Growing a community of early career researchers

Jessica Lazarus, PhD candidate and 2014-2015 Co-Chair of the NeuRA Early Career Committee, enthuses about research, networking, and building professional skills.

I began my PhD at NeuRA in March 2014 after finishing a Bachelor of Medical Science (Honours) at the University of New South Wales. My current research focuses on the potential role that epigenetic modification plays in extreme longevity. I hope to contribute to the wider scientific understanding of the processes involved in human ageing, and to potential therapeutic avenues for managing and treating age-related neurodegenerative diseases like Alzheimer’s disease. My project follows on from work I completed during my Honours program, which was also based at NeuRA, and from which I am fortunate to have published a first-author paper in the Journal of Alzheimer’s Disease.

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Shortly after beginning my PhD program I was elected as Co-Chair of the Early Career Committee (ECC). My decision to run for this position came from my desire to gain new skills in a leadership role and become more proactive in my position at NeuRA.

The ECC is a representative body for all early career researchers (ECRs) at NeuRA. It works collaboratively and proactively in response to ECR needs and interests, in concert with existing structures in the institute. The ECC aims to promote smooth career transition into a PhD program; from PhD into postdoctoral status; and from postdoctoral status into lab group leadership.

Moreover, the ECC provides networking opportunities and a strong social culture by facilitating a host of activities that help ECRs feel supported and a sense of belonging in the NeuRA family.

So far, my experience as Co-Chair for the NeuRA ECC has been fun and rewarding. I have developed new skills in leadership and met many new people at NeuRA, both junior and senior. I have also faced the reality of the various challenges to ECRs, including the accessibility of PhD scholarships, fellowships, grants, and conference travel opportunities. Fortunately, organisations like the ECC are committed to providing support and a voice for ECRs in order for them to achieve their research goals and gain opportunities in the competitive career path of academia. I am especially pleased to be part of this committee that supports NeuRA’s ECRs, many of whom will make valuable contributions to science.

Recent ECC activities include:

  • Seminar Series – designed to encourage professional growth and stimulation through the knowledge and wisdom of senior researchers, seminars include invited speakers from a range of academic institutes who present recent innovative research. This series is also an opportunity for ECRs at NeuRA to showcase their research or discuss topics like using social media in science communication.
  • Methods Workshops – specifically designed sessions that share peer-to-peer knowledge about techniques and methods used in research. These provide accessible and ongoing regular support to ECRs in a comfortable learning environment.
  • Coffee Meet-ups – monthly social events at which early career researchers discuss a research-related theme over coffee, such as completing a PhD by publication or by thesis. These allow ECRs to discuss any qualms and possible solutions with peers.
  • Monthly Happy Hours – a relaxing and social end to each month of hard work. These are a perfect way to meet other ECRs.
  • NeuRA Football Team – a fortnightly social game of soccer at a local reserve, allowing ECRs to gain a healthy dose of exercise.

In other words, we work hard and play hard!

Eating and metabolism in frontotemporal dementia

When thinking about frontotemporal dementia, we often focus on cognitive and behavioural symptoms. Memory loss, personality changes, and trouble speaking and understanding language are among some of the more recognised FTD symptoms. However, there is a physical side to neurodegenerative illnesses that is the subject of Dr Rebekah Ahmed’s research at NeuRA.

Eating abnormalities are present in 6 out of 10 people with frontotemporal dementia. We set out to measure whether hunger and satiety (the sensation of feeling full) were responsible for differences in eating behaviour in these people.

DSC_9153 smallWe asked carers of patients with different types of dementia to complete a questionnaire about the patients’ eating behaviours. The results showed that people with the behavioural variant of FTD have increased appetite, abnormal eating habits (such as table manners), and increased preference for sweet foods, compared with patients with Alzheimer’s disease and to healthy controls. Patients with semantic dementia (the language variant of FTD) also have similar abnormalities, but to a lesser extent. Both groups of FTD patients have increased carbohydrate and sugar intake, and as a result, an increased body mass index (BMI).

Despite these abnormalities, the two FTD groups have similar ratings of hunger and satiety to controls, suggesting that their increased food intake is not simply related to increased appetite. Similar findings have emerged in people with genetic obesity syndromes and may be related to changes in the hypothalamus, the part of the brain that regulates appetite hormones.

