fundraising for Brain Foundation in 2012.

In that time, they raised tens of thousands of dollars and the teams have been getting larger and larger with 2017 being the biggest team ever.

But 2017 is a special year.

2017 Team Steph

To remember the 10 year anniversary of Stephanie’s passing, the Ledonne family held a Memorial Dinner to raise even more in her memory. Representing the Brain Foundation, A/Prof Karl Ng and Fiona along with 300 guests attended the Memorial held at the end of June. Entertainment, food and prizes were generously donated to help make this a very

Stephanie Ledonne Memorial Dinner

– for Chiari Research, of course

Zombies have risen and seen the light

Thank you to Chloe Koch who again rallied her friends at Harristown State High School, Toowoomba for a day in purple. Chloe has been very active over the last few years raising awareness of this terrible condition.

A great big thank you to the organisers of the many Zombie walks around the country. Coinciding with Halloween, the Zombies offer an opportunity to dress up and have some gruesome fun.

Thank you Chloe for all your work and we wish you well with your future studies.

They are also valuable support for our research programme.

Purple Reign

Many thanks to the organisers of Melbourne, Sydney, Canberra, Tamworth, Townsville and Cairns zombie walks.

successful and enjoyable evening.

The families fundraising efforts over the last five years have been spectacular and have funded many projects along the way. We are very grateful for the efforts they have gone to on our behalf and recognised the family at this years’ award ceremony.

Daniel Ledonne recognised at the recent Research Gift Awards.

Ray White – what a night!

Andrew and Greg Bell and their Events Manager, Selena Carson were again in control of the 23rd Gold Coast Charity Ball this year. This is great community service from the proprietors of Ray White Real Estate, Surfers Paradise, and the community responded with all 750 tickets sold The bidding was strong for the auction items and it is not surprising that the digital age has arrived for the silent auction. All the items are now on an “app” and everyone who wants to bid uses their mobile phone. How easy is that?

Proceeds from the Ball are shared between the Brain Foundation to build a fund for research into Muscular Dystrophy and Muscular Dystrophy Queensland to support those suffering and their families.

Thank you to everyone for another terrific night.

Tamworth Fair – where the sun always shines Thank you to the organisers and helpers at the Tamworth Fair. This is always a great event and if you are ever passing by Tamworth in November and would like to go along, then call our office for the details!

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The Newsletter of the Brain Foundation

Belinda and the terrible day Belinda Cordery from NSW north coast is a very lucky person.

Struck down by a burst aneurysm, no one was aware just how serious her condition was.

Transported by ambulance to a larger hospital and then by helicopter to an even larger hospital in Brisbane, she survived the ordeal with her sense of humour intact and a new lease on life. Feeling blessed to have fully recovered, Belinda is now spreading awareness about just how quickly an aneurysm can take hold and fundraising to help find better treatment options.

Thanks for your fabulous efforts, Belinda and to the local Lismore businesses supporting you.

Headache Australia Headache and Migraine Awareness Week – September 2017 During this year’s Headache and Migraine Week, Headache Australia aimed to reach as many sufferers as possible.

Over the last few years, our register members have told us that it was difficult to get to the live talks that we were presenting, so this year we offered a series of Webinars on various topics over several nights, culminating in a live discussion in Sydney by two leading Headache professionals – A/Prof Susan Tomlinson and Dr Bronwyn Jenkins. This talk was streamed to a larger audience and a question and answer segment was included. This was very well received by both the audience and the on-line audience.

If you would like access to these Webinars and video, you need to be a Headache Australia Register member. Please join up and then email info@brainfoundation.org.au for the links.

Our very sincere thanks go to Susan and Bronwyn for very kindly donating their time for this event.

Cefaly Trials – more popular than Santa Claus In our last issue of Brainwaves, and following a media push by the distributors of Cefaly, we now have a very long waiting list for the “try before you buy“ Cefaly programme.

If you have contacted our office, your name will be on the list. If you would like to be on the list, you are most welcome to put your name down, but please be aware you will be waiting until at least the middle of next year before we can offer you a trial. We do have over a dozen machines in the programme. A credit card number is required for the secure return of the machine.

Please email Brain Foundation with your contact details and phone number.

WORLD FEDERATION OF NEUROLOGY (WFN ) Honour for Brain Foundation (Victoria) Director, Professor Tissa Wijeratne.

The WFN recognised the considerable contributions of Professor Tissa Wijeratne to their educational activities over many years, at the World Congress of Neurology (hosted by the WFN) during September in Kyoto. The award is named for the late Professor Ted Munsat and his pioneering work, over many decades of contributions, establishing advances in diagnoses and treatments of patients.

Professor Wijeratne is the first recipient of the prize.

Other Australian neurologists making significant contributions to the WFN Neurological Research Foundation are Professor Bill Carroll from Sir Charles Gardiner Hospital in Perth and Professor Richard Stark from the Alfred Hospital in Melbourne. Professor Carroll is the President designate and Professor Stark is the Treasurer.

There’s light on the horizon Our supporters with migraine will be excited to hear about a new treatment in the pipeline. It is called the CGRP monoclonal antibodies. CGRP stands for calcitonin gene-related peptide. CGRP is an important molecule that is involved in the migraine cascade. These new treatments will be used preventatively meaning they are prescribed to be taken on a regular basis to prevent attacks from occurring.

