Progress magazine: Summer 2008

The research magazine of the Parkinson’s Disease Society

Issue 4: Summer 2008

Spotlight on stem cells

Compulsive behaviours and Parkinson’s Tackling speech problems How cueing helps walking Meet... Professor Paul Bolam, Chair of Research Advisory Panel Progress I

Issue 4: Summer 2008

Contents Welcome

1

from Dr Kieran Breen, Director of Research & Development

Spotlight on... stem cells

2

a possible cure for Parkinson’s?

New research projects

7

a round-up of Project and Innovation Grants

Themed research

19

looking into compulsive behaviours and Parkinson’s

Research Equipment Shopping List

23

a PDS branch supporting local stem cell research

Site visit

25

tackling speech problems in Parkinson’s

Completed research

27

how cueing helps walking in Parkinson’s

Meet...

29

Professor Paul Bolam, Chair of the Research Advisory Panel

60 seconds with...

31

Bunia Gorelick, Research Grants Manager

Front cover illustration Jim Dowdalls / Science Photo Library Embryonic stem cells changing into three kinds of cells Stem cells sit inside a 5-day old embryo (yellow ball in the centre), which is the same size as a grain of sand. They can turn into any of the different types of cells that make up our body (shown in blue, red and purple).

Summer 2008 :Issue 4

Welcome Welcome to the summer issue of Progress, the research magazine of the Parkinson’s Disease Society (PDS). We have been as busy as ever in our fight to conquer Parkinson’s. This issue gives you a snapshot of what’s happening in research and how we are working hard to develop a cure – that is a treatment to allow people with Parkinson’s to live a life free from symptoms.

We are delighted to announce that our Board of Trustees have recently approved over £1.8million of new research projects. These include studies on what causes nerve cells to die, searching for a cure and better treatments, practical therapy and support for carers – turn to page 8 to find out more.

The PDS is the largest non-commercial funder of Parkinson’s research in the UK, but this is only possible because of the generous donations made to the Society. To ensure your donations are carefully spent on high-quality research, all of our projects undergo a rigorous vetting system. Professor Paul Bolam, who is the Chair of our Research Advisory Panel, talks about this on page 29.

To develop a cure for Parkinson’s, the PDS is proactively investing in one of the more promising routes – stem cells. We support research into both adult and embryonic stem cells within a strict legal and ethical framework. The PDS has been campaigning hard on behalf of people living with Parkinson’s to drive forward the research effort in the UK. The first article in Progress outlines the importance of stem cell research and what it means for Parkinson’s.

Finally, you may have seen or read in the media about the link between certain antiParkinson’s drugs and changes in people’s behaviours. This side effect of compulsive behaviours is a real problem for some people with Parkinson’s and can have potentially life-shattering effects. To address this, the PDS has invested £640,000 into a research programme on compulsive behaviours. Turn to page 19 to read about one person’s addiction to gambling and how we are tackling these devastating behaviours.

Dr Kieran Breen Director of Research & Development

Progress I

Issue 4: Summer 2008

stem cells Spotlight on...

More than 100 trillion cells pack together to make up all the tissues and organs in our bodies. Throughout our lives, these cells are constantly ageing, dying and being replaced. Each cell works hard to keep us fit and healthy but sometimes the machinery in cells can go wrong – they get sick and die.

Parkinson’s arises when nerve cells die in the part of the brain called the substantia nigra. Once around 80% of these cells are lost, an assorted mix of symptoms appear. They affect a person’s everyday activities – simple things like walking, talking and writing.

Right now, over 120,000 people in the UK are living with Parkinson’s. There is no cure – that is, a treatment that allows people to lead a normal life free of all the symptoms – and most of the causes are unclear. For that reason, research into Parkinson’s is essential, and one of the more promising routes is using extraordinary cells called stem cells.

What’s special about stem cells?

Stem cells are exciting because they have the potential to revolutionise medicine (see Fact box 1). They are like ‘blank’ cells, which can divide forever. We have more than 200 different types of cells such as nerve cells and muscle cells in our bodies – and each of these originates from a stem cell.

Basically, there are two main types of stem cells – embryonic stem (ES) cells and adult stem cells.

Without them, babies wouldn’t grow and wounds in our skin wouldn’t heal.

Fact box 1: How stem cells could revolutionize medicine Research tools • to figure out how cells work, how humans develop and how we get diseases

Drug discovery • to find new drugs and check they are safe and effective

Cell-based therapies • to replace or repair damaged tissues and organs

How could stem cells help people with Parkinson’s?

The idea behind healing the brain is simple – we know that the symptoms of Parkinson’s appear when the supply of dopamine falls in the brain. So scientists are figuring out how to turn adult or ES cells into dopamineproducing nerve cells. These cells could then be grown in the laboratory and transplanted into a person’s brain.

Once integrated into the brain, the healthy cells would I Progress

Summer 2008 :Issue 4

raise the levels of dopamine, allowing the different parts of the brain to communicate properly again. This would hopefully ease the symptoms of Parkinson’s.

The idea of using stem cells to treat Parkinson’s is now becoming a realistic possibility. However, these therapies are still experimental and under development.

At the moment, it is impossible to predict how long it will take for a stem cell therapy to become available to people with Parkinson’s. Also, if a therapy is approved, it is unlikely to work for everyone but only a specific group of people. This is similar to how people respond differently to anti-Parkinson’s drugs.

Fact box 2: Tackling the research challenges Scientists need to answer questions like: • what the best source(s) of stem cells is

Getting stem cells from an embryo When a sperm fertilizes an egg, a one-cell embryo is formed. Pretty soon, the embryonic cell starts to divide and five days later has grown into a tiny ball of around 100 cells. To give you an idea of size, this embryo is about the same size as a grain of sand (Figure 1). Inside the embryo, there is a tiny clump of ES cells. They are powerful cells whose destiny is to make every cell, tissue and organ in our bodies.

