In his blog, exuberant maths teacher Mr Zuber from Randwick Girls’ High School, said that the NeuRA building could be used to explain concepts of integration and that the building “…screams at me ‘Area under the curve!’ every time I walk past it.”

Do you see maths concepts, or anything else unusual when you look at the building?

What do you see in this image of the NeuRA building?

It’s a memorable structure on a historically interesting site, and to many it’s no surprise that the building and COX Architecture have been nominated for the People’s Choice Award in Randwick City’s Urban Design Awards.

The NeuRA building, which will be opening soon, has been nominated for the award in the category of Public Buildings, as we are a medical research facility – you can read more about what we research on our website.

The voting in the Urban Design Awards is only open until 3 May 2013 – so please vote for NeuRA now!

Dr James Burrell researches frontotemporal dementia. One of the symptoms of this type of dementia is forgetting language and words, which can be tested by asking a volunteer to name toy animals.

Frontotemporal dementia (FTD)  is the second most common degenerative disease causing dementia in younger adults, with onset typically occurring in the 50s or 60s. In FTD, damage to brain cells begins in the frontal and/or temporal lobes of the brain, which often results in personality and behavioural changes or losing the ability to speak or understand language.

When conveying a new diagnosis of frontotemporal dementia the clinician almost invariably encounters the following questions “Why has this happened?” “Is there any treatment?” and “Will our children get it?”.

Recent discoveries of genetic causes in familial FTD have given us a much firmer handle on the last question, and have undoubtedly shed light on the cellular processes leading to the death of brain cells in people with familial FTD. Nonetheless, we still know little about causation in non-familial FTD, which accounts for around 90% of cases. Without a clear understanding of these processes it is hard to visualise the development of an effective treatment for this devastating disease.

One potential avenue of exploration is the role of inflammation and the immune system.(2) Recently, Miller et al (3) reported the prevalence of autoimmune disease in two FTD subtypes in which the underlying pathology is quite predictable. The authors reviewed cases files seeking evidence of autoimmune diseases in these two FTD subtypes. A history of non-thyroid autoimmune disease was roughly 3-4 times more common in the FTD disease groups compared to controls or patients with Alzheimer’s disease. A second aspect of the study involved the measurement of an inflammatory marker in the blood, which was found to be elevated in both groups compared to controls, reinforcing the apparent association of neurodegeneration and immune disease. A wide variety of non-thyroid autoimmune diseases contributed to the elevated prevalence in the two groups. Why were only non-thyroid autoimmune diseases more common in the FTD subtypes? The answer may be found in examining so-called “clusters” of autoimmune disease, which may partly represent the expression of certain genetic factors.(4)

The study offers a tantalising clue but much remains to be understood. Is this apparent increase in autoimmune disease only true for one of the pathological processes that underlie FTD? If so, could measuring inflammatory blood markers help identify individuals with that pathology in other FTD subtypes, where the pathology is more varied? What is main determinant in non-familial disease: autoimmunity or systemic inflammation more generally? What is the relationship between FTD pathology and autoimmunity: which is the chicken and which the egg? Could immune modulation offer a route to disease modification? We hope that this important paper opens the way to a more complete understanding of the processes underlying neurodegeneration in FTD and the development of new therapies, which are needed desperately to halt the progression of this dreadful disease.

REFERENCES

1. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011 Oct 20;72(2):245–56.

2. Czirr E, Wyss-Coray T. The immunology of neurodegeneration. J. Clin. Invest. 2012 Apr 2;122(4):1156–63.

3. Miller ZA, Rankin KP, Graff-Radford NR, Takada LT, Sturm VE, Cleveland CM, et al. TDP-43 frontotemporal lobar degeneration and autoimmune disease. J Neurol Neurosurg Psychiatry. 2013;

4. Mackay IR. Clustering and commonalities among autoimmune diseases. Journal of Autoimmunity. 2009 Nov;33(3–4):170–7.

Assoc Prof Bowman and Ben Cassidy, relaxing at the end of the workshop.

Over the past few decades, the neuroscience community has seen a huge growth in new types of experiments, and methods for analysing data.

But there is no magic wand for data analysis: having a large, flexible toolbox of methods can accidentally lead to the equivalent of baking a cake using salt instead of sugar: the ingredients look sensible and might give great-looking results, but overall you didn’t get what you thought you were making.  Similarly, we could use the correct ingredients, but pour them in the toaster rather than the oven. What’s wrong with that? It still cooks, doesn’t it?