There are over four different companies who are testing and manufacturing this new generation treatment which will provide some competition and choice for patients. Results from Phase 3 clinical trials show a strong safety profile and significant reductions in migraine frequency. These treatments are expected to be available in Australia in the next few years shortly after the US.

Register Member?

Or know someone who would benefit?

Call us or join on the Headache Australia web page Our register members receive regular emails with current information and research opportunities.

They also have access to our online webinars and seminars – which many have said they find very helpful.

As a Headache Australia member, all of your donations go directly to Headache Research projects.

Disclaimer: Headache Australia is not a medical office and cannot offer medical advice. We stress the importance of discussing any issues you have with your medical practitioner.

Summer 2017-2018

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2017 Research Gift Awards September is always an exciting time in the Brain Foundation office. We have received the award winning applications for the grants and are organising the award event, which is always characterised by the enthusiasm of the recipients for the research they are doing. Australians are truly lucky to have the talented researchers that we have. We only wish we could support more projects every year with larger funding.

You can read all about the latest 2017 Awards on the following pages.

This year we were grateful to have Mark Haberlin, Chair of the PwC Governance Board, as our guest of Honour to present the award recipients with their certificates. Thank you Mark.

The Directors and staff extend their thanks to the scientific committee for their work assessing the many applications that we received. Each one is assessed before the final decision is made.

We also extend our very sincere thanks to all our donors, fundraisers and corporate sponsors, without whom our valuable work could not continue.

▼ ALZHEIMER’S AND NEURO DEGENERATIVE DISEASES

A novel biomarker for younger-onset dementia A diagnosis of dementia results in significant distress for the individual, their family, and wider social network, and places considerable burden on already overstretched health resources.

Frontotemporal dementia (FTD) is the second most common type of presenile dementia, after Alzheimer’s disease, resulting in progressive changes in behaviour, language, and thinking.

Chief Investigator: A/Professor Muireann Irish Brain and Mind Centre, University of Sydney Co-Investigator: Dr Christopher Madan

Using patient stem cells to model Alzheimer’s disease Chief Investigator: Dr Damian Hernandez Centre for Eye Research Australia, Victoria Co-Investigator: A/Professor Alice Pébay Alzheimer’s disease, the most common type of dementia, is a chronic, progressive disease that leads to the degeneration of neurons which are key to the function of the brain. Despite enormous research efforts Alzheimer’s disease still not fully understood. One of the major

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The ideal time to treat neurodegenerative disease occurs before clinical presentation, at a point when the minimum disruption to the brain has occurred. One of the greatest challenges in clinical neurology therefore is to identify individuals most at risk of developing dementia, prior

limitations of understanding Alzheimer’s is the technical difficulty of studying the human brain. Additionally, current animal models used to model Alzheimer’s do not fully recapitulate the disease.

Understanding the mechanisms that result in pathology is crucial for developing treatment strategies to prevent or slow progression of this disease.

We propose to develop a human model of Alzheimer’s disease using patient stem cells.

Advances in stem cell technology now allow researchers to generate induced pluripotent stem cells from adult tissue samples such as skin biopsies. These stem cells have the capacity to become

The Newsletter of the Brain Foundation

to the emergence of cognitive impairment or behavioural changes. Here, we address this research challenge by exploring potential biomarkers that allow early identification of dementia, and ensure patients gain access to appropriate disease-modifying treatments.

This research project seeks to optimize the early and accurate detection of FTD using novel neuroimaging analysis techniques.

FTD is highly heritable, caused by genetic mutations in one third of cases. Using cutting-edge neuroimaging techniques, we will screen for subtle changes in the overall shape of the brain’s cortex in individuals with increased genetic risk for developing FTD.

We will determine signature changes in the shape of cortical and subcortical brain structures in high-risk relative to matched low-risk individuals, and will clarify how these differences in brain structure predict subtle changes in cognition.

Our novel approach will contribute the essential information to guide the screening, clinical diagnosis, and tracking of younger-onset dementia syndromes.

With Australia poised on the brink of a dementia epidemic, this project has the potential to significantly address this crucial challenge, optimising our ability to intervene effectively, and to improve the overall prognosis of the individual living with dementia.

any cell type of the human body, including brain cells. We use specific methods to create brain tissue in a three dimensional form that show some level of organisation corresponding to that found in the human brain.

In this body of work we will generate brain tissues from skin biopsies of patients with a specific form of a protein, APOE, that is associated with a very high risk of developing Alzheimer’s diseases. Using the latest gene editing technology, “CRISPR”, we will modify the APOE gene to investigate the role of APOE protein in Alzheimer’s disease.

The development of a human model of Alzheimer’s diseases

could be key to the generation of novel therapies for dementia, as this model will help researchers better understand Alzheimer’s disease and be a tool for new drug development.

▼ ALZHEIMER’S AND NEURO DEGENERATIVE DISEASE CONT.