Metabolism in FTD

Now that we have quantified these changes in eating behaviour and nutrient intake in FTD, the question arises of how they affect metabolism. In other words, are there changes in markers of healthy metabolism in the blood, such as insulin and cholesterol?

A second study by my colleagues and I looked at exactly this question.

We assessed FTD patients using a clinical interview, neurological exam, cognitive assessment (including a questionnaire on eating habits), MRI, and measurement of blood cholesterol and insulin. As in the first study, we compared these measurements with people with Alzheimer’s disease and healthy controls.

We found peripheral insulin resistance in FTD patients, and increased incidence of diabetes mellitus in patients with the behavioural variant subtype of FTD. These patients also had abnormal ratios of ‘good’ dietary fats in their blood. These changes may be due to the abnormal eating patterns that we found in the first study, coupled with a high BMI.

This study of peripheral metabolism in FTD represents the first study of its kind. It is the first step in understanding how energy metabolism may affect the process of neurodegeneration.

Linking metabolism and neurodegeneration

There are still some questions to be answered. It is known that abnormal energy metabolism, such as in glucose regulation, is detrimental in people with Alzheimer’s disease and Parkinson’s disease. However, people with motor neurone disease (MND), which is closely related to FTD, also have distinct abnormalities in cholesterol and other dietary fats (triglycerides), but with the critical difference that these abnormalities actually seem protective against the progression of MND. In fact, a clinical trial showed an increased likelihood of death in MND patients treated with an antidiabetic medication. The theory is that MND patients have a hypermetabolic state and that increased eating and higher cholesterol and insulin levels maintain the energy balance.

Dr Rebekah Ahmed

Dr Rebekah Ahmed

Future research will examine how energy metabolism affects disease progression and whether variations in metabolism are detrimental or protective. One hypothesis in FTD is that they may be detrimental in terms of cognition, but protective in terms of muscle health in those patients who also develop MND. In the long term, studies that also examine the effects of lifestyle, sleep and physical activity on individuals with genetic susceptibility to these neurodegenerative diseases, before they have developed disease symptoms, will increase our understanding of the role of peripheral metabolism on central and peripheral neurodegeneration.

Binge drinking and brain development

The effect underage drinking has on a developing brain is a question Prof Caroline Rae is seeking to answer. An alarming 19-23% of adolescents have binge-drunk in the last week, and this proportion is increasing in young females. 13% of all deaths in young Australians are a direct result of alcohol use, with alcohol use patterns in the young becoming more extreme.

Drunk teens with vodka bottle

At this age, the frontal lobes of teenagers are still developing. This development progresses into the early 30s, but most occurs in the teenage years. Alcohol is very likely to be affecting the development of the brain and its connections. The recent trend to mix high-caffeine drinks with alcohol could be exacerbating the problem.

Currently, there is very little scientific evidence on the effects of early binge drinking. Prof Rae and her collaborator, Prof Maree Teesson at the National Drug and Alcohol Research Center (NDARC), aim to uncover what happens in a teenager’s brain when binge drinking occurs. They will then identify the neurocognitive consequences of binge drinking, such as whether it affects memory, the ability to recognise emotions on other people’s faces, or the ability to inhibit impulses. The structural and functional effects of binge drinking on the brain are also under examination.

Targetting the impact of HAND

HIV-associated neurocognitive disorder (HAND) is a major neurological complication in HIV-positive persons. It impairs cognitive activity, including memory, learning, attention, problem solving and decision making. Symptoms can vary from confusion to forgetfulness, behavioural changes, nerve pain and sometimes apathy.

Dr Lucette Cysique

Dr Lucette Cysique

The widespread use of combined antiretroviral treatment has reduced the incidence of the most severe form of the disorder, HIV-associated dementia, from 8% to 2%. However, the prevalence of mild to moderate degrees of neurocognitive deficits persists in up to 50% of sufferers, with phases of relapse and remission. Symptoms are not severe enough to be referred to as dementia, yet they impact on quality of life and independence.

Research questions being asked at NeuRA include: to what extent does HAND regress with antiretroviral treatment or cognitive training? Can early treatment reduce HAND incidence? Are HIV-positive persons more likely to have HAND as they age, and could this accelerate common neurodegenerative diseases? Do alcohol and substance use disorders exacerbate HAND? How can we improve the early detection of HAND using improved neuropsychological and/or neuroimaging methods?

