Improved treatment for Parkinson’s on the way

Professor Winston Byblow

Professor Winston Byblow

CBR member Professor Winston Byblow is the recent recipient of a grant from the Neurological Foundation of New Zealand.  His research aims to develop behavioural tests and identify genetic markers which may be used in future to indicate whether or not a patient with Parkinson’s is a good candidate for dopamine agonist medication, and is entitled: Falling off the curve: the link between impulsivity and dopamine.

Dopamine agonists, which mimic the action of dopamine upon its specific receptors, are a mainstay of the treatment regimen for Parkinson’s disease, and lead to significant improvements in quality of life for the majority of patients.  However, like all medications, they have side effects, and these manifest in different ways in different people.  For some people (10-20%), side effects include the development of impulse control disorders such as gambling addiction, hypersexuality, and compulsive spending.

The possibility for these side effects to occur in patients receiving dopamine agonist therapy was noted about a decade ago, but at that time scientists were not able to tell whether or not the affected patients had any particular features which made them especially vulnerable to developing compulsive behaviour disorders.  Later studies have suggested that this sub-population may have a particular profile, and Professor Byblow’s study aims to further identify this, and develop a tool for clinicians to make good prescribing choices for their patients in future.

Funding boost for CBR researchers

The latest round of project grants from the Health Research Council of New Zealand were announced last week, and three CBR members have received sizeable grants – a real vote of confidence in what is a highly competitive process which often sees less than ten percent of applications go on to receive grants.

Professor Peter Thorne (below) receives $966,266 over 36 months for Imaging the labyrinthine-blood barrier in Meniere’s disease.  Meniere’s disease is a disorder of the inner ear that affects hearing and balance, leading to hearing loss and episodes of vertigo.

Peter Thorne

Dr Ben Thompson receives $1,167,538 over 36 months for A randomized clinical trial of a new binocular treatment for amblyopia.  You can read more about this research here: http://www.fmhs.auckland.ac.nz/faculty/newsandevents/new_news_details.aspx?Id=1027

Dr Ben Thompson

Dr Ben Thompson

Dr Deborah Hay receives $1,199,853 over 36 months for Adrenomedullin 1 receptor antagonists as novel anti-angiogenic agents.  An excellent result for these researchers and for CBR.

Debbie Hay

World first treatment helps with lazy eye

Playing Tetris under controlled conditions may be a cure for lazy eye in both children and adults. Although amblyopia is often known as “lazy eye” the impairment in vision is due to abnormal development within visual areas of the brain, not a defect of the eye.

Dr Ben Thompson

Dr Ben Thompson

The world first Tetris experiments were devised by vision scientist Dr Ben Thompson, from The University of Auckland’s Centre for Brain Research, in collaboration with a team including Professor Robert Hess from McGill University.

You can watch Dr Ben Thompson discussing his work, and see examples of the special tetris being played, on One News’ broadcast of 26 April by clicking here.  (content loads slowly)

These experiments showed that presenting a higher intensity Tetris stimulation to the affected eye than the good eye, helps train both eyes to work together.  Different blocks are presented to each eye and the two eyes must work together for the game to be played.

The team’s latest study published in ‘Current Biology’, demonstrated fast improvements in vision after the Tetris treatment, and that the benefits have so far proven to last at least three months.

“We found much larger improvements in patients who were treated with the version of the Tetris game that encouraged both eyes to work together than those that played Tetris with their good eye patched.”, says Dr Thompson.

Participants in the study were given special video goggles to help their eyes work as a team and asked to play Tetris for one hour a day for ten days.  At the end of the period, their lazy eye showed significant improvement in binocular ability.

Dr Thompson is a co-inventor of the Tetris game-based treatment for amblyopia and holds patents for the treatment regime.

Amblyopia is a disorder of binocular vision and with the way that the brain interprets information as it suppresses or ignores signals to one or other of the eyes.  The treatment is a new way of training both eyes to work together.

It’s estimated that one in 50 children has lazy eye, or amblyopia. This condition occurs when the brain receives different images from each eye during childhood which can be due to the eyes being misaligned.. Without intervention, it can lead to permanent loss of vision in the weaker eye.

The traditional treatment for lazy eye has been to patch the good eye to force the lazy eye to work. This treatment can be effective, but many children object to wearing the eye patch.

It was originally assumed that patients with amblyopia did not have the connections in the brain to use both eyes at the same time.  This study shows that patients could use both eyes at the same time, if the images to the lazy eye were more visible than those to the good eye.  The level of visibility is changed until both eyes are trained to work together – this takes about 10 days.