▼ PARKINSON’S DISEASE

A blood based method for diagnosis and monitoring of Frontotemporal Dementia

Pre-clinical model in-vitro of human brain disorders

Chief Investigator: Dr Zac Chatterton Brain and Mind Centre, University of Sydney

Chief Investigator: Dr Cedric Bardy South Australia Health and Medical Research Institute

Co-Investigators: A/Professor John Kwok Professor Olivier Piguet

Co-Investigator: Professor Fred Gage South Australian Health and Medical Research Institute (SAHMRI Mind & Brain)

Frontotemporal Dementia (FTD) is a common early-onset neurodegenerative disorder in adults aged 45 to 64 years. It can be subtyped into behavioral-variant frontotemporal dementia (bvFTD), clinically defined by changes in personality and behavior, and primary progressive aphasia (PPA), the progressive impairment of language capabilities. The earliest neurodegeneration observed in bvFTD patients is found within the medial frontal and orbitofrontal brain regions. Similarly, in PPA patients, language disturbances are correlated with neurodegeneration of the languagedominant hemisphere. However, brain imaging (MRI) may appear normal in these early stages of disease. Therefore, neuropsychological symptoms represent the earliest indicators of FTD in such patients, and are correlated with neuroanatomical loss.

Two copies of DNA are found within each cell of the body. Upon cell death, DNA may be released within the bloodstream, termed cell-free DNA. Using residues bound to these DNA strands, termed epigenetic modifications, we have recently created a technique capable of distinguishing cell-free DNA that is derived from the brain, as opposed to other bodily tissues. More than that, we are able to distinguish which region of the brain such cell-free DNA has originated from.

The Brain Foundations research gift will allow us to identify epigenetic modifications that distinguish the DNA from each distinct brain region effected within FTD to provide targets for our cell-free DNA technology.

This will give us a new, more robust way of diagnosing FTD beyond the current reliance on behavioral or language changes, from little more than a blood test. We hypothesize that neurodegeneration in FTD will be associated with the presence of DNA derived from brain-cells of regions that are correlated with patient’s neuropsychological symptoms. We believe it is an important step towards creating a technique for blood based diagnosis, disease subtyping and disease tracking of FTD patients.

Funded by the North West Committee of the Brain Foundation

Today, between five and ten millions of patients in the world are fighting Parkinson’s disease. It is becoming so common that most of us know someone close living with the disease. The movement symptoms in Parkinson’s are caused by the loss of dopamine cells in the midbrain, in a region called substantia nigra. The best available drugs against Parkinson’s act to compensate the low level of dopamine in the brain. These drugs, mostly developed in the 1960’s, are helpful. However, they only mask the symptoms for a short period. They cannot stop the progression of the disease. In other words, patients cannot win the fight against Parkinson’s. At best, they may manage to hide most of the disease symptoms for a while, but every day they will get worse.

Our goal is to advance the understanding of Parkinson’s neurobiology to at least slow down its progression. The task is undoubtedly challenging.

Like most brain disorders, Parkinson’s is a complex disease. Each patient is unique, and the initial cause of the disease may result from different combinations of genetic predispositions, lifestyle, exposure to chemicals and aging. However, despite several possible etiologies, we hypothesize that there must be a point of convergence at the molecular level before the loss of dopamine cells. In this project, we aim to identify such molecular target which may be shared by most patients. Because of significant shortcomings of animal models and human postmortem brain tissue, we will take a new scientific strategy to study live human brain cells derived from the patients themselves. We will use a recent technology that consists in reprogramming skin cells into stem cells, and stem cells into brain cells. We will generate live human brain tissue that we will study extensively in the laboratory. We will compare the brain tissue from the patients and healthy subjects, find differences, and screen compounds to correct them. The hope is that if the treatment works on the patient cells in the lab, there will be a much higher chance of success in clinical trials.

▼ PARKINSON’S DISEASE CONTINUED

Investigating molecular causes of multiple system atrophy Multiple system atrophy (MSA) affects over 2000 Australians.

MSA is a distinct member of the group of neurodegenerative diseases called α-­synucleinopathies whereby the fibrillar protein α-­ synuclein aggregates in brain tissue. Although well-­ defined clinically the molecular causes of MSA has not yet been elucidated.

We recently discovered that hemoglobin genes are highly expressed in the MSA brain.

Hemoglobin protein transports oxygen throughout our tissues. It is the largest source of peripheral iron in the human body and it may play a role in regulation of iron level in the brain. We hypothesize that the increased levels of hemoglobin cause oxidative stress, which leads to impairment of brain cells functionality. Moreover, oxidative stress, together with increased

levels of hemoglobin proteins, might have a direct impact on α-­synuclein aggregation.

This project employs comprehensive molecular analysis to discover a mechanism through which increased amounts of hemoglobin lead to MSA onset and progression. This ambitious goal will be achieved through determination of different cell types involved in MSA, physiological effects of hemoglobin overexpression in the

Chief Investigator: Dr Michael Janitz University of NSW brain and relationship between hemoglobin and α-­synuclein deposits. This project, for the first time, will establish a link between MSA-­specific neurodegeneration, iron levels and α-­synuclein aggregation. This proposal is significant because it will not only provide insights into MSA disease mechanism but also will lead to identification of new molecular targets for MSA early diagnosis and therapeutic intervention.

Summer 2017-2018

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2017 Research Gift Awards â–ź CEREBRAL DISEASES

Glutamate imaging to predict seizure risk after stroke Chief Investigator: Dr John-Paul Nicolo Royal Melbourne Hospital Co-Investigators: rofessor Terence O’Brien, P Professor Patrick Kwan, A/Professor Bernard Yan, Dr Andrew Neal, Dr Bradford Moffat, Prof Patricia Desmond Stroke is an important cause of epileptic seizures in adults. While several factors associated with the development of epilepsy after stroke have been identified, predicting which patients will develop seizures remains difficult.

