Beyond DNA code: epigenetics

Why is it that if you keep an active mental life by playing complicated board games or learning a language, or if you keep physically fit, you are less likely to succumb to dementia? A/Prof John Kwok is addressing this question by looking at how lifestyle can alter the function of genes related to dementia.

A/Prof John Kwok

A/Prof John Kwok

To do this, he is engaging with the burgeoning field of epigenetics. Genes have to be expressed (i.e. switched on or off) in a tightly regulated manner for our bodies to function correctly. For example, genes get switched on and off when we are born, or when we hit puberty, in response to hormones or tissue growth. While there are parts of our DNA that control how genes are switched on, there are also epigenetic factors, outside our DNA, that can do this. These factors act like a dimmer switch that changes the brightness of a light.

Diet, exercise, and mental activity can ‘dim the brightness’ of genes that might lead to illness, or enhance genes that promote brain health. Not only do these lifestyle factors change gene expression, but their effect might be inherited by the next generation, even if the relevant gene’s DNA sequence itself is not inherited. Understanding the mechanisms of how this happens is a focus of many areas of NeuRA’s work. The study of epigenetics is important in exploring new possibilities for health care.

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.

What about resilience and wellbeing? The flipside of mental illness

Dr Justine Gatt is an NHMRC Research Fellow who has recently joined the NeuRA team. Her research focuses on understanding the flipside of mental illness: why some people are more resilient to stress than others. It is hoped that these characteristics can be promoted in people who may be less resilient.

Dr Justine Gatt

Dr Justine Gatt

In Australia, nearly half of the population experience a mental disorder at some point in their lifetime, with the most common disorders being anxiety or depression. These disorders can occur in anyone, at any age, but adolescents and young adults are particularly vulnerable as their brain is still undergoing the final stages of development. Exposure to trauma or adversity during childhood or adulthood can often trigger symptoms of these disorders. On the other hand, the presence of certain protective factors may make an individual more resilient to the effects of stress and adversity. Notably, the absence of mental illness does not necessarily imply the presence of optimal mental health, and only a small proportion of people who have no mental illness symptoms are actually functioning optimally and are resilient.

Most psychiatric research has focused on understanding mechanisms of risk for different mental disorders and ways to diagnose and treat them. In comparison, there are very few studies that try to understand the mechanisms of resilience. Our research program aims to understand mental health using a new framework. This includes defining the neural underpinnings of resilience using techniques such as magnetic resonance imaging (MRI) and electroencephalography (EEG) measures of brain function. We also examine the genetics of resilience using saliva samples for DNA analysis.

I am currently analysing data from over 1,600 healthy adult twins who participated in the TWIN-E Study of Emotional Wellbeing. Our team has developed a new questionnaire called COMPAS-W to measure wellbeing. It measures qualities, such as composure, positivity, self-worth and mastery over one’s environment, that are self-reported by study subjects. The questionnaire has been validated against objective psychological tests for symptoms of depression and anxiety. Using measures from this broad source base is helpful when linking biological variables like genetics and brain function, and allows us to explore how innate and environmental factors may moderate our wellbeing, with twin heritability estimates at 48%. The good news is that this means that wellbeing is malleable and can be promoted with intervention.

Comparing between twins allows us to determine the relative contribution of genetics and environment to changes in the volume of grey matter in different parts of the brain. Changes are highlighted in colour. (Gatt et al 2012, Twin Research and Human Genetics)

Comparing identical and non-identical twins allows us to determine the relative contribution of genetics and environment to differences in the volume of grey matter in different parts of the brain. Differences are highlighted in colour. (Gatt et al 2012, Twin Research and Human Genetics)

Another aspect of our research tests how interventions work to promote resilience. We are working with industry partners to test different e-health tools. One of these tools, called MyBrainSolutions, provides targeted, personalised emotional and cognitive solutions over the Internet. To measure resilience, we are testing games that promote positivity (e.g., gratitude training and positive affirmations) and stress management (e.g., the negative thought challenger and MyCalmBeat), as well as executive control games that aim to boost working memory, attention, and goal setting.