Although you wouldn’t last long making these mistakes as a chef, it’s often less obvious when analogous mistakes are made in science. In my research, I am developing analysis methods for functional neuro-imaging. It’s always fun to facilitate new experiments which were previously out of reach, but equally as important  – though less glamorous – is to generate proper diagnostic tests to validate the research method. This has often been ignored in the excitement of tackling the big questions in brain science.

Neuro-imaging is a particularly difficult field to work within, since it requires collaboration between statistics, physics, psychology, engineering, neuroscience and many other disciplines. No-one can be an expert in everything, but we can at least know what common mistakes to watch out for.

With that in mind, NeuRA hosted a workshop on Skeptical Neuro-imaging Analysis: a course to keep our researchers at the forefront of statistical methods. The workshop was presented by a range of local experts as well as two international speakers, DuBois Bowman (Emery University, USA) and Roland Henry (UCSF, USA).

Key ideas from all speakers were to appreciate the range of assumptions we make at every step in the scientific process, and what we can reasonably assume to gain from different imaging modalities. For example, we can gain more information from an experiment mapping the white-matter pathways in the brain by including information about the heartbeat – otherwise, the heartbeat distorts the measurement.

Overall, the workshop successfully put researchers into a more skeptical mindset when conducting their own research.

Not surprisingly, 48% of carers involved in our study reported high levels of carer burden. This is understandable because MND is a devastating disease with a very short prognosis. However, and more importantly perhaps, we found that non-motor symptoms were the major causes of carer burden, with the best predictor being abnormal behaviour, followed by the carer’s own stress. Our investigation also included classic MND motor symptoms, but these were not found to be the main reasons behind carer burden.

Importantly, our study demonstrated that carer burden is complex and multidimensional in MND. This is in line with a previous study by our group, which identified that carer burden in frontotemporal dementia, a disease related to MND, is also partly explained by carers’ own characteristics, and not only the symptoms exhibited by the patient.

Understanding the burden on carers is important, especially for a disease as debilitating as MND.

Studies like this demonstrate to health professionals the impact of these non-motor symptoms on carer burden in MND. Crucially though, our study highlights a major gap in what happens to the families of people with MND. Non-motor symptoms such as cognitive deficits and behavioural changes are not accounted for in the current diagnostic criteria for MND, yet these symptoms aggravate carer burden substantially.

There is important evidence that MND services based on multidisciplinary approaches prolong a patient’s life. However, these services are based on the current description of the disease and do not cater for non-motor symptoms. Until we include these symptoms in diagnostic criteria, many professionals are likely to under-recognise them, and will therefore not be able to advise carers accordingly. This means that carers will not know these behavioural changes are common symptoms, rather than actions personally directed towards them by the person with MND.

In our opinion, the burden and difficulties experienced by people caring for loved ones with MND would surely be improved if they at least had warning of these non-motor symptoms from the time of diagnosis. In short, it’s time the clinical diagnostic and clinical guidelines for MND were reviewed and updated.

Eneida Mioshi is a NHMRC Postdoctoral Research Fellow with the Kiernan Group. She is interested in how the behavioural and cognitive changes caused by disease, affect disease progression, prognosis and care.

Patricia Lillo, is currently an assistant professor of neurology at the University of Chile. She completed her PhD with the Hodges Group at NeuRA in 2012.

Diagnosis is currently made by checking patients for ‘key symptoms’ – symptoms found in one dementia only. For example, Alzheimer’s disease patients have memory problems early on in the disease and memory problems are a ‘key symptom’ in the diagnosis of this dementia…but should they be?

Telling dementias apart is difficult because of overlapping symptoms, such as memory problems. Brain scans provide a clearer idea of which parts of the brain are affected by which dementia.

Recent findings from my group have challenged this notion. We’ve found that patients with a different dementia (frontotemporal dementia) can also have memory problems. Memory problems in frontotemporal dementia were thought to only appear late in the disease, however, our findings show that frontotemporal dementia patients can develop problems with memory at a very early stage and to the same degree as in Alzheimer’s disease. This is a problem for the diagnosis of dementia, as memory problems are not specific to Alzheimer’s disease alone.

Digging deeper into dementia

In a recent study, we explored memory problems in greater detail by investigating specific regions of the brain in people with frontotemporal dementia and people with Alzheimer’s disease. We found that structures deep in the brain (mammillary bodies and fornix) are associated with memory problems in frontotemporal dementia, while more superficial brain regions (temporal cortex, hippocampus) are associated with memory problems in Alzheimer’s disease.

The five major components of our memory circuit and how they are affected by dementia. The memory regions shaded blue are most affected by frontotemporal dementia, the memory region shaded red is more affected by Alzheimer’s disease.