Dr Thompson is now hoping to gain funding for a large clinical trial that will take up to a year, again in collaboration with the study team.  If the clinical trials are positive the hope is that the treatment will become available to patients.

The study was funded by the Health Research Council and the Auckland Medical Health Research Foundation.

Written by Suzi Phillips, s.phillips@auckland.ac.nz

CBR scientists boosted with support from AMRF

The Auckland Medical Research Foundation has announced its latest round of grants, with several innovative projects funded in the Centre for Brain Research. The research will help to develop new treatments for Huntington’s disease, obesity, visual defects, and hearing loss.

THE SYNAPTIC BASIS OF HUNTINGTON’S DISEASE
– $141,154
Dr Johanna Montgomery, Dr Ailsa McGregor Dept of Physiology & Centre for Brain Research, The University of Auckland

All neurodegenerative diseases have direct or indirect effects on synapses in the brain. Therefore a major step towards understanding what goes wrong in the diseased brain is to understand how synapse function is altered by disease. In this proposal we seek to determine the source of synapse dysfunction in Huntington’s Disease (HD). Previous work on HD mouse models has shown that receptors on the surface of neurons are mis-localised, inducing changes in synapse function. Here we will focus on two synaptic proteins, bSAP97 and aSAP97, which we have recently shown can control the distribution of receptors on neurons (Li et al., 2011, J. Physiology 589, 4491-4510). We will utilise a cellular and an animal model of HD to determine whether changing the expression levels of bSAP97 or aSAP97 can rescue normal receptor distribution, and whether this subsequently rescues normal synapse function. These cellular data will identify whether a and/or bSAP97 are part of the pathological signature for HD and also whether they could be potential therapeutic targets.

THE EFFECT OF NEONATAL HYPOGLYCAEMIA ON VISUAL DEVELOPMENT
– $97,250 Mr Nabin Paudel
Dept of Optometry & Vision Sciences, The University of Auckland

Newborn babies commonly experience low blood sugar, a condition known as neonatal hypoglycaemia.  As glucose is the brain’s main energy source, this condition may impair neurological function, however, at present, very little is known about the effect of neonatal hypoglycaemia on brain development.  As a consequence, the level of neonatal hypoglycaemia that requires treatment in early infancy is currently unknown.  This PhD project forms part of a large multidisciplinary study known as the Children with Hypoglycemia and their Later Development (the CHYLD study) which aims to assess the developmental effects of neonatal hypoglycaemia in a cohort of 500 children whose blood glucose levels were measured continuously for several days after birth.  The aim of this specific project is to assess visual function in these children at the ages of 2 and 4.5 years.  Vision is of particular interest as neonatal hypoglycaemia may preferentially affect visual brain areas.  The assessments include a range of vision tests targeting specific regions of the visual cortex and will therefore provide new insights into the effect of neonatal hypoglycaemia on the rate and extent of visual cortex development.  The study will also provide important information regarding the treatment and management of hypoglycaemia in newborns.

MELANOCORTIN TREATMENT FOR OBESITY
– $166,636
Dr Kathy Mountjoy, Dr Ailsa McGregor Dept of Physiology, The University of Auckland

Stress, weight gain and glucose metabolism are influenced by a group of hormones called melanocortin peptides. These peptides comprise chains of amino acids, of varying length, and are derived from one large precursor protein found in the brain and pituitary gland, called proopiomelanocortin (POMC). Special enzymes chop-up POMC to form the melanocortin peptides, according to the body’s requirement. We have developed a mouse that lacks a particular 13 amino acid melanocortin peptide called adrenocorticotropic hormone (ACTH1-13). These mice can be used to study what effects of ACTH1-13 on physiological function. The mice appear normal until they reach puberty and then they develop obesity, but not diabetes. Treatment of these obese mice with ACTH1-13 or a natural variant that is slightly chemically altered, called -melanocyte stimulating hormone (-MSH), reduced mouse body weight and fat mass when mice were fed a normal diet. In light of the worldwide obesogenic environment, we will now test whether obesity and diabetes in these mice is exacerbated by a feeding a high-fat diet, and whether melanocortin hormone treatment can reverse obesity while animals feed on a high-fat diet. These studies should aid the development of improved tests and treatments for obesity and type 2 diabetes.