One of the most important biological factors that may be relevant is an elevation in the concentration of glutamate, a

chemical involved in electrical activity in the nervous system.

Excessive glutamate activity in the brain has been implicated in several neurological disorders including epilepsy, stroke and brain injury. In particular, glutamate plays a critical role in initiating and sustaining seizure activity. Measuring brain glutamate levels may, therefore, predict which patients will develop seizures after stroke.

While glutamate can be measured directly from brain tissues and cerebrospinal fluid, these sampling methods require brain biopsy or lumbar puncture, which are not practical for widespread clinical use because they are invasive.

For glutamate measurement to be more readily accessible we need an alternative measurement tool.

This study aims to develop one such method using MRI. Conventional MRI technology is not sensitive enough to measure glutamate levels. There are, however, two MRI techniques called Magnetic Resonance Spectroscopy (MRS) and GluCEST, which can more accurately measure brain glutamate levels. The advantage of GluCEST in particular is that it has very good spatial resolution and can be used to produce maps reflecting glutamate concentrations in different brain regions. GluCEST has been used to study patients with epilepsy, brain tumours and psychiatric illness, but not yet patients with stroke.

Our study will test these imaging methods to analyse brain glutamate levels in stroke

patients and will explore whether measurement of glutamate levels may be able to identify people at higher risk of developing epilepsy after a stroke. If this is possible these patients may be targeted for preventative treatment with drugs that modulate glutamate levels.

Understanding brain injury from stroke and recovery and complications after treatment Stroke is the most frequent cause of permanent disability in adults and a major cause of death worldwide. Caused by a sudden blockage in important blood vessels that supplies oxygen and nutrients to the brain, brain cells can quickly die due to starvation.

Opening blocked blood vessels urgently to restore blood flow (Revascularisation) is therefore the main aim of current treatment.

Chief Investigator: Dr Felix Ng Austin Health, Victoria Co-Investigators: A/Professor Bruce Campbell Professor Stephen Davis

However, even after successfully re-opening occluded vessels and completely restoring blood flow as quickly as possible, many brain cells that were living at the time of revascularisation still progress to cell death for reasons not completely understood.

Many stroke

patients still have devastating disability despite receiving the best available treatment.

Furthermore, some brain cells have unpredictable bleeding and swelling after revascularization.

These unexplained events have major impact on how effective treatments works and directly affect stroke sufferers’ recovery and quality of life.

This research is focused on understanding these processes by using advanced MRI brain imaging to analyse how human brain cells die and recovery after revascularization in stroke.

We will be recruiting stroke patients at the Royal Melbourne Hospital to undergo a series of specialized MRI scans over

12 months that will simultaneously examine the structure, function and metabolism of brain cells and their blood vessels within and around the stroke area as they progress through the different stages of injury, recovery and reorganisation.

Understanding these processes will be major step towards maximising the benefits of current treatment as well as discovering new therapies by helping brain cells become more resilient and recover better following a stroke.

Ultimately, we hope to help stroke survivors live with less disability thereby reducing the devastating disease burden for them and their carers.

DID YOU KNOW?

Traumatic Brain

Injury or Acquired Brain Injury is any

damage that occurs

to the brain after

6

birth.

The Newsletter of the Brain Foundation

Injury can occur from a trauma or accident, stroke,

Two out of three

or alcohol / drug

with

infection, disease abuse.

injuries

occur

before

25. Three four people

the age of

out of

a TBI/ABI are

under the age of 65.

Three out of four people with a brain injury are men.

â–ź CEREBRAL DISEASE CONTINUED

â–ź EPILEPSY

Understanding insulating cell death due to ageing and stroke

Improving glucose energy metabolism in epilepsy Chief Investigator: Dr Karin Borges University of Queensland

Chief Investigator: Dr Carlie Laura Cullen Menzies Institute for Medical Research, University of Tasmania Co-Investigators: Dr Kaylene Young Dr Brad Sutherland Stroke is the second leading cause of death in the world and a major source of disability affecting quality of life. In Australia, approximately 50,000 people per annum experience a stroke, causing death in ~25% of cases. Over the last 30 years, numerous therapeutic strategies to protect the brain following ischemic stroke have failed. Therefore, there continues to be an unmet need for the development of treatments that can be delivered after a person experiences a stroke, to promote brain cell survival and repair.

Oligodendrocytes are a type of brain cell that is particularly sensitive to death following a stroke. They are the insulating cells of the brain, that wrap up the nerve cells like electrical tape thereby increasing the speed and reliability of information transfer between brain regions.

Oligodendrocytes also provide critical metabolic support to sustain nerve cells. Following stroke, these information transfer areas (white matter tracts) can become damaged and dysfunctional, contributing to the disability incurred by stroke patients. It is oligodendrocytes within these areas that die following a stroke, but the way in which they die is unclear. By modelling the ischemic (oxygen and nutrient deplete) conditions characteristic of a stroke in live brain slices, this project aims to understand the mode of oligodendrocyte death induced by a stroke, particularly by investigating a newly described mode of cell death triggered by inappropriate iron breakdown known as ferroptosis, and determine the capacity for already developed therapeutics to rescue these cells. By saving oligodendrocytes from death after stroke, we aim to reduce the lesion size, but also keep these critical cells in place to support nerve cell survival and function.