To answer these questions, Dr. Lucette Cysique leads and co-leads several studies in Australia working with partners including the UNSW, St Vincent’s Hospital, The Alfred Hospital in Melbourne, and HIV clinics in NSW. Internationally, the University of California San Diego and McGill University in Canada are also part of the research program. NeuRA’s research is pivotal to this exchange network.

A pilot study to assess if computerised cognitive training will improve symptoms of HAND is currently recruiting participants.

Visible neuroscience

Imaging techniques enable neuroscientists to learn about the structure and function of cells in the nervous system. Here, Dr Zoltán Rusznák shares some captivating images of the brain and how they were made.

Neurons are the building block cells of the brain and spinal cord, communicating with each other through synapses to regulate nervous system function. Relating the shape, size, and location of neurons to their function is important in understanding mechanisms in brain health and disease. However, because neurons are small, three-dimensional, and embedded among many other cells in the nervous system, special techniques are required to be able to see them. The following pictures show neurons in the cochlear nucleus, which is the part of the brain that decodes sound information from the ear.

Stacking up to localise sound

Globular bushy cells illuminated by a fluorescent stain

Globular bushy cells illuminated by a fluorescent stain

What’s in this picture? Globular bushy cells are neurons in the cochlear nucleus that act as sophisticated timing devices. They measure tiny delays in how quickly a sound reaches both ears, which is the basis of how we localise the source of a sound.

How was it made? The picture on the left was taken with a camera attached to a microscope. It shows a round bushy cell body in the middle of a single, very thin slice of brain tissue – a slice only 0.06% of the thickness of a grain of salt! The right-hand picture is a stack of 40 images taken from successive slices of the same piece of brain tissue – imagine a stack of salami coming out of a deli slicer. The image stack results in a view of much greater depth, so that a second bushy cell body becomes visible, as well as a detailed view of the synaptic nerve terminals, indicated by the several bright green structures on the cell bodies.

Putting the puzzle together

Giant neurons illuminated by a fluorescent stain

Giant neurons illuminated by a fluorescent stain

What’s in this picture? ‘Giant neurons’ of the cochlear nucleus receive sound information from the ear and help to localise the source of sound from a single ear.

How was it made? These pictures are also made from stacks of single images, like in the previous picture. However, since the giant neurons are so, well, giant, many adjacent image stacks have to be assembled like a puzzle in order to capture the many branching nerve endings. Each square in the pictures corresponds to a single field of view of the microscope.

Merging muscarinic receptors

Granule cells and muscarinic receptors illuminated by fluorescent stains

Granule cells and muscarinic receptors illuminated by fluorescent stains

What’s in this picture? These small round neurons in the cochlear nucleus are called granule cells. Neurons have proteins on their surface called receptors that respond to chemical messengers and transmit signals throughout the neuron. Sometimes we want to know the specific type and location of receptors that a messenger binds to in order to transmit its signal.

How was the picture made? Different fluorescent dyes are used to distinguish the receptor from the rest of the neuron. The left-most image shows green, bead-like dots that indicate the presence of a particular type of receptor called a muscarinic M3 receptor in a slice of brain tissue. The middle picture is taken from the very same piece of brain tissue, but the tissue is instead stained blue to define the nucleus of the granule cells. When the green and blue images are merged (right-hand picture), the green dots are showed to be surrounding the blue cell nuclei. This tells us that the receptors are located on the surface of the granule cells, and suggests that these receptors mediate the effects of certain neurochemical messengers in the cochlear nucleus. This information is helpful to determine how hearing works and what might go wrong in auditory disorders.

Dementia: when do I know I have a problem, and what is happening in my brain?

Dr James Burrell is a Senior Research Officer and clinical neurologist whose research interests lie in linking clinical symptoms and pathology in dementia syndromes.

Dr James Burrell

Dr James Burrell

In my work as a clinical neurologist, I often encounter people who are concerned that they might be developing the dreaded d-word: dementia. They report being more forgetful than previously, forgetting the names of people, places or things, or perhaps just not feeling as ‘sharp’ as they once did. In my experience, these sorts of concerns are common. Importantly, however, only a proportion of people with such symptoms actually go on to develop dementia.

Working out who will develop dementia, and more specifically which type of dementia will be developed, is one of the major challenges cognitive researchers and clinicians face. We are presented with two separate, but related problems: first, how can we tell when minor forgetfulness heralds the onset of something more serious? Secondly, if someone has an obvious dementia, how can we make an early and accurate molecular diagnosis?