OTOPROTECTION BY ADENOSINE RECEPTORS
– $146,752 Dr Srdjan Vlajkovic, Prof Peter Thorne, Dr Detlev Boison, Prof Gary Housley
Dept of Physiology, The University of Auckland

Hearing loss affects 10-13% of New Zealanders and this prevalence will increase with the aging population. Exposure to noise and drugs toxic to the inner ear are major contributing factors to this disability. Prosthetic rehabilitation via hearing aids and cochlear implants is the only current treatment for hearing loss. Hence, it is essential to develop therapies that can ameliorate or repair injury to the delicate structures of the inner ear. We have shown that hearing loss in experimental animals exposed to traumatic noise can be substantially restored by administration of drugs acting on adenosine receptors. Here we propose a set of studies that will utilize transgenic mice that lack genes for the two main types of adenosine receptors found in the inner ear to assess their responses to aging, noise stress and drug toxicity. This is critical translational research for therapeutic management of noise, age and drug-induced hearing loss.

Dream money for neuroscience research

Generous donors have kick-started two exciting new neuroscience projects in the Centre for Brain Research.

The first donation will enable our NeuroDiscovery Unit (formerly called the Integrative Neuroscience Facilities) to appoint a new Technical Manager in 2013. The generous support of $100,000 comes from Dame Jenny Gibbs, a CBR Ambassador and long-time friend of the University of Auckland. Funding has also been boosted by a donation of $50,000 from an anonymous donor via our website.

CBR Director Professor Richard Faull says, “I call this dream money, as it gets these imaginative blue sky projects off the ground. We are just so grateful for this generous support to help fight neurological disease.”

The NeuroDiscovery Unit is led by Associate Professors Bronwen Connor and Nigel Birch and undertakes pre-clinical neuroscience research. The technical manager will organise and run the unit to enable collaboration across the CBR.

A grant of $50,000 from the Freemasons of New Zealand has also supported an imaginative new initiative for Alzheimer’s research led by Professor Russell Snell. This will bring a group of international experts together to plan a worldwide collaborative research programme for the development of a transgenic sheep model for Alzheimer’s disease. This research will be driven from the CBR and involve leading geneticists and Alzheimer’s researchers from the UK, USA, Australia and New Zealand.

Marsden funding to boost brain research

The latest round of grants from the Marsden Fund, administered by the Royal Society of New Zealand, brought good news for three CBR researchers, who have each  been given an opportunity to establish or substantially extend their research programmes.  The Marsden Fund supports research excellence in science, engineering and maths, social sciences and the humanities, and competition for grants is intense.   Marsden funding is regarded as the hallmark of excellence for research in New Zealand.

Professor Michael Corballis [pictured below with collaborator Dr Gurjica Badkova], has been granted $760,000 to extend his research into the relationship between handedness and cerebral asymmetry for language, which helps to reveal information about the origins of speech in humans.

Donna-Rose Addis, pictured below, received a grant of $780,000 which will enable her and her team to continue their investigations into ‘future memory’, and its relationship to imagination and creative thinking, aided by the latest imaging technology.

Lastly, Dr Meagan Barclay received a ‘fast-start’ grant from the Marsden council.  These grants are specifically targeted toward promising researchers at the beginning of their careers, and are intended to facilitate researchers in beginning an independent research programme.  Meagan will use her grant of $345,000 to establish a project which will characterise synaptic structure and function in the cochlea.

Funding Successes

The Centre for Brain Research congratulates our researchers for attracting over $5M of external funding for innovative brain research projects focusing on neurological disorders affecting premature babies and children.

Professor Alistair Gunn and Dr Justin Dean both received funding for their work with premature and newborn babies, while Dr Johanna Montgomery and Dr Jessie Jacobsen received funding to further our understanding of the factors underlying Autism, a neurological disorder which is usually diagnosed in early childhood, and Dr Trecia Wouldes was granted funding to study executive function in pre-schoolers exposed prenatally to methamphetamine.

Professor Alistair Gunn and his team received a grant of $4.8 million over five years, from the Health Research Council, to grow their research into perinatal brain injury.  They will utilise a fetal sheep model to compare and evaluate the impact of current standard treatments for hypoxia, and to investigate new possibilities for blocking the spread of brain injury as a result of hypoxia.  EEGs of the fetal sheep model may also provide useful future directions for rapid diagnostic criteria of perinatal brain injury, potentially increasing treatment efficacy.

Dr Justin Dean’s grant, from the Auckland Medical Research Foundation, totals $140,000 over two years, will enable him and his team to investigate the activity of a newly discovered enzyme in the brains of pre-term infants.  The enzyme, titled PH20, is thought to play a key role in pre-term brain injury, and treatments which block its activity will be trialled as a possible therapeutic target for reducing pre-term brain injury caused by inflammation.