Co-Investigators: Dr Mark Hodson Professor Ingmar Blumcke About 1% of people worldwide suffer from epilepsy. Human temporal lobe epilepsy (hTLE) is the most common type of epilepsy among adults. Many anti-seizure drugs are available, but are often ineffective.

Around 50% of all TLE patients still suffer from seizures. Thus, there is an urgent need to find new treatments. This proposal aims to identify a new mechanism that can contribute to the generation of epileptic seizures, which could then be targeted by novel therapies. Specifically, we aim to improve the impairments in energy metabolism found in epileptic brains.

A healthy brain relies on high amounts of energy. Neuronal membrane potentials and signalling are crucial for normal brain function and to prevent seizure generation, but are disrupted during lack of energy. In the brain, energy is largely derived from glucose. It provides much of the energy needed for maintenance of normal brain activity in brain cells via oxidative glucose metabolism. In epileptic brain areas, glucose oxidation is decreased, which limits the ability to produce energy and will promote the generation of abnormal electrical activity and ultimately seizures.

Available anti-seizure medications act by limiting the abnormal electrical activity in the brain and commonly lead to (unwanted) sedative side effects. No treatment is currently available that can improve the oxidation of glucose or generate energy without drastic dietary changes. We propose that the activity of one key enzyme, which is crucial for glucose oxidation, namely pyruvate dehydrogenase, is reduced in hTLE. This will be assessed in surgically removed epileptic tissue and in a mouse TLE model. We will also test if PDH activity can be restored and block seizure generation in the mouse model. If successful, we plan to bring our new anti-seizure approach into clinical trials in the near future.

DYSTONIA Support Group Dystonia is the third most common movement disorder worldwide.

The cause, while neurological in origin, is unknown.

ADSG Website: australiandystoniasupportgroup.wordpress.com/ ADSG Community Page: facebook.com/AustralianDystoniaSupportGroup ADSG Closed Support Group on Facebook: facebook.com/groups AustralianDystoniaSupportGroup/

Support Groups we can Support Are you part of a support group for another neurological condition that you would like to share with other sufferers.

Please let us know so that we can publish the details.

No one should have to go it alone. Being with others with the same condition offers a great deal of comfort and support!

Summer 2017-2018

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2017 Research Gift Awards ▼ BRAIN TUMOURS

Powering and arming the immune system to combat Glioblastoma and sometimes eliminate several types of advanced cancers that were previously considered untreatable.

Chief Investigator: Dr Roberta Mazzieri The University of Queensland Co-Investigator: Professor Ricardo Dolcetti A new type of cancer treatment, called “immunotherapy”, stimulates the patient’s immune system to fight their brain cancer.

The first immunotherapies were recently introduced into medical practice and have already demonstrated the ability to shrink

Better Drugs for Brain Cancer

Glioblastoma is a highly aggressive, incurable cancer with uniformly poor outcomes for patients diagnosed with primary tumours (median OS = 1-2 yrs; 5 year survival rate <10%). Affected patients suffer devastating impact on their quality of life, with symptoms including headaches, nausea and vomiting, seizures, changes in sensation, personality and mood and venous thromboembolism, leading to further complications. Available therapies, including surgery, chemotherapy, whole-brain radiation and anti-angiogenic drugs only interrupt disease progression temporarily, and do so at a tremendous cost in the form of major toxicities and side effects. Current therapies aim to slow disease progression and Today in Australia, 4 people will be diagnosed with a brain tumour.

This equates to 1600 tumours in Australia each year. These may be benign or malignant. Present day treatments include surgery, radiotherapy, chemotherapy, drug treatments or a combination of these. Mortality is high in patients with a malignant tumour with only 22% of these patients being alive after 5 years. For those who do survive, the side effects of the current drug treatments are often truly terrible.

Chief Investigator: Dr Theo Mantamadiotis The University of Melbourne Co-Investigator: A/Professor Philip Thompson

Our work involves looking at how to effectively kill brain cancer cells

relieve symptoms, but have only modest impact on the course of disease progression and nearly all patients will relapse.

The proposed research aims to improve the quality of care and quality of life for those affected by glioblastoma by developing new, potentially curative therapies.

The proposed research investigates strategies to harness the power of immunotherapy to improve glioblastoma treatment.

Available immunotherapies are only effective against some cancers. The main obstacles limiting its efficacy against other cancers are: 1. That the cellular environment within tumours contains signals that actively suppress the activity of immune cells and 2. That some types of tumour are poorly “immunogenic”, meaning that they lack signals to make them visible to immune cells.

The proposed studies will investigate new and innovative approaches to overcome these obstacles and thereby extend the use of immunotherapy to glioblastoma and other poorly immunogenic cancers.

To combat suppression of immune activity within tumours, we will use genetic engineering technology to reprogram a class of cell which normally inhibits immune cells to instead produce a powerful immune stimulant within glioblastoma tumours. To make gliblastoma tumours more immunogenic, we will apply a technique to kill tumour cells in a manner that causes them to release powerful immuneactivating signals.