Scientists mainly get ES cells from ‘spare’ embryos that would have otherwise been thrown away. Created in the test tube by in vitro fertilization (IVF), these extra embryos are no longer required for fertility treatment.

Some couples, therefore, decide to donate them to medical research. The use of human embryos in UK research is carried out under strict guidelines put into place by an organisation called the Human Fertilisation and Embryology Authority (HFEA).

• how to change a stem cell into a dopamine-producing nerve cell • how to grow large quantities of nerve cells • how many nerve cells should be used in a transplant • where is the best place in the brain to transplant cells • how to check that transplanted cells become ‘wired’ into the brain • how to be certain that transplanted cells make and release dopamine • how to stop transplanted cells from dying or growing into tumours The PDS knows stem cell science is an extremely fast moving field that has many hurdles to overcome (see Fact box 2). So over the last seven years, we have invested £2million into 16 stem cell projects throughout the UK. Our scientists are working hard to understand adult and ES cells so they can potentially harness their power to treat Parkinson’s.

It is very important that both avenues of stem cell research (ES and adult) are kept open to move as swiftly as possible towards developing a potential cure for Parkinson’s. This is because developments in one type of stem cell can help bring forward a scientific breakthrough in another. At this stage, scientists do not know which type of stem cell, if any, will eventually lead to a successful treatment or cure.

Figure 1 Clump of ES cells sitting in the eye of a needle

Unfortunately, scientists don’t have enough human ES cells for their research projects, so they have been looking at other ways of making them.

Getting stem cells from an adult Scientists now believe that most of our bodies’ tissues and organs contain adult stem cells. They are hidden deep within organs and provide a constant supply of new cells, such as blood and skin. Acting like our very own built-in repair kit, adult stem cells replace cells damaged by disease, injury or everyday wear and tear. Recently, scientists have also found them in surprising places like the brain, which is not known to readily regenerate itself.

Compared to ES cells, adult stem cells are less flexible and somewhat limited in what they do. For example, bone

Progress I

Issue 4: Summer 2008

marrow stem cells mainly give rise to the different types of blood cells. However, scientists are working hard to find ways of making adult stem cells more versatile.

If they succeed, a person’s blood stem cells might one day be persuaded to turn into nerve cells. More research needs to be done to understand how adult stem cells work and if they could be used in Parkinson’s.

Cytoplasmic hybrids – an answer to the ES cell shortage?

Besides getting human ES cells from spare IVF embryos, they could potentially be made by an extraordinary technique called therapeutic cloning (Figure 2). Here a cell, like a skin cell, would be taken from a person’s body. The nucleus, which houses the genetic material of DNA, would then be removed and put into an ‘empty’ human egg from which the nucleus has previously been removed. Scientists would then spark the egg to start dividing until it grows into a very early embryo from which the ES cells are extracted.

the DNA (99.9%) in a cytoplasmic hybrid is human. A tiny amount (less than 0.1%) is animal genetic material.

If cytoplasmic hybrids are grown in the laboratory, the ES cells could then be extracted and used for vital research experiments (see Fact box 3).

At the time of publication, the UK Parliament is still debating the Human Fertilisation and Embryology Bill and the use of cytoplasmic hybrids for research.

If approved, research using cytoplasmic hybrids will be very tightly regulated. They will only be used as a research tool for experiments in test tubes.

Cytoplasmic hybrids will only be grown in the laboratory for a maximum of 14 days. They will not be put inside a woman or animal and scientists cannot create children from cytoplasmic hybrids.

Fact box 3: What would cytoplasmic hybrids be used for?

Understanding Parkinson’s • helping scientists work out the mechanics behind the condition – what causes nerve cells to die and how to stop this from happening

Credit: James King-Holmes / Science Photo Library

• figuring out how stem cells can change into nerve cells

Figure 2 Therapeutic cloning – DNA from an adult mouse cell is

being injected into an ‘empty’ mouse egg

To date, scientists have used therapeutic cloning to make ES cells from animal skin cells. In theory, the same could be done with human skin cells but so far this has not been achieved.

At the moment, the big problem is that there are not enough human eggs and embryos to make ES cells for research purposes. One way of solving this is to use eggs from animals and creating cytoplasmic hybrids.

A cytoplasmic hybrid is a cell that consists of elements from an animal and a human. It is created by putting a person’s DNA into an empty animal egg. Nearly all of I Progress

Drug discovery • finding drugs that are more effective at treating Parkinson’s or stopping the condition from getting worse

Drug safety • checking new Parkinson’s drugs are not harmful before giving them to people

Personalised nerve cells can treat mice Another advantage of therapeutic cloning is the possibility of making personalised nerve cells. This would help stop transplanted cells from dying (see Fact box 4). New and exciting research has suggested that personalised nerve cells from sick mice appear to relieve Parkinson’s-like symptoms. Researchers from the United States and Japan took skin cells from mice with a Parkinson’s-like condition and injected the DNA into ‘empty’ mouse eggs. They used therapeutic cloning to create ES cells that were then turned into dopamine-producing nerve cells.

Summer 2008 :Issue 4

The newly-made nerve cells were genetically matched to each sick mouse. When the nerve cells were transplanted into the mouse from which the genetic material had been obtained, they seemed to improve the symptoms. What’s more, the transplanted cells were accepted by the brain and there were no signs of rejection. In contrast, when the nerve cells were transplanted into a different mouse, which did not have the same genetic material, the cells did not survive and the mice did not recover.

If therapeutic cloning could be repeated in people, it would open the door to potential new treatments that reduce transplant rejection. However, moving science from mice to humans is a massive step and it is unknown at this stage whether it would work in people.

Fact box 4: Personalised nerve cells One of the biggest obstacles in stem cell therapy is overcoming a process called immune rejection.