Meanwhile, Dr Jessie Jacobsen has been awarded a repatriation fellowship of $100,000 by the Neurological Foundation of New Zealand.  Jessie will focus on investigating autistic traits and their relationship to genetics, using DNA sequencing technology, with a view to establishing a genetic profile which can indicate a predisposition to Autism Spectrum Disorders.

Dr Johanna Montgomery has also received funding from the Neurological Foundation of New Zealand to take a closer look at Autism.  Johanna’s grant of $156,000 will enable her and her team to pursue a potential treatment for the synaptic deficits which occur in Autistic patients.  They will investigate the efficacy of zinc in stabilising synapse proteins, to determine whether this results in recovery of synapse function, ultimately enhancing the ability of the brain’s cells to communicate with one another.

Dr Trecia Wouldes and her team will use their funding to extend the scope of their longitudinal study of methamphetamine exposed babies to determine whether early behavioural changes detected in these babies are associated with deficits in higher order thought at 4.5 years of age, in an attempt to determine whether the early effects of methamphetamine exposure persist.

Picking the ideal treatment for people with schizophrenia – new project funded in the CBR

Patients with schizophrenia could soon be prescribed tailored drugs for their biology, as a new project gets underway in the Centre for Brain Research. Funding from the Auckland Medical Research Foundation has enabled promising Research Fellow Dr Valerie Anderson to undertake the research.

Standard medications are not affective in approximately a third of people with schizophrenia, and these patients are considered ‘treatment-resistant’. Alternative medication and combinations of antipsychotics must be used, but these medications have a greater risk of inducing serious side effects and therefore are avoided where possible. Consequently, people with treatment-resistant schizophrenia often experience many years of unsuccessful therapy with standard medications before alternatives are prescribed, during which time their symptoms severely affect daily living and have a significant impact on long-term outcomes.

 The Psychopharmacology team will now investigate whether they can identify measurable biological characteristics (biomarkers) that could be used to predict whether people with schizophrenia will be treatment-resistant. Brain magnetic resonance imaging, electroencephalography, and neuropsychological data will be collected and analysed to investigate the structure and function of the brain in people with schizophrenia who are treatment-resistant, and the findings compared to people with schizophrenia who respond well to standard medications and normal subjects.

 Identification of reliable biomarkers to predict treatment-resistant schizophrenia would enable alternative medications to be prescribed earlier in the disease course. This will ultimately minimise the time that these patients experience debilitating symptoms, leading to improved outcomes for them, and reducing the burden on their families and health care providers.

 The Auckland Medical Research Foundation has also funded two new PhD scholarships at the Centre for Brain Research. Foundation Executive Director Kim McWilliams says: “Many of these researchers already have and will go on to become leaders and internationally recognised in their particular discipline or field of medicine.”

 Projects:

Biomarkers for treatment resistant schizophrenia ($179,267 – two years)
Dr Valerie Anderson, Psychopharmacology and Neurodynamics

 
 
Preterm stem cell therapy (Doctoral Scholarship $122,000 – three years)
Miss Lotte van den Heuij, Fetal Physiology

Visual brain plasticity in adult humans (Doctoral Scholarship $122,000 – three years)
Mr Victor Borges, Visual Neuroscience Group

Promising young brain researcher returns to NZ

Hawkes Bay-born Dr Erin Cawston has been named the 2011 Neurological Foundation Repatriation Fellow. Erin will return from her position as Research Fellow at the Mayo Clinic Arizona next month, in order to further her research into Huntington’s disease at the Centre for Brain Research.

 The Repatriation Fellowship ensures outstanding young researchers who have completed postdoctoral studies overseas can return home and continue to develop their research careers in their specialist area. Dr Cawston says “I am incredibly grateful to the Neurological Foundation for this Repatriation Fellowship allowing me to come home to New Zealand. I look forward to working with Associate Professor Michelle Glass and Professor Mike Dragunow on such an exciting project as well as being back amongst the New Zealand scientific community.” Dr Cawston begins her Fellowship at The University of Auckland in February.

 Alongside this exciting research, the Neurological Foundation has also funded a number of exciting new research projects at the CBR.