Understanding the biology of resilience is the first step towards personalised health solutions. It provides the foundation of features that could be nurtured in low-resilient individuals in order to prevent psychiatric illness. This ‘resilience bio-signature’ could be used as a diagnostic tool for predicting risk for developing mental illness following trauma. At-risk children or adults could then be provided with simple tools to train them to better adapt to life stressors and make them more resilient for the future.

Justine was recently awarded a competitive National Health and Medical Research Council (NHMRC) Career Development Fellowship to conduct this research program. As evidence of innovation and research excellence, Justine was lucky enough to receive the Commonwealth Health Minister’s Award for Excellence in Health and Medical Research in June 2014. The TWIN-E study was a collaborative study with Prof Leanne Williams (Stanford University, previously University of Sydney) as Chief Investigator and co-investigators Prof Peter Schofield (NeuRA), A/Prof Anthony Harris (University of Sydney), Prof Richard Clark (Flinders University), and Dr Justine Gatt (previously as ARC APDI postdoctoral research fellow, University of Sydney) and supported by an Australian Research Council Linkage (LP 0883621) grant with Brain Resource as industry partner.

 

 

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.

NeuRA Magazine #10 is here!

The Spring edition of the NeuRA magazine is ready to read!

This issue, we feature our new clinical trial to improve memory, language and learning in people with Down syndrome. We report our latest research findings, from new genetic sequences in mental illness to how testosterone affects brain growth. You can also read about our Books for Brains challenge.

Subscribe to read future print or email editions of the NeuRA magazine here to stay tuned into all NeuRA news.

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.

A ride for my Dad

NeuRA volunteer Lizzi Mallett explains why she decided to participate in the Memory Cycle to Cambodia in March 2015 and why fundraising for NeuRA’s research is so important to her.

Six years ago my family and I said goodbye to my dad, John Mallett, as he slipped away from our world after suffering from the rapidly progressing motor neurone disease (MND) and frontotemporal dementia for five short years. His battle with these awful diseases started when I was 15 and he was only 58. He lived life each day as if it was his last. His thirst for life took us on a wild journey and he loved every second of it. It is because of my dad that I have decided to dedicate my life to supporting and helping NeuRA. At the beginning of the year I moved to Sydney from Perth and began volunteering with NeuRA’s Foundation team.

When the opportunity for the Memory Cycle came up, I thought that there was no way someone like me, who doesn’t cycle regularly, could do a challenge like this. We would be cycling from Vietnam to Cambodia, and I would have to fundraise a minimum of $3,500 while living on the other side of the country from my entire support network. However, my mother reminded me of my dad’s determination in life and how he purchased a bike when he was ill but could not ride it. He taught me that if I put my mind to something, that I could achieve anything! And by *anything*, I mean the time he sneakily planned a trip from Perth to Hampton Island all on his own when he had already lost the ability to speak and swallow – however, that’s a story for another time. With this determination in mind, I thought, ‘yes, I can do this, I’ll cycle for my dad’. After all, Dad was the one who taught me how to ride a bike and we used to do everything together. This is something he would like to have done and if he was still here with us today, I’m sure he would have signed up for the challenge too. So I signed up and started my fundraising page. Almost instantly, thanks to social media, I raised $1,000 in under a week. Whoa!! Who knew I could do that. I am extremely close to reaching my minimum fundraising goal. See, my dad was right! The mind works wonders; you can achieve anything when you put your mind to it. The Memory Cycle is the best way to fundraise for NeuRA as I get to travel, meet new people, do really cool things with the Inspired Adventurers, and work out, all at the same time.

I had an unbelievably close bond with my dad and it breaks my heart seeing people suffering from neurological diseases just like he did. If you have a desire to help NeuRA and make a difference to so many families suffering from the illnesses that NeuRA researches, then please donate or sign up for Memory Cycle and ride in Cambodia with me. We will have an absolute ball! If you would like to contribute and cannot join the cycle team (even though you really want to!) then you are more than welcome to give a little donation on my fundraising page, and follow my journey on my blog.

I hope to see your pretty little faces on NeuRA’s Memory Cycle team; otherwise, we appreciate every little cent that comes our way. NeuRA is making a huge difference to so many people’s lives, including my own family. Your donation will help NeuRA conquer neurological disease one step at a time.

Dad and I

Dad and I

 

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.