The body recognises cells transplanted into the brain as being ‘foreign’. So it triggers an immune attack that can cause the transplant to fail and even endanger the patient’s life. This can also occur following the transplant of other organs and tissues in the body. To overcome this, patients who receive transplants would have to take drugs to suppress their body’s natural defences. However, these drugs have side effects and can leave patients vulnerable to catching dangerous infections.

Personalised nerve cells would be genetically identical to those already present in the patient.

If these cells are transplanted, it is unlikely that the patient’s body would reject them. The transplant is more likely to be successful and the patient could avoid taking drugs to suppress the immune system.

In theory, personalised cells could be created using stem cells from:

iPS cells – another way of getting ES cells?

At the end of last year, two teams of researchers from Japan and the United States announced an exciting breakthrough. They had discovered a brand new way of rewinding time to turn ordinary adult cells back into ‘blank’ stem cells, which appear to be very similar to ES cells.

The researchers took human skin cells and added just four genes. This ‘reprogramming’ created a new kind of stem cell called induced pluripotent stem cells or iPS cells. They appear to have the potential of turning into any type of cell without using human eggs or embryos to do it. What’s more, a few months ago, researchers announced that they had successfully used reprogrammed skin cells to form nerve cells that ease the symptoms of rats with a Parkinson’s-like condition.

Although these are gripping discoveries, some scientists are remaining cautious. iPS cells are not identical to ES cells – and any differences need to be carefully explored. On top of that, there are two major stumbling blocks that make this approach unsafe before they could even be considered for use in people.

Firstly, the DNA in the cell must be permanently changed to trigger reprogramming. At the moment, scientists don’t know if this causes any long-term harmful effects. Unlike cells made from ES cells that have shown to be genetically stable by many researchers around the world, cells made from iPS cells might not be stable over long periods of time.

Secondly, the approach uses viruses to carry the genes into cells, which may cause cancer. Scientists hope to solve these problems and create safer iPS cells that could one day be used to treat people.

• adult stem cells • therapeutic cloning • induced pluripotent stem (iPS) cells

Can nose stem cells treat Parkinson’s?

At the moment, only therapeutic cloning has been shown to make personalised nerve cells that successfully treat Parkinson’s-like mice. Scientists are still trying to develop personalised nerve cells using the other techniques.

Along with ES cells, there have also been advances with adult stem cells. Australian scientists have recently discovered that human nose stem cells appear to treat rats with Parkinson’s-like symptoms. The stem cells were taken from the back of a person’s nose and then transplanted into the brains of rats. These human stem Progress I

Issue 4: Summer 2008

cells turned into dopamine-producing nerve cells and were found to improve the symptoms of rats. This is a fascinating discovery because it means that adult stem cells might eventually be used to treat Parkinson’s.

Best research to get the quickest results Stem cell research is a dynamic and fast-moving field.

Over the last year, there have been many thrilling new discoveries and scientific developments. All of these bring researchers another step closer towards a treatment for Parkinson’s.

The PDS strongly supports research into both adult and ES cells. We are working hard to drive forward the research effort in the UK that will ultimately benefit people with Parkinson’s. But it is important for people to keep in mind that research is still in the early stages.

At the moment, it is impossible to say which type of stem cell will give us a treatment for Parkinson’s.

Compared to adult stem cells, human ES cells have only been studied for a short time. Most laboratories around the world have only been working on them for five years. Despite this, a great deal of progress has been made in a relatively short time.

Each type of stem cell has its own strengths and weaknesses, and abandoning one of them could be disastrous. If it wasn’t for research on ES cells, scientists would not have made the breakthrough discovery with iPS cells. For this reason, the PDS strongly believes in keeping all options open, so that the scientific community has the best research environment to get the quickest results for people with Parkinson’s.

I Progress

Human Fertilisation and Embryology Bill At the time of printing, the Human Fertilisation and Embryology Bill has been completing its passage through Parliament.

The Bill updates the 1990 Act and brings cytoplasmic hybrids under the same rigorous ethical and regulatory framework that already exists for human embryonic research.

This represents a major campaigning success for the PDS, who along with our members, including our special research interest group SPRING, scientists and other research and patient groups, played a crucial role in building it’s support.

Over the last 18 months, our campaign has involved direct lobbying of Government ministers and parliamentarians, securing influence through the media, submitting evidence to two Parliamentary committees and contributing to the HFEA’s own consultation on this issue.

Following this consultation, in January 2008, the HFEA granted one-year licences to two groups of scientists to conduct research of this kind. One of these groups has now successfully created cytoplasmic hybrid embryos.

Steve Ford, Chief Executive of the PDS said:

“The PDS has worked very hard to campaign, raise awareness and build support for research into cytoplasmic hybrids.

We believe that research should be allowed into all types of stem cells. This gives scientists the best chance for developing a potential cure for people living with Parkinson’s.”

Summer 2008 :Issue 4

New

research Projects The PDS has recently approved funding for 12 Projects and two Innovation studies. This new research into Parkinson’s costs over £1.8million. The researchers talk to us about their projects and plans. To help us meet these costs, we welcome donations to the PDS’s ‘the next step’ appeal and grants to support individual projects (see back cover).

What causes nerve cells to die?

What’s the link between nerve cell death and mitochondria in Parkinson’s?

The mitochondria do this by going through a constant cycle where they split apart and then come together again. This cycle is known as fission-fusion. The latest studies have shown that problems with fission-fusion mean the mitochondria can’t move around the cell properly and this triggers the cells to self-destruct and eventually die.

Lead researcher: Dr Alex Whitworth, University of Sheffield Cost: £99,881 over 36 months We know that Parkinson’s is caused by the progressive death of certain nerve cells in the brain. However, we still don’t know the reasons why the cells die.

So scientists are working hard to answer three main questions: • What causes Parkinson’s?

• Why are particular nerve cells vulnerable?

• How does the disease develop?

By answering these questions, we are optimistic of finding better ways of treating the condition, and, ultimately, a cure.