If successful, this research will identify new treatments for glioblastoma with the potential to substantially prolong quality survival and possibly even cure some patients.

with minimum side-effects. We will examine the use of several FDAapproved drugs currently used in other neurological diseases, such as severe anxiety; drugs not previously considered for brain cancer therapy. The benefit of using drugs already approved for use in humans is that the massive time and financial investment in developing and testing these has already occurred and therefore the time to market for a new application is likely significantly reduced. Additionally we will test novel related drugs, developed by our collaborators, for their ability

to kill brain cancer cells in the same experiemental system we have developed.

Only 2 in 10 people

$10 million from Andrew Forrest,

This funding from the Brain Foundation will allow us to bring together an experienced team of experts in a collaboration between Melbourne University, Monash University Faculty of Pharmacy, The Royal Melbourne Hospital and the Peter MacCallum Cancer Centre. Together we will work towards our goal of finding more effective and safer therapies that are better tolerated by patients diagnosed with malignant brain cancer.

DID YOU KNOW?

Today in Australia

There are 1600

diagnosed

tumours

4 people will be with

a

brain tumour.

8

The Newsletter of the Brain Foundation

benign or malignant,

diagnosed

in Australia each year.

diagnosed with primary brain cancer will survive for

at least

5

years.

other contributors and

the Government is committing $100 million to research.

Spectrum of immune-mediated neuropathies

▼ NEUROMUSCULAR DISEASE

Characterising the immune response associated with Inclusion Body Myositis Chief Investigator: Professor Merrilee Needham Murdoch University, Western Australia

Chief Investigator: Dr Nidhi Garg University of Sydney, Brain and Mind Centre

Co-Investigators: Dr Jerome Coudert, Professor Frank Mastaglia Dr Susan Herrmann, Dr Elizabeth McKinnon, Mr Shay Leary

Co-Investigators: Dr Susanna Park, Dr Emily Mathey A/Professor Michael Barnett Professor John Pollard

Inclusion Body Myositis (IBM) is the most common type of inflammatory muscle disease that affects adults over 40 years old. IBM leads to progressive wasting and weakness of muscles, particularly the thighs and forearms. Because of non-specific initial symptoms, which include difficulty in climbing stairs, rising from a seated position and using utensils and tools, many patients seek medical attention only once they start to have falls. Difficulty in swallowing often develops. In addition sleep-disordered breathing causing daytime fatigue is common.

Chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) are immune disorders of the peripheral nerves.

Both conditions can cause significant weakness and functional disability including difficulty with walking and ability to carry out self-care. CIDP and MMN are extremely heterogenous with varied clinical presentations, prognosis and response to therapy. The diagnosis can be difficult and patients are often required to undergo numerous investigations over a prolonged time period before a diagnosis is established. Standard treatment is with regular intravenous immunoglobulin (IVIg), an infusion which is administered in hospital, often at monthly intervals. Response to IVIg is extremely variable between patients and often a “trial and error” approach is used which is an inefficient means of utilizing a limited and expensive resource such as IVIg.

IBM is associated with an abnormal immune response with invasion of killer white blood cells (cytotoxic T-cells) into the diseased muscles.

The mechanisms responsible for the onset and progression of the disease remain unclear. IBM patients do not respond well to traditional immunosuppressive treatments and there is currently no cure available.

This research project led by Professor Merrilee Needham aims to define the changes that affect the populations of immune cells by analysing blood samples collected from IBM patients and from healthy donors.

We expect that identification of characteristic changes within the immune system will provide information about the abnormalities and dysregulation of immune cells that occur. We will also collect muscle biopsies from IBM patients and analyse the immune cells that invade the muscles. The molecules that trigger immune cells activation within the muscles (the antigen) remain to be identified. We will sequence the DNA of the cytotoxic cells in order to define the genes encoding the receptors that drive the self-directed immune response. We expect that characterization of the receptors will constitute a significant step in the process of identifying the antigen in the muscles.

We anticipate that the knowledge gained from this study will provide us with novel insights into the mechanisms causing and perpetuating the disease, as well as provide us with new diagnostic tools (biomarkers) to assist in earlier and more accurate diagnosis when treatments will be likely more effective. We ultimately aim to identify targets for novel therapies.

Muscle excitability techniques in hyperthyroid myopathy

Chief Investigator: Dr Chantal Baldwin Royal North Shore Hospital Co-Investigator: A/Professor Karl Ng Thyroid hormone is essential for regulation of cell metabolism.

Hyperthyroidism is an elevation of thyroid hormone levels. It is a common condition affecting up to 1.3% of the population.

Muscle weakness involving the shoulders and hips is a wellrecognised complication and affects 60-80% of patients with untreated hyperthyroidism.

In most cases of CIDP, no causative antibodies are identified. However, in 5-10% of cases, IgG4 antibodies targeting neurofascin-155 or contactin-1, protein components found on peripheral nerves, are identified. Identification of these antibodies is highly important as patients with these antibodies tend to have more severe disease and treatment responses differ.

As part of this project we will identify specific clinical and electrophysiological biomarkers which predict response to treatments such as IVIg, allowing for targeted treatment approaches. In addition, we will investigate the utility of new MRI techniques to aid in the diagnosis of the immune neuropathies and to differentiate specific subtypes so that patients can be diagnosed earlier and receive the best therapy. Furthermore, we will identify patients with antibodies targeting neurofascin-155 and contactin-1 and determine how clinical and neurophysiological markers and antibody titres can be used to provide the most effective therapy whilst minimizing side-effects in this subgroup of patients.

