Category Archives: Inflammation

Star-shaped cells: a clue to differences in schizophrenia pathology?

Dr Vibeke Sørensen Catts is a schizophrenia researcher. Her interests lie in exploring the biological factors that help brain cells grow and die, and how these pathways might be altered in schizophrenia. Here she describes her discovery that certain types of brain cells are inflamed in some people with schizophrenia. This recent finding opens new understanding of what goes wrong in this disorder and how it might be treated.

Dr Vibeke Catts

Dr Vibeke Catts

One of the problems with trying to understand a serious mental illness like schizophrenia is that it doesn’t manifest in the same way in all people. In fact, there is a wide range of symptoms and brain abnormalities across its sufferers, who number 1 out of every 100 people.

My colleagues and I were able to turn this variability to some advantage in our research, by deliberately grouping the people we studied according to the molecular features associated with their illness.

A previous study in the Schizophrenia Research Laboratory had found that one third of people with schizophrenia had high levels of biological markers of inflammation in their brain. The identification of this ‘high inflammatory’ group contributed to an increased understanding among researchers that inflammation contributes to schizophrenia pathophysiology, but the ‘how’ of this process was still not well understood.

Inflammation is a protective bodily response to injury or illness, and in the short term is important for normal processes like muscle growth, but is detrimental over a chronic time course. During inflammatory processes, certain specialised cells are activated, releasing chemicals that regulate symptoms such as swelling and pain. In the brain, this process is known as gliosis, and involves extra growth of the ‘support cells’ of the brain, such as microglia and astrocytes. Earlier studies have shown that microgliosis is present in the brains of people with schizophrenia, but it has not been determined how this links to the increased inflammation in the brain that we had observed in some schizophrenia patients.

To see whether the activation of astrocytes (named for their star-shaped appearance) might be the missing link between a general marker of inflammation such as microgliosis and the other inflammatory markers observed in the brain of this group of schizophrenia patients, we measured a protein called GFAP in the prefrontal cortex of people with schizophrenia. GFAP stands for glial fibrillary acidic protein, and it is a marker for astrogliosis.

Taking a closer look at the brain

We did not find an overall difference in GFAP between people with schizophrenia and healthy controls. This didn’t surprise us, since there is so much variability between schizophrenia patients, and because we had previously observed inflammation in the brain of only a subset, rather than all of the schizophrenia patients. However, when we measured GFAP in that ‘high inflammatory’ subset, this group had increased evidence for astrogliosis than the ‘low inflammatory’ group of schizophrenia patients. Furthermore, the shape of the astrocytes in the ‘high inflammatory’ group was different to the ‘low inflammatory’ group.

Questions, answers, and . . . more questions

Our findings are interesting, but highlight the need for further research. Is the response of astrocytes lower in some people with schizophrenia than in other brain illnesses such as Alzheimer’s disease where inflammation and astrogliosis is abundant? Or perhaps the response starts out normally, but is halted over time due to other factors at play in the illness? For example, antipsychotic medications used to treat schizophrenia symptoms may inhibit the process of gliosis, and so an individual’s exposure to these medications needs to be considered in trying to sort out the contribution of these cellular processes to disease.

Regardless, a continuing discussion of whether gliosis plays a major role in schizophrenia is important. Schizophrenia is considered a disorder of aberrant brain development rather than of brain degeneration. However, our data suggest that it is premature to rule out the idea that some individuals experience a different course of illness such that neurodegeneration associated with inflammation is an integral part of what goes wrong. This would in turn inform tailored treatment development for these people.

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.


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.

Could immunological mechanisms trigger neurodegeneration in frontotemporal dementia?

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.

Parkinson’s disease, LRRK2 and inflammation

Over the past decade geneticists have discovered a number of genes that can cause familial or inherited Parkinson’s disease. There are almost twenty known genes that can increase the risk or even cause Parkinson’s disease if they become mutated. There is much hope amongst scientists that by understanding the function of these genes new ideas about how Parkinson’s disease starts and progresses will be discovered. Read more