A lot of research suggests that tiny batteries in cells might play a vital part in Parkinson’s. These batteries are called mitochondria and they are central to the life and death of cells (see Fact box 5 on page 8).

Nerve cells are a real challenge for mitochondria. This is because the cells are very long – up to one metre in length in humans, and have a high demand for energy.

So the mitochondria have to whizz around different parts of the cell to supply much-needed energy in the right place and at the right time.

Dr Alex Whitworth Our research group is interested in learning how altered fission-fusion of mitochondria is linked to the nerve cell death seen in Parkinson’s. Recently scientists have shown that two genes involved in inherited Parkinson’s, called parkin and PINK1, somehow keep the mitochondria in good working order.

We believe that these genes work together with other parts of the fission-fusion machinery to move mitochondria around the cell. So any defects in the nuts and bolts of the machinery will lead to nerve cell death.

Our research project is designed to test this theory.

We will do this by performing a series of genetic studies using fruit flies (see Figure 3 and Fact box 6 on pages 8 and 9).

Progress I

Issue 4: Summer 2008

The results from these experiments will help us understand the link between defects in the way mitochondria move and nerve cell death in Parkinson’s.

This will help guide researchers to develop new drugs that may help stop or slow down the death of nerve cells.

We don’t know what causes Parkinson’s but up-to-date research suggests the cell’s mitochondria, together with oxidative stress, seem to be pivotal factors.

Mitochondria (see Fact box 5) are of vital importance and generate energy through a chain of chemical reactions. However, these reactions are never ‘clean’ and produce hazardous things called free radicals (see Fact box 7 on page 11).

Figure 3 Normal eye of a fruit fly (left) and PINK1-parkin mutant (right). A healthy eye is made up of around 800 specialised nerve cells but the mutant eye is much smaller as a lot of the nerve cells have died

Fact box 5: Mitochondria What do they do?

• Mitochondria are tiny batteries that power cells.

• Cells need energy to move, grow and repair.

• Nerve cells need a lot of energy so have lots of mitochondria.

What’s the link with Parkinson’s?

• In Parkinson’s, the mitochondria don’t work properly.

• Some people have a faulty component called ‘Complex I’.

• Complex I is a major player in energy production.

• Faulty Complex I is thought to make nerve cells more sensitive to free radicals, which may cause them to become sick and die.

Dr Frank Hirth Too many free radicals are bad for the cell. If they pile up, they harm the mitochondria and put the cell under a lot of strain or ‘oxidative stress’. Scientists think this might be fatal for nerve cells. However, there is a lack of conclusive evidence and a direct link needs to be proven.

What key factors are responsible for nerve cell death?

Lead researcher: Dr Frank Hirth, Kings College London Cost: £184,696 over 36 months Parkinson’s develops after cells are lost from the region of the brain that controls movement. These cells produce dopamine, a chemical that enables people to perform smooth, co-ordinated movements. When about 80% of the dopamine-producing cells are gone, the symptoms of Parkinson’s emerge.

I Progress

Figure 4 Dopamine-producing nerve cells (coloured green) in the brain of an adult fruit fly

Our research group believes that both the mitochondria and oxidative stress are directly responsible for the loss of dopamine-producing nerve cells in the brain. To show

Summer 2008 :Issue 4

this, our team proposes a series of experiments using the brains of fruit flies (see Figure 4 and Fact box 6). We will expose dopamine-producing nerve cells to chemical and genetic damage. This will cause the mitochondria not to work properly and lead to oxidative stress. We will then look at whether dopamine-producing nerve cells in the fly brains live or die.

If the results from these experiments support our theory, we will be able to prove that impaired mitochondrial function and oxidative stress directly cause nerve cell death. The research outcomes will open doors to the different pathways involved in neurodegeneration. This will assist scientists in discovering new ways of rescuing or protecting nerve cells in people with Parkinson’s.

Fact box 6: Fruit flies Why do scientists use fruit flies?

• People and fruit flies share many genes with similar functions.

• Scientists can easily change (add or subtract) the genes in flies.

• Each fly only lives for about 100 days, so they can be studied over several generations.

As little as £5 a month can help us find a cure for Parkinson’s You can play a major part in the fight against Parkinson’s.

‘The next step’ is a new initiative that enables people to donate directly to research. By agreeing to make a monthly or annual gift, you’ll be playing a vital role in making the next breakthrough.

Download a Direct Debit form at www.parkinsons.org.uk/donate or call 01753 688 687 (quoting reference Progress)

Nicotine-related substances – a potential treatment for Parkinson’s?

Lead researcher: Dr Stephanie Cragg, University of Oxford Cost: £177,041 over 36 months Despite having been introduced almost 40 years ago, levodopa is still the most common treatment for Parkinson’s. Although initially very effective, levodopa loses benefit with time and is troubled by side effects.

Scientists are therefore keen to develop other treatments with fewer side effects.

We have found that nicotine has crucial effects on the working of dopamine in the normal healthy brain, and nerve cells that make dopamine can react to nicotine.

Adult fruit fly

What’s the link between fruit flies and Parkinson’s?

• Each fly only has around 100 dopamine-producing nerve cells in the brain (Figure 4). By contrast, a person has millions of cells. Since people and flies share many genes, they are a great tool for understanding why nerve cells die as they are easy to study.

• Fruit flies can be created that have some symptoms like Parkinson’s. For example, trouble controlling movement, Lewy bodies in the brain and age-related death of dopamine-producing nerve cells.

Our research team is interested in a group of chemicals called nicotine-related substances. We think that these substances may have two possible benefits for nerve cells. They might: • boost the amount of dopamine being produced to help relieve the symptoms • protect the nerve cells from further damage – that is, to stop the progression of Parkinson’s Our group plans to test whether nicotine-related substances can act on nerve cells and boost dopamine production. We will see if this has any effect in mice with Parkinson’s-like symptoms. Our studies aim to provide a better understanding of how and why this happens. We hope that the knowledge and outcomes from this research will inform the design and development of drugs that mimic the effects of nicotine with minimal side effects.