 Optimising a novel induced neural precursor-like cell line Associate Professor Bronwen Connor, Department of Pharmacology and Clinical Pharmacology, Centre for Brain Research University of Auckland, $136,862 

 The generation of ‘embryonic-like’ stem cells from adult human skin was first demonstrated in 2007. This project will advance this capability by directly generating immature brain cells (neural precursor cells) from adult human skin. Of major significance is that this will avoid the need to generate an intermediate embryonic-like stem cell phase, providing neural precursor cells for therapeutic applications without risk of tumour formation from stem cells. This project provides a unique opportunity to establish a novel technology which is likely to have wide-reaching applications for future research in the areas of neurological disease modeling, drug development, and potentially cell replacement therapy.

 A genetic mechanism underlying late-onset Alzheimer’s disease Professor Russell Snell, School of Biological Sciences University of Auckland, $86,875

 Alzheimer’s disease is a debilitating disorder affecting up to 50 per cent of those aged over 80 years old. Despite decades of research and innumerable clinical trials, there are no treatments that prevent or reverse the progression of the disease. There is currently some evidence that patients have a small proportion of brain cells with three copies of chromosome 21 instead of the normal two, leading to an increased production of the toxic protein amyloid-beta peptide. This study aims to confirm this observation, determine the pathological consequences of these cells and look for markers that make these cells different, which may lead to new therapies.

 Immodulation of stroke with risperidone Associate Professor Bronwen Connor, Department of Pharmacology and Clinical Pharmacology, Centre for Brain Research, University of Auckland, $11,999

 Stroke is a leading cause of disability in New Zealand and the burden associated with this neurological disorder is increasing. Treatment of stroke represents a large, unmet medical need. Neuroinflammation is an important pathophysiological mechanism involved in stroke and impacts profoundly on the extent of cell loss, as well as injury progression. Neuroinflammation therefore offers an exciting therapeutic target for the treatment of stroke. It has been recently demonstrated that the anti-psychotic drug, risperidone, is effective at reducing neuroinflammation and disease progression in a model of multiple sclerosis. This project will now explore whether the anti-inflammatory properties of risperidone can reduce the progression and severity of stroke. 

 Do BMP antagonists play a role in directing the fate of adult neural progenitor cells following neural cell loss?
Shwetha George, Department of Pharmacology and Clinical Pharmacology, Centre for Brain Research, University of Auckland, $4,000

 The ability for adult neural stem cells to migrate to areas of brain damage and generate replacement brain cells may provide a unique mechanism by which to develop novel therapeutic strategies for the treatment of brain injury or neurological disease. However, the local environment appears to be critical for directing the final fate of adult stem cells in the damaged brain. This study will investigate whether brain injury alters the expression of a group of compounds known as bone morphogenic protein antagonists to promote adult neural stem cells to form glial rather than neuronal cells. The results of this study will enhance our knowledge as to how stem cells respond to brain cell loss and may assist in the development of novel therapeutic strategies for the treatment of brain injury or disease.

Funding for innovation

Four CBR researchers have been awarded prestigious Marsden grants for innovative New Zealand research.

The Marsden Fund is regarded as a hallmark of excellence, allowing New Zealand’s best researchers to explore their ideas. It supports projects in the sciences, technology, engineering and maths, social sciences and the humanities. The fund is administered by the Royal Society of New Zealand on behalf of the government.

Associate Professor Michelle Glass was awarded $900,000 for her work on G-protein coupled receptors. This class of receptors represents the target for 50% of all drugs on the market, and Michelle aims to find a new way of altering G protein signalling.

Associate Professor Nigel Birch was awarded $895,000 for research on neuroserpin and its potential role in the human immune system. Professor Margaret Brimble was awarded $825,000 to determine the structure of proteins through racemic protein crystallography. Meanwhile evolutionary psychology research Professor Russell Gray was awarded $775,000 to use his methods of studying evolution to look at how religion has developed.

Marsden Fund Council chairman Professor Peter Hunter said he is proud to be part of the Marsden Fund system and is continually impressed at the quality of the applicants and the proposals.

“The Marsden Fund supports leading-edge research, which creates economic growth and increases our understanding of issues, from medical advancements to social change and development.

“Most breakthroughs around the world come from this basic science end of the research spectrum, which is what makes the Marsden Fund both exciting to be part of and vital for New Zealand to invest in.

“The newly funded projects from the country’s top researchers are all excellent. However, we are very aware that there were many more extremely worthy projects that we were unable to fund.”

Applications to the Marsden Fund are extremely competitive. Of the 1078 preliminary proposals received, 250 were asked to submit a full proposal with 88 ultimately funded, giving a success rate of 8.2%. All of the funded proposals are for three years.