Despite hyperthyroidism being a common cause of muscle weakness, the mechanism for how high thyroid hormone levels results in weakness remains unclear; however, several theories based on animal models have been proposed.

Muscle excitability is a novel electrical technique used to study muscle cells. It is a quick, repeatable test that provides a means to look at the electrical state of muscle cells in vivo.

This is a potentially powerful technique that is furthering the understanding of muscle disease

and may eventually aid in its diagnosis.

Our project will use muscle excitability and other neurophysiology techniques to assess patients with hyperthyroidism and muscle weakness prior to and following treatment. With this study, we aim to gain insight into what is occurring at a muscle cell level. This information will result in a greater understanding of hyperthyroid myopathy with the potential to influence future diagnostic testing and treatment.

Summer 2017-2018

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2017 Progress Reports ▼ NEUROMUSCULAR DISEASE CONTINUED

Tremor – a clinical and neurophysiological study

Chief Investigator: Dr Alessandro Fois Westmead Hospital Co-Investigators: A/Professor Victor Fung Prof Steve Vucic Dr Neil Mahant

Tremor is the rhythmic shaking of a body part and is a common and disabling problem seen in diseases such as Parkinson’s disease and Essential Tremor. At present there is no single diagnostic test to determine the cause of a person’s tremor. This represents a key barrier to progress in developing new treatments since the success of clinical trials of new drugs is highly dependent on accurately recruiting patients with the disease the treatment is for (and not one of its mimics). Trials also require accurate monitoring of the effects of treatment, preferably with the help of tools that can detect subtle, early improvements

(biomarkers) so that promising treatments can be identified more quickly. Neurophysiological techniques, using sensors to measure the frequency and other properties of tremor as well as the activity of the muscles that are producing the tremor, represent a safe and non-invasive method of accurately measuring tremor.

This project aims to combine the use of sensors that measure tremor (accelerometry) and muscle activity (surface electromyography) with clinical assessment to develop new tests for reliably diagnosing and monitoring tremor. We will use a data-driven approach, involving

carefully studying the clinical and neurophysiological features of patients with tremor and then performing a cluster analysis to see if we can identify subgroups of patients who behave in a similar way. We hope that we can identify subgroups that more accurately bring together patients with the same disease process than current diagnostic criteria which may lump together patients with different disease processes under the same diagnostic label (e.g. Essential Tremor). These diagnostic subgroups would hopefully then provide a better framework for future research and clinical trials.

▼ PAEDIATRIC NEUROLOGY

Identification of treatable neurological and psychiatric disease to improve clinical outcomes Chief Investigator: Dr Kavitha Kothur Institute of Neuroscience and Muscle Research, Westmead Co-Investigators: Professor Russell Dale Dr Louise Wientholt

Funded by Ledonne Family in memory of Stephanie

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Tourette syndrome/tics, obsessive compulsive disorder and autism are very common neuropsychiatric diseases with onset in childhood affecting 1 in 50-200 people.

Tourette syndrome is characterized by multiple motor tics and vocal tics.

Obsessive-compulsive disorder (OCD) in children causes unwanted thoughts resulting in repetitive compulsive behaviors and anxiety. Autism spectrum disorders (ASD) are characterized by social-interaction difficulties, communication challenges and a tendency to engage in repetitive behaviors.

These three conditions are often seen together and cause major burden to society in the form of severe behavior problems, frequent jerking affecting mobility, sensory overload, social impairment, attention concentration difficulties and affect learning and day to day functioning of the patients and their families. In a recent UK health economics assessment, autism and obsessive compulsive disorder have been defined as two of the top ten economically costly diseases to society. A number of factors including genetic/ environmental and immune mechanisms have been

The Newsletter of the Brain Foundation

proposed as etiological factors for these disorders. Current treatment is mainly symptomatic directed against psychological strategies and psychotropic medications to correct neurochemistry in the brain.

Over the last ten years, there has been an increasing literature on the role of possible immune activation.

Our clinical experience tells that a subgroup of these ‘immuneautism spectrum disorders-ticobsessive compulsive disorder patients respond to immune treatment.

Despite reported immunological abnormalities and response to immune treatment, we unfortunately do not have biomarkers to identify inflammation and monitor disease response in these children. If inflammation is identified, immune treatment strategies may help modify the disease course, relieve symptom burden of the patients and improve their function.

Cytokines and chemokines are biological polypeptide molecules that have been shown to be elevated in cerebrospinal fluid of a number of inflammatory disorders of the brain, and can be potentially used as markers of inflammation.

The CSF neuroaxonal and glial

protein biomarkers help identify extent of brain injury. In this study, we will collect the clinical data and treatment response of large number of children with tics, obsessive compulsive disorder and autism who have a fluctuating or relapsing clinical course and will measure cytokine/chemokine and neuronal/glial markers in spinal fluid to help identify patients with immune activation and brain injury respectively. Through this study, we hope to identify treatable forms of immune mediated subgroup of tics- obsessive compulsive disorder -autism, describe the clinical phenotypes, treatment response and identify children at risk of long-term neurological deficits, who can be treated aggressively with immunomodulatory treatment to avoid neurological sequelae. The cytokine/chemokine profiling in these disorders will provide new insight into poorly understood immune mediated pathogenesis, and improve our ability to diagnose, monitor and treat inflammation which may lead to development of new treatment strategies in future.