Progress I

Issue 4: Summer 2008

How alpha-synuclein and nitric oxide synthase cause nerve cell death Lead researcher: Dr Richard Wade-Martins, University of Oxford Cost: £171,423 over 36 months We would like to thank The George John and Sheilah Livanos Charitable Trust for supporting this project Over recent years, two big themes have emerged in Parkinson’s research – the role of a protein called alpha-synuclein and an enzyme called nitric oxide synthase (NOS).

Scientists now know that the alpha-synuclein gene is involved in the rare inherited type of Parkinson’s, as well as the more common non-inherited form of the condition. What’s more, abnormal alpha-synuclein protein is a key component of Lewy bodies. These are small round clumps of debris found in nerve cells of people with Parkinson’s.

Scientists are still figuring out why these clumps form and the importance of alpha-synuclein in how this happens. They think it may have something to do with how cells get rid of old or damaged proteins.

Dr Richard Wade-Martins On the other hand, the enzyme NOS influences the amount of stress a cell is placed under. It is important in producing chemicals called free radicals (see Fact box 7). However, when there are too many free radicals the cell is said to be under ‘oxidative stress’. This is thought to damage nerve cells and cause them to die.

Our research aims to study how alpha-synuclein and NOS contribute to the death of nerve cells. We believe that they somehow come together to alter the amount of free radicals.

To investigate their joint role, we plan on growing mouse and human nerve cells in the laboratory. We will turn off the genes for either alpha-synuclein or NOS in these cells. After exposing the cells to a neurotoxin that causes oxidative stress, we will measure the levels of free radicals and NOS activity. Finally, we look at the expression of certain genes and proteins using brain tissue from people who had Parkinson’s and donated to their brains to the Tissue Bank.

Research in this project uses human brain tissue such as that donated to the PDS Tissue Bank 10 I Progress

We hope that these experiments will help fill some of the blanks in our knowledge. If successful, we will be able to work out how alpha-synuclein and NOS combine to potentially lead to the loss of nerve cells.

By targeting specific proteins, we could find more effective ways of treating Parkinson’s.

Summer 2008 :Issue 4

Fact box 7: Free radicals What do they do?

• Free radicals are chemicals that take part in a cell’s everyday activities.

• Mitochondria make free radicals when they generate energy.

are running into many obstacles. For example, we are still trying to work out the best source of stem cells, how to grow large quantities of high-quality cells in the laboratory and how to stop cells from dying once they are transplanted into the brain. To tackle these problems, stem cell research is being carried out in many different avenues.

• The amount of free radicals is controlled by chemicals called antioxidants.

• Antioxidants immediately ‘mop up’ and neutralise excess free radicals.

What’s the link with Parkinson’s • Most people with Parkinson’s have high levels of free radicals in their brains.

• Too many free radicals and not enough antioxidants places a terrible strain on a cell – it is said to be under ‘oxidative stress’.

• Extra free radicals are thought to lead to nerve cell death.

Searching for a cure and better treatments Can human stem cells repair the brains of rats?

Lead researcher: Dr Maeve Caldwell, University of Bristol Cost: £170,649 over 36 months We are grateful to the Medlock Charitable Trust for supporting this project Stem cell therapies potentially offer great promise to people with Parkinson’s. The goal of stem cell research is to replace dead dopamine-producing nerve cells with new, healthy cells. This would restore the supply of dopamine in the brain and allow the brain to work properly again.

Scientists are working hard to establish a possible stem cell treatment for Parkinson’s. Unfortunately, we

Our team plans to study how human embryonic and fetal stem cells can be used to treat rats with symptoms similar to Parkinson’s. We will engineer human stem cells to make a protein called Lmx1a that appears to influence how the cell behaves. We believe that it will help human stem cells turn into dopamineproducing nerve cells. These cells will be transplanted into the brains of rats with Parkinson-like symptoms.

We will then look to see if there are any changes in the treated rats symptoms. This will tell us whether the transplanted cells are having a beneficial effect.

Our team will also design human stem cells to make other proteins, including those called JBD and Bcl-2.

We believe these proteins will help the dopamineproducing nerve cells live longer after transplantation.

This project will lead to a major advance towards building our understanding of how stem cells are changed into nerve cells and the proteins required to help them stay alive. If successful, we will establish a way of growing large amounts of dopamine-producing nerve cells that live longer when transplanted into animals.

For more on stem cell research and what it means for Parkinson’s, turn to page 2.

Progress I 11

Issue 4: Summer 2008

Why does DBS cause depression in some people with Parkinson’s?

Lead researcher: Dr Trevor Sharp, University of Oxford Cost: £156,830 over 36 months Deep brain stimulation (DBS) is an operation that has striking results in some people with Parkinson’s who are having problems with their current medication (Fact box 8). Unfortunately, DBS causes almost half of people with Parkinson’s to experience unpleasant feelings such as despair and worthlessness. These symptoms resemble clinical depression and are a terrible burden for people with Parkinson’s and their families.

To conquer this problem, we plan to investigate how DBS changes the level of this chemical in the brains of rats who have undergone the treatment. This will give us a better understanding of what is happening in people with Parkinson’s. We are optimistic that if our results are positive, it will help us develop new and better ways of preventing depression after DBS.

Fact box 8: What is deep brain stimulation?

Deep brain stimulation (DBS) is a type of surgery that can help people with Parkinson’s control their body movements. The surgery was pioneered in the 1980s

by French scientists and is now carried out in several specialist centres across the UK.

At present, our knowledge of DBS is incomplete. There is no way to pinpoint which people with Parkinson’s might experience depression as a side effect of DBS. We do not know the reason(s) why DBS produces these symptoms or the best way to treat them.