We know from many well-designed studies that neurodegenerative disorders begin years before any symptoms develop, and that to be effective a treatment will most likely need to start at the very earliest stages, before any significant and permanent damage develops. On the other hand, not everyone with mild cognitive symptoms actually progresses to develop dementia. Being able to accurately identify patients at risk of developing dementia at a very early stage is one of the major goals of research in neurodegenerative diseases.

In the Frontier clinic based here at NeuRA, we are often faced with the opposite problem: we assess patients with early dementia who present with memory, language, or behavioural disturbances, but it can be difficult to work out the specific underlying brain disease. In many ways, our research aims to bridge this gap between the problems related to ageing that people face in their everyday lives and the physical changes in the brain that are ultimately responsible. We use a combination of methods, including detailed clinical assessment, neuropsychological or cognitive testing, sophisticated brain imaging, neurophysiological techniques, gene testing, and even blood and tissue biomarkers, to try and better link cognitive symptoms and specific brain diseases. With collaborators in the UK we have even developed a new app, for cognitive testing in clinical practice (ACEmobile™ for iPad, available from the Apple App Store). Only after we can make an early and accurate diagnosis of a neurodegenerative brain disorder will the hunt for a meaningful treatment really forge ahead.

Contracture: understanding mechanisms and testing treatments

As part of a new National Health and Medical Research Council Program Grant on motor impairment, Prof Rob Herbert aims to advance the transfer of new understanding of physiology and pathophysiology in motor impairment toward the clinical outcome of improved motor function.

Prof Rob Herbert

Prof Rob Herbert

Motor impairment is a common consequence of a number of illnesses and injuries. One type of motor impairment that is an important cause of physical disability is muscle contracture. A contracture is a stiffening of the muscles that limits normal joint movement, and severe contractures cause deformities that are the most visible manifestation of brain damage. Contractures arise when brain lesions, including those that arise from stroke or traumatic brain injury, cause paralysis or spasticity. Paralysis and spasticity change the mechanical environment of muscles – that is, they cause muscles to experience different patterns of activity, different changes in length and different forces than would normally be experienced. The muscles adapt in response to their altered mechanical environment by becoming stiffer, causing joints to become less mobile.

Contracture is a common problem. In a recent study, my colleagues and I monitored 200 consecutive people admitted to a Sydney hospital with the diagnosis of stroke. Six months after admission, half of all those people had developed at least one contracture. Contractures are also common in people with many other sorts of brain lesions. For example, contractures are prevalent in people who have had a traumatic brain injury, or who have multiple sclerosis or cerebral palsy.

Contractures prevent joint movement, so they cause physical disability. For example, many people who have had a stroke or traumatic brain injury develop contractures of the calf muscles. Calf muscle contractures impede ankle motion, making it difficult to stand up from a chair or walk normally. In the same way, contractures of shoulder muscles can impair the ability to reach and contractures of wrist and finger muscles can impair grasp. Severe muscle contractures can cause the limb to adopt a fixed position. For many people, contractures become a much greater impediment to normal movement than the paralysis or spasticity that initially caused the contracture to develop.

There has been surprisingly little research into the mechanisms of contracture. As a result, the mechanisms are poorly understood. Studies on animals have shown that it is possible to make muscles become short or stiff with a number of experimental procedures. For example, leg muscles can be made short by immobilising the leg in a plaster cast, and diaphragm muscles can be made short by inducing emphysema (a lung disease). These studies show that the stiffening of muscles can occur either because of changes in the muscle tissue (the muscle “fibres” or “fascicles”), or because of changes in the tendons that join muscle fascicles to bones. But studies on animal muscles can’t tell us about the mechanisms of contractures seen in human populations. Surprisingly, it is still not clear whether contractures in people who have had a stroke or traumatic brain injury are due to changes in the muscle fascicles or tendons.

There is just as much uncertainty about how to prevent and treat contracture. For the last half-century, physiotherapists and nurses have applied stretches to muscles, or passively moved limbs, or applied splints or casts to stretch the limb, with the aim of preventing or treating contractures. But recent research suggests these interventions have little effect. For example, in one study, 63 volunteers who had experienced a stroke were randomly allocated to receive either a wrist splint or no splint. Two months later there was no discernable difference in the stiffness of the wrist of people who had or had not been splinted. There have now been over 35 studies like these, and they quite consistently show little or no effect of stretch or movement-based interventions. For now at least, there are no treatments that have been clearly shown to prevent or reverse contracture.