This is important for diagnosis because it suggests that memory problems in the two diseases are caused by damage to different brain regions. When a patient has memory problems, clinicians can use this data to check which brain regions are affected and this will improve the diagnosis of these dementias and make them easier to distinguish. Now that we better understand the source of memory problems in these two dementias, future therapies can be developed to target the different brain regions.

Why does this matter?

Frontotemporal dementia patients may receive an incorrect diagnosis of Alzheimer’s disease if they present with memory problems early in their illness. A correct diagnosis is crucial because potential treatments for these dementias are different, and the impact of the disease on the family and carers varies with each dementia.

Our findings have important implications for the international diagnostic criteria for dementia. These criteria currently state that Alzheimer’s disease has memory problems and frontotemporal dementia does not. We recommend that the criteria be updated as soon as possible as there is a risk of misdiagnosing and incorrectly treating many dementia patients.

Dr Michael Hornberger heads a research group at NeuRA investigating the neural correlates of behaviour and cognition in ageing and neurodegenerative diseases. The title of this blog post ‘People should be what they appear to be’ is a quote from Othello by William Shakespeare.

Our ability to predict future events based on cues in the environment is a fundamental aspect of our daily lives and is dependent upon specific structures in the brain. Two brain regions implicated in this kind of learning are the striatum and the orbitofrontal cortex. If these structures are damaged, we lose the seemingly simple ability to learn that specific cues (e.g. dark clouds and thunder) are likely to lead to a specific outcome (e.g. rain). These regions are damaged in a rare form of dementia known as frontotemporal dementia (FTD). People with FTD also have problems predicting the future based on environmental cues, but is this problem related to damage in the striatum or orbitofrontal cortex?

This study used the weather prediction task. In this task people look at playing cards with different symbols and learn to predict which combinations of cards announced rain and which sunshine. Each combination of cards are associated with a certain probability of good or bad weather.

We tested the ability of FTD patients to predict outcomes (e.g. rain) based on environmental cues (e.g. dark clouds and thunder) and compared their performance to MRI scans of their brains. We found that FTD patients performed as well as control subjects on this task but some FTD patients were very slow at learning the correct outcomes. Interestingly, the results of our imaging analysis revealed that the FTD patients who were slow at learning on this task had atrophy (brain cell loss and damage) specific to the striatum and orbitofrontal cortex.

This suggeststhat some, but not all, patients with FTD develop problems predicting the future based on cues in the present, and that damage to the striatum and orbitofrontal cortex may be responsible for this. These patterns may explain the decision-making problems commonly seen in FTD patients, leading to inappropriate choices in day to day life.

Atrophy (brain cell loss and damage) to coloured areas in the top images is correlated with slow learning on the weather prediction task, but fast learning in the weather prediction task is correlated with atrophy to coloured areas shown in the bottom images.

But the picture is not straightforward. Some FTD patients learned faster than control subjects on the task, and when we looked at the brain images of these FTD patients we found significant brain atrophy in a different region altogether – the medial temporal lobe. It appears then that damage to the medial temporal lobe may paradoxically facilitate learning on this task.

The next step is to investigate if there are differences in the rate of atrophy in the striatum and orbitofrontal cortex in different sub-types of FTD and also how the striatal and medial temporal lobe memory systems interact.

Marshal Dalton is completing his PhD on memory impairments in dementia and theoretical models of episodic memory with Frontier at NeuRA.

Sharon Osbourne is a fan of the cosmetic use of Botulinum toxin. (Image: Wikimedia Commons)

The botulinum toxin (botox) is a neurotoxin found in soil and produced by the bacterium Clostridium botulinum. The botulinum toxin is toxic because it inhibits the release of the neurotransmitter acetylcholine. In the peripheral nervous system, acetylcholine is released by nerves to activate  muscles. When the secretion of acetylcholine from nerves is disrupted by botulinum toxin, the muscles become weak and unable to contract.

Botulinum toxin as medicine

The medicinal use of botulinum toxin is possible because of its effect on our peripheral nervous system and is used to treat spasticity, headaches, migraines, excessive sweating (hyperhidrosis) and  abnormal muscle twitching such as in the eyelid (blepharospasms) and face (hemifacialspasms).

Peripheral nervous system + central nervous system

Given that botulinum toxin affects the peripheral nervous system, could it possibly be affecting the central nervous system too?

A recent study at NeuRA investigated the effect of peripheral injections of botulinum toxin on activity within the cortex – the part of the human brain responsible for movement, learning, memory and sensory processing. The study involved chronic stroke patients suffering from disabling limb spasticity and used paired-pulse transcranial magnetic stimulation to measure electrical activity and patterns in the cortex before and after the injection of botulinum toxin in muscles in the arms or legs.