Although DBS can greatly improve a person’s wellbeing and ability to carry out everyday activities, it is not suitable for everyone. Mostly, DBS is recommended for people who are not responding well to their anti-Parkinson’s drugs.

Latest research suggests that stimulating the subthalamic nucleus (STN), part of the brain that is targeted by DBS, appears to affect a chemical called 5-hydroxytryptamine or 5-HT.

DBS involves inserting a thin wire into the brain.

The tip of the wire contains an electrode which is carefully positioned into one of three parts of the brain, known as:

5-HT plays an important role in a person’s mood and state of mind. Our research team believe that depression after DBS is caused by changes in the levels of 5-HT.

• the thalamus • the subthalamic nucleus (STN) • the globus pallidus These are parts of the brain that are involved in movement. The wire is connected to a device – like a pacemaker – that is implanted under the skin near the collarbone. The person with Parkinson’s can turn the device on and off on a daily basis using a handheld programmer or magnet. When it is switched on, it sends a small electrical signal to the brain to stop or reduce the symptoms of Parkinson’s.

Dr Trevor Sharp 12 I Progress

Summer 2008 :Issue 4

How can we improve DBS?

Discovering drugs that slow down the progression of Parkinson’s

Lead researcher: Dr Ian Stanford, Aston University Cost: £203,059 over 36 months Parkinson’s develops when people lose a lot of the chemical messenger dopamine. This loss affects an area of the brain called the subthalamic nucleus (STN), which plays a crucial role in the control of movement.

It causes the nerve cells in the STN to become overexcited and behave unpredictably. People therefore start to experience problems, such as tremors and inability to move – the key symptoms of Parkinson’s.

At the moment, there is no cure for Parkinson’s and existing therapies only ease the symptoms.

Unfortunately, there is also no treatment that can stop dopamine – producing nerve cells from dying.

For that reason, there is a great need to develop new medicines that slow down the rate at which Parkinson’s progresses. This kind of treatment is called a diseasemodifying therapy and our research team is focused on finding drugs which may have these properties.

© Vasiliy Yakobchuk - Fotolia.com

At the moment, surgery such as DBS is used to ‘calm down’ the over-excited nerve cells in the STN (see Fact box 8). However, DBS involves surgery and researchers still don’t fully understand the reasons why it helps relieve the symptoms of Parkinson’s.

Lead researcher: Dr Oliver Bandmann, University of Sheffield Cost: £184,287 over 36 months

Interestingly, new research has suggested that stimulating another part of the brain, called the motor cortex, might relieve some of the movement problems for some people with Parkinson’s. To investigate this further, we plan to study how nerve cells in the motor cortex and STN talk to each other. We will do this by comparing the brains of rats that are healthy and those that have Parkinson’s-like symptoms.

Our research will help us understand the mechanics of why stimulating the STN provides relief from the symptoms of Parkinson’s. By understanding how the motor cortex might influence the STN, we hope our research will open up the possibility of targeting other parts of the brain, to produce an effect similar to DBS but without the associated side effects.

Dr Oliver Bandmann A big problem in Parkinson’s is that the ‘batteries’ of the cell, called the mitochondria, don’t work properly (Fact box 5). If the mitochondria don’t work properly, our cells will die. In some people with Parkinson’s, there seems to be something wrong with the mitochondria, not only in the brain, but also in other cells of the body, such as the skin cells. However, nerve cells are very fragile and that is why these are the main cells to die in Parkinson’s.

Progress I 13

Issue 4: Summer 2008

Our research team plans to use the fact that there are problems with the mitochondria, even outside the brain, to discover new drugs that will slow down or even stop the nerve cells from dying.

We propose to do this by taking skin biopsies from people with Parkinson’s that carry mutations in one of the genes associated with Parkinson’s, called parkin. It is the most commonly mutated gene in people with the rare inherited form of early-onset Parkinson’s. We will grow the skin cells in the laboratory and use them to screen around 2,000 different drugs. These include about 1,000 drugs which are already licensed and in use for other diseases, but also around 500 natural products and further substances known to influence brain activity in a particular way.

© Steve Baskauf

Our team will look to see if any of the drugs appear to repair the abnormal mitochondrial function. We believe that if the drugs have an effect in Parkinson’s skin cells, they will hopefully have an effect on nerve cells as well.

Adult zebrafish After we have shortlisted potentially useful drugs, we will test their effect on nerve cells in the embryos of zebrafish. We have chosen zebrafish as their brain is, in some ways, very similar to the human brain. We will check to see if these drugs affect the survival of dopamine-producing nerve cells (Figure 5).

Together, we hope that our drug screen in skin cells from people with this rare type of Parkinson’s and zebrafish will be a powerful new tool for the discovery of disease-modifying drugs. If we do find a drug that slows down the progression of Parkinson’s, it will enormously help not only people with early-onset Parkinson’s and parkin mutations, but their families as well. Further studies will then be carried out to reveal whether these ‘positive hits’ may also benefit the more common, non-inherited form of Parkinson’s.

A new way of controlling dyskinesia?

Lead researcher: Professor Peter Jenner, Kings College London Cost: £171,011 over 36 months

Professor Peter Jenner Levodopa is still the most effective and widely-used drug to treat the symptoms of Parkinson’s. Unfortunately, most people who have been taking it for a long time can experience severe side effects and difficult complications including: • ‘wearing-off’ – when the effects of levodopa dwindle before it is time for the next dose • ‘on off’ effects – this is when a person’s response to levodopa begins to fluctuate. They find themselves switching quite suddenly between being ‘on’ and able to move, and being ‘off’ and immobile • dyskinesia or uncontrollable jerky movements

Figure 5 Zebrafish embryos – arrows point to dopamine- producing nerve cells (purple dots) 14 I Progress

Problems like these are disabling, tiring and painful for people with Parkinson’s. Tackling them will greatly improve how people cope with the activities of everyday life.