Eventually, scientific research will provide answers, both about the mechanisms of contracture, and about how to prevent and treat contracture. The first steps have been made in identifying the abnormalities of gene expression that are ultimately expressed as contracture. New ideas for treatments are being generated by basic research, for subsequent testing in clinical trials. Our motor impairment program will study human volunteers and patients to learn more about normal motor function and the mechanisms of motor impairment, and to test the clinical efficacy and mechanisms of novel treatment interventions. The development of new techniques for imaging and measuring the internal architecture of muscles using MRI provides one promising advance. One study will look at how muscle tendons and fascicles are recruited during movement, which will inform subsequent clinical studies in people in whom contracture is common, such as people with stroke, spinal cord injury and multiple sclerosis.

Hopefully, the next decade will see major advances in both our understanding of the mechanisms of contracture and how to treat them.

An example of one of the unique muscle images generated by Prof Herbert's team. In the centre is a human leg muscle. The blue lines show the course of muscle cells in six locations in the muscle. The insets provide information about how the cells terminate on the tendinous sheets that cover the upper and lower surfaces of the muscle.

An example of one of the unique muscle images generated by Prof Herbert’s team. In the centre is a human leg muscle. The blue lines show the course of muscle cells in six locations in the muscle. The insets provide information about how the cells terminate on the tendinous sheets that cover the upper and lower surfaces of the muscle.

An international approach to tackling Parkinson’s disease

Dr Nic Dzamko and Prof Glenda Halliday have put together an international team dedicated to researching the causes of Parkinson’s disease. They will be the first in the world to use valuable early clinical samples to identify the genetic and molecular underpinnings of this brain illness.

Parkinson’s disease is a debilitating neurodegenerative disorder with no current cure. 1 in every 30 Australians is diagnosed with Parkinson’s disease, and these numbers are predicted to rise. Over the last 10-15 years, it has emerged that genes play an important role in the risk of developing Parkinson’s disease. Approximately 16 genes have now been identified that increase the risk of developing Parkinson’s disease. Understanding what these genes do in the healthy brain, and how their functionality might go wrong, has become a major focus in the search for clues about the cause of this disease.

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Dr Nic Dzamko in the laboratory

One of these genes, called LRRK2, has received considerable attention. The LRRK2 gene encodes a protein that belongs to a class of enzymes called kinases, which is interesting to researchers because many anti-cancer drugs developed by the pharmaceutical industry also act by blocking kinases. In the past few years, more than 20 drugs that can block the kinase LRRK2 have been patented. While it is hoped that these drugs may be beneficial for the treatment of Parkinson’s disease, more work needs to be done to understand exactly what LRRK2 does, and therefore whether drugs that block its action will be safe and therapeutically useful. To better understand the function of LRRK2, our team at NeuRA has initiated two new projects in collaboration with scientists from around the world.

The first project involves us leading a group of scientists from London, Tokyo, California and the Netherlands. Using 400 samples that have been sent to us from these locations, and that cover a range of brain regions at different disease stages, we will determine if, when and where the expression of the LRRK2 enzyme goes wrong in the Parkinson’s brain.

The second project aims to investigate the idea that inflammation is linked with Parkinson’s disease, in collaboration with researchers in the US and Europe. This project is particularly exciting, as it may identify much-needed markers of early disease. By working with the worldwide LRRK2 Cohort Consortium, established by the Michael J Fox Foundation for Parkinson’s Research, we have access to more and better samples to ultimately obtain more meaningful data. We will measure a range of biological markers associated with inflammation in serum and cerebrospinal fluid. By comparing the extent and type of inflammation in people who do and do not have certain genetic mutations, and between people with Parkinson’s disease and healthy controls, we will identify whether inflammation is an early sign of Parkinson’s disease. This world-first access to blood samples from people with a large genetic risk of getting Parkinson’s, but who do not yet have the disease symptoms, is a chance to try and identify potential treatments for the early stages of this illness.

These projects have taken about a year and over 300 emails to come together. Although meetings are often scheduled in the very early hours of the morning to accommodate time zones, working together as an international team to leverage skills and resources is an important step toward solving the problem of Parkinson’s disease. Of course, our work would not be possible without the funding we have received for these projects from the Michael J Fox Foundation and the Shake it Up Australia Foundation.