Clostridium botulinum is a Gram-positive, rod-shaped bacterium that produces several toxins.

Weaken a muscle, change the brain

The study showed that prior to the injection of botulinum toxin, chronic stroke patients with significant spasticity in their limbs had altered brain activity compared to healthy people.  The study also demonstrated that using botulinum toxin in the affected muscles improved limb spasticity and normalised brain activity. However, just as the effects of botulinum toxin on muscles wear off, changes in electrical activity in the cortex also reverted over time.

What now?

This study suggests that the clinical benefits of botulinum toxin in treating spasticity from stroke are related to its effects on the peripheral and central nervous systems. The early use of botulinum toxin in stroke patients at risk of developing disabling spasticity will now be studied.

Dr William Huynh is currently completing a PhD investigating the mechanisms of neuroplasticity following stroke with the Kiernan Group at NeuRA.

Ben Bravery is a science communicator and writer at NeuRA.

A small section of brain tissue, stained to reveal particular structures or the presence of certain chemicals.

When tissue arrives at the Sydney Brain Bank it goes through a thorough examination to determine whether the donor had a brain disease and if so, how widespread and severe it was. Only by doing this can we classify large numbers of similar cases required for meaningful research. Once the tissue is characterised, it’s stored by us and made available for approved scientists to carry out scientifically valid and ethical research projects. All scientific applications are independently reviewed by a panel of experts in the field to ensure the tissue is contributing to world-class research.

Me in the lab

If the donor suffered from a neurodegenerative disease it’s often also comforting for the family to have confirmation of the reason for their physical or cognitive decline. However, the overall reason for becoming a brain donor is purely altruistic and stems from a desire for others not to have to suffer from these conditions. Every donation we receive (of a brain or funds) is achieving this outcome, with over 17 national and international scientific research projects facilitated by the donation of tissue to the Sydney Brain Bank in 2012 alone.

Dr Claire Shepherd is the Manager of the Sydney Brain Bank and is currently working with the NeuRA Foundation to help raise funds for this important facility.  Not many people are aware of why brain banks are so important, and even fewer people know that it takes a surprisingly large amount of money to carefully store, process and handle the precious brain tissue that is generously donated.

In 1855, sixty acres were selected as the site for the new Destitute Children’s Asylum for orphaned children. The main buildings were located north of our NeuRA site on Avoca Street; some still remain.

The only contemporary image of the buildings was taken in 1915 from Barker Street

The NeuRA land was sparsely covered with grass and on the side of a sand dune with a shallow dip to the west. Facing north, a cemetery for the Asylum was established in 1863. To make way for further hospital development, it was excavated and relocated several years ago.

In 1884, two pairs of semi-detached cottages were built on waste ground south of the main buildings (NeuRA’s current site) for staff working at the Asylum at a cost of £2191-13-11.

Reports for the Asylum record improvements in 1889 and 1904 and the buildings were described as “renovated in 1913”. Around this time the Asylum had been converted for use as a military hospital and has continued as a public hospital since.

Throughout the twentieth century, the cottages were still used as private houses while the hospital expanded up to and around them. They were demolished in the 1980s to make way for a new hospital building (the Villa), since demolished for the present building.

As part of NeuRA’s redevelopment of the site in 2011, an extensive archaeological program was undertaken to document the evidence of the cottages and surrounding land.

The dig, showing the historic foundations

The construction of the Villa building had removed large parts of the cottages but sufficient remained to allow our archaeologists a reconstruction of their plan. Consistent with many buildings of that era, each cottage had large sandstone foundations dug into the underlying dune sand. Each had four rooms and a corridor leading to a back verandah with washroom and kitchen at the back and a small laundry behind. They originally had cesspits but these were superseded by water closets that were found in the yards. The latter were found to be largely bare earth with a number of rubbish pits dug into them.

Next to the cottages was vacant ground and large numbers of rubbish pits were found here also yielding domestic waste including broken plates, bottles and scrap bones plus other fragments dating from the late nineteenth century. Some pits were certainly dug to dispose of wastes from around the house; one large one in the yard of 85 Barker Street had a quantity of broken window glass. Remains of the fence separating the cottages from the vacant land were also found.

This archeological dig has given us an interesting insight into the lives of those families who previously lived on the current NeuRA building site. Aboriginal archeological excavation was also undertaken… but that’s for another post.

“Archaeology is the peeping Tom of the sciences.” Jim Bishop, American journalist.

Anne Graham is Communications Manager at NeuRA.