Summer 2008 :Issue 4

At the moment, little can be done to relieve dyskinesia.

There are two potential ways of treating this common side effect. Firstly, to control it after they have already appeared and, secondly, to prevent dyskinesia from occurring in the first place. Unfortunately, over the years, researchers have made no real progress in developing such a drug.

Do changes in blood vessels make Parkinson’s worse?

Our research team believe that we can overcome dyskinesia – and it is based upon a chance discovery involving a chemical called nitric oxide. People with Parkinson’s have high levels of nitric oxide in their brains. Too much of this chemical affects how dopamine is released from nerve cells and seems to damage the brain.

To work properly, the brain need a good supply of blood.

This is essential to feed nerve cells with oxygen and other nutrients, keeping them healthy and alive. It is the job of the vascular system to carry blood to the cells.

Lead researcher: Dr David Dexter, Imperial College London Cost: £164,680 over 36 months

In our laboratory, we have been experimenting with an enzyme that makes nitric oxide in cells. It is called nitric oxide synthase (NOS). We were very excited to find out that drugs stopping NOS, appear to stamp out dyskinesia in animals with Parkinson-like symptoms.

So we believe that, if these drugs help hamper dyskinesia in animals, there is a strong likelihood they may be able to do the same in people with Parkinson’s.

We are now very keen to investigate our discovery further. Our research team has proposed a series of investigations to test these drugs in rats and monkeys with Parkinson-like symptoms. We plan to test if those drugs can prevent dyskinesia occurring during levodopa and dopamine agonist therapies. We also would like to explore the link between nitric oxide, nerve cells in the brain and dyskinesia. By doing this, we hope it may reveal important information about how dyskinesia is caused.

If successful, our project could lead to an effective drug to treat and/or prevent dyskinesia in animals with Parkinson’s. Eventually, this would be tested in people with Parkinson’s. Managing this common side effect would prolong the usefulness of Parkinson’s drugs and improve the lives of many thousands of people.

The importance of NOS is also being investigated by Dr Richard Wade-Martin. See page 10 for details.

Dr David Dexter The vascular system is basically a network of blood vessels – similar to a collection of pipes. If any of the pipes get blocked, it affects the blood flow to a particular path of the brain (Figure 6). A severe blockage can stop blood reaching the nerve cells, which eventually die because they are starved of oxygen and nutrients.

Progress I 15

Issue 4: Summer 2008

To do this, we plan on investigating the brains of people with Parkinson’s that have been donated to the PDS Tissue Bank here at Imperial College London.

Our team will analyse brain tissue using advanced MRI scanning technology and microscopic examination.

First, we will see if there are any changes to the blood vessels in the brains of different people. Next we will look at each person’s medical history, which was also provided when they donated their brain. For example, facts like the age at onset of Parkinson’s, response to their medication, how frequently they fell, plus treatments for high blood pressure, cholesterol, heart disease or diabetes.

Figure 6 Network of blood vessels to the brain. Arteries (red) carry oxygen and nutrients to nerve cells. Veins (blue) take away waste products made in cells

We know that a number of conditions, like high blood pressure and elevated cholesterol, can damage our blood vessels. On top of that, our western diet does not help as it is rich in foods high in salt and fat. Salt raises our blood pressure and fat can build up inside the walls of blood vessels and narrow them (Figure 7).

All this leads to vascular disease in the brain during old age. This is dangerous as damaged blood vessels might leak or blood clots might form, which increases a person’s likelihood of a stroke.

Recent studies have shown that damage to the brain’s blood vessels has been found in around 30% of people who have been diagnosed with Alzheimer’s. Risk factors, such as diabetes and high blood pressure, are known to make people more prone to vascular disease.

New research has suggested that people with Alzheimer’s, who have these risk factors, have a more aggressive form of the disease as well. Despite the connection between vascular disease and Alzheimer’s, little research has been done to see if damage to the brain’s blood vessels is linked to other neurodegenerative conditions, like Parkinson’s.

Our research group is interested in exploring this possibility further. We want to see if the symptoms of Parkinson’s are only produced by the gradual loss of nerve cells, or whether in some people, as with Alzheimer’s, vascular factors influence the progression of symptoms.

16 I Progress

Figure 7 D amaged blood vessel in the brain. Because of the salt deposits (dark purple), the hole in the middle is narrower and carries less blood to the brain

This will allow us to compare changes within the brain with the clinical aspects of Parkinson’s and the person’s other health history. We will then be able to determine if there is a link between changes in the brain’s blood vessels and the progression of Parkinson’s.

If our study is successful, we will be able to show whether damage to blood vessels in the brain may play a role in the progression of Parkinson’s. On top of that, we will be able to draw up a set of vascular risk factors to assess whether a person is potentially more vulnerable to vascular diseases in addition to Parkinson’s.

This information might help us treat people with more appropriate drugs at an early stage. Doctors could prescribe medicines such as lipid lowering drugs, which reduce their risk of vascular disease and possibly slow down the progression of Parkinson’s.

Summer 2008 :Issue 4

PDS Tissue Bank A vital gift The projects on page 10 and 16 use human brain tissue. This research only happens because people with and without Parkinson’s generously donate their brains.

The PDS Tissue Bank collects and provides brain tissue to researchers around the world.

Help us drive forward towards a cure for Parkinson’s - donate your brain as a vital gift.

(See the back cover for more details).

Practical therapy and support for carers How to stop people with Parkinson’s from falling during turning Lead researcher: Professor Ann Ashburn, University of Southampton Cost: £75,861 over 18 months One of the most challenging movement problems in Parkinson’s is turning. This can have a huge impact on a person and how they go about their everyday activities.

For example, not being able to turn or roll in bed makes sleeping very difficult. Also, trying to turn when standing or walking can trigger freezing and even falling.