â&#x2013;ź DAWN WALLACE FELLOWSHIP

Hyperexcitability of motor neurons in Motor Neurone Disease

affected by motor neurone disease with an average life expectancy of 2.5 years.

Classical amyotrophic lateral sclerosis (ALS) accounts for some 80% of MND sufferers, and a clinically definite diagnosis requires progression of symptoms in the upper motor neurons (nerve cells in the motor cortex of the brain) and lower motor neurons (nerve cells in the spinal cord) of several body regions.

Chief Investigator: Dr James Howells The University of Sydney Motor neurone disease (MND) is a universally fatal neurodegenerative disease with no known cure. More than 2000 people in Australia are

Diagnosis of ALS is delayed because there is no good biomarker for the disease and diagnosis requires the exclusion of all other mimics. The time from onset to confirmation of diagnosis has stubbornly remained around

12 months for the last 20 years.

This diagnostic delay represents nearly half of the total disease duration and this prevents early intervention.

It has been argued that motor neuron disease begins in the upper motor neuron in the brain, but it can be very difficult to demonstrate early upper motor neuron dysfunction clinically.

Over the past decade, we have undertaken research on a noninvasive technique for assessing the excitability of the brain using transcranial magnetic stimulation, and have presented evidence that measurements of cortical excitability may provide a sensitive and specific biomarker of ALS. A robust marker of upper

motor neuron dysfunction is also essential for clinical trials of new treatments that are in the pipeline.

The primary objective of this fellowship is to translate this research into a clinical tool for measuring cortical excitability in motor neurone disease. In support of this goal I intend to: further research looking at patterns of progression by correlating cortical excitability to clinical deficits; and quantifying the variability and minimum detectable changes in healthy controls and MND cohorts.

I will also examine mechanisms of lower motor neuron degeneration which may be compensatory or secondary to the primary insult, but nonetheless contribute greatly to the patientâ&#x20AC;&#x2122;s disability.

Exercise your brain A HEALTHY BRAIN IS A HAPPY BRAIN. Give yours a workout today.

Thanks to Dana Alliance for the great word game.

KEEP YOUR MEMORY SHARP JUMBLE The following jumbled words are skills you can practice to help keep your memory sharp (hint: we've underlined the first letter of each word for you), Once you figure out the answers, unscramble the highlighted letters to answer the riddle (one letter has been filled in for you):

"Why for reptiles have such good memories?"

"Because they have !"

What may seem like faltering memory may in fact be a decline in the rate at which we learn and store new information. Visit dana. org for more information on memory, and practice these memory skills to enhance learning and make remembering easier.

Solutions on back page Summer 2017-2018

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Get Involved Fundraising for a cause is made very easy by the following sites.

Our thanks to the following fundraising champions.

Join a community event, such as a fun run or walk, zombie walks or make up your own event. These sites make it easy for schools and community groups to raise money without the hassle of collecting funds or issuing receipts.

My Cause:

See – mycause.com.au. gofundraise.com.au or everydayhero.com.au, and choose the one which suits you best.

Melbourne Zombies, Canberra Zombies and Cairns Zombies.

Caulfield Grammar – Shaw House fun run and Tegan Baker and Belinda Cordery who are raising awareness of aneurysms.

Go Fundraise: Deb Nelson – Stadium Stomp Sam Edmonds – Melbourne Marathon Festival.

Find us on Facebook.

Like us today!

Everyday Hero: City2Surf Sydney – Team Steph, Ryan Costello, Claire Balken and family, Cathy Brockwell, Patrick Mellor and Sarah Lievore.

Bridge2Brisbane – Chelsea Keynes, Karli Martin, Terese Griffith, Heidi Jennings.

In Memorium We sincerely thank the families of the following who supported our Research Gift Programme in memory of their loved ones.

Gloria Dawn STEPHENSON

Pub2Pub – Harry Gosling and

Francesco LA ROCCA

City2Bay – Adam Grope

Elliot Penrod VERRALL Joseph CHENG Matthew BELLEVILLE Alison MILHAVET

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.

Thanks to the following companies for their support:

Thank you for supporting brain research through the Brain Foundation brainfoundation.org.au/donate or use the donation form on the letter enclosed.

Rev Dr Stephen REID John ‘Jack’ SMITH Sylvio BARBALICH Mathew DOEPEL

Bequests We acknowledge the following and give our thanks for their very generous contributions.

Pat GREGORY Kathleen Marion ROBERTS Daphne Violette INNES and Dawn Wallace Fellowship for Motor Neurone Disease

PUZZLE SOLUTION:

• Call our office for a package, some great entertaining ideas and further details.

Kerry GOVAS

“WHY DO REPTILES HAVE SUCH GOOD

With all you need to hold a great event for family and friends, plus new questions and online registration, this is a very easy way to put together a good time for a few or for many!

Elsa DELLA GIUSTINA

MEMORIES?”

Following the success earlier in the year of the Big Trivia events, we would just like to remind our supporters that the package to hold a personal Trivia event is available from Brain Foundation.

John Alan STONE

“BECAUSE THEY HAVE

Then you should try BIG TRIVIA

Narelle FORD

TURTLE RECALL

Want some BIG FUN?