Loss of balance and falling is a great problem for most people with Parkinson’s. As the symptoms progress and different muscles become affected, falling down becomes increasingly common. A stooped posture, rigid muscle tone and freezing all contribute to the risk.

Around two-thirds of people living with Parkinson’s will have fallen in the last 12 months, and these people are very likely to fall on a relatively regular basis.

The effects of falling can lead to both physical and social problems. They can make a person vulnerable to minor injuries and, more seriously, broken bones. The fear of falling again can also give rise to anxiety and a loss of confidence. This has the potential to start a vicious circle as a person restricts their normal everyday activities.

The subsequent lack of exercise can make Parkinson’s worse. It stiffens joints and weakens muscles. This, in turn, increases the likelihood of further falls.

For those reasons, there is a great need to find new ways of preventing or reducing falls. When turning round, a healthy person first moves their eyes towards where they want to go, then their head, followed by their body and legs. People use this ‘eyes first’ approach to maintain balance. Unfortunately, we do not think that this happens in people with Parkinson’s.

Until now, there has been no research on how the ‘eyes first’ part of the process is used in someone with Parkinson’s. We suspect that one reason why people with Parkinson’s find turning so troublesome is that the sequence of eye, head, body and leg movement is altered.

Our research team plans to investigate the sequence and timing of the eye, head, body and leg movements of people with Parkinson’s. We will do this as they turn both during sitting and standing. We think that the head and body may move together, as a block, and this frequently ends in falls. To help prevent falls, we believe that it will be possible to separate the eye and head movements in people with Parkinson’s. This could be done in response to a cue.

Progress I 17

Issue 4: Summer 2008

We hope the outcomes of the research will help answer questions about how movement changes in people with Parkinson’s. The results from the study may guide the development of treatments that help reduce the number of falls associated with turning.

Can the stress of caring be reduced by cognitive-behavioural therapy?

Lead researcher: Professor Richard Brown, Kings College London Cost: £71,537 over 30 months Family and friends who care for people with Parkinson’s play an essential and much-needed role. Over time, however, the physical and emotional demands of caring can affect the carer’s own health and wellbeing. This impacts on the individual’s ability to provide care to the person with Parkinson’s.

Our research group has developed a form of CBT that has been tailored to meet the needs of Parkinson’s carers. In an earlier PDS-funded study, we successfully showed one-to-one CBT can help reduce the stress of long-term caring. Unfortunately, there is a shortage of clinical psychologists in the NHS. This means that this type of CBT is unlikely to be available to the high number of carers that need it.

To address this, we propose to develop a new package of CBT that can be delivered to larger numbers of Parkinson’s carers by a Parkinson’s Disease Nurse Specialist. We will also carry out a controlled trial to test how effective CBT is in reducing a carer’s distress and burden. If we can show that the treatment is effective, it would support making CBT more widely available on the NHS and help many Parkinson’s carers.

The PDS has approved two new Innovation Grants: What happens in the cell when PINK1 gene is mutated?

Lead researcher: Professor Anthony Schapira, University College London Cost: £10,000 over 12 months

Professor Richard Brown There is a lot of research that says giving extra assistance and support to carers can reduce the level of stress and burden that they experience. One type of treatment that has been shown to work is called cognitive-behavioural therapy (CBT).

CBT is a common treatment delivered by clinical psychologists. It is used to improve a person’s state of mind by changing how they think and what they do.

These changes can help the person feel better and cope with stressful situations.

18 I Progress

How effective are different cueing devices for people with Parkinson’s with gait initiation difficulties?

Lead researcher: Professor Jim Richards, University of Central Lancashire Cost: £9,969 over 12 months

Summer 2008 :Issue 4

Themed research

Compulsive behaviours and Parkinson’s Over the last few years, research findings have strengthened the link between some Parkinson’s medicines and a change in people’s behaviour.

These changes are known as compulsive behaviours and they are a potential side effect of certain drugs – mainly dopamine agonists.

their movement. This happens even though they are ‘on’ and experience severe dyskinesia (involuntary jerking).

People may also have very bad mood swings throughout the day. These can vary from feelings of depression, irritability and anxiety when they are ‘off’, all the way to euphoria and hyperactivity when they are ‘on’.

Dopamine agonist is a class of drug that treats Parkinson’s by mimicking the effect of dopamine in the brain. At the moment, scientists think that up to 14% of people with Parkinson’s taking dopamine agonists experience some problem with compulsions. If untreated, they can escalate and lead to uncontrollable addictions that devastate people’s lives.

Little is known about what goes wrong in the brain to trigger compulsive behaviours, so research is urgently needed to figure out: • the causes • how to treat those affected

A compulsive behaviour is when a person is unable to resist an impulse or temptation. The person can’t stop themselves from doing an activity repeatedly, excessively or obsessively.

What kind of compulsive behaviours are seen in Parkinson’s?

© milosluz

understanding who is most at risk

© hannahfelicity - Fotolia.com

• how to stop them happening in the first place by

Dopamine addiction Some people with Parkinson’s become addicted to their dopamine replacement drugs. Here, the addiction is so powerful that they start taking more and more of the drug – exceeding the dose prescribed to control Progress I 19

Issue 4: Summer 2008

Compulsive gambling, shopping and eating, and hypersexuality Unlike dopamine addiction, people can develop other compulsive behaviours by simply taking standard doses of certain dopamine agonists. These behaviours can be expressed in a number of different ways: • a failure to resist gambling • an irresistible need to buy things • binge eating large amounts of food in a short space of time • a pre-occupation with sexual thoughts or inappropriate sexual behaviour • an obsessive fascination with hobbies and repetitive activities such as cleaning, collecting or sorting things In a lot of cases, the behaviour is out of character for the person. Unfortunately, the consequences can be very dramatic and bring about terrible work, social and financial problems.

Patricia’s story: my addiction to gambling

getting hallucinations. But he said not to worry – that hallucinations were way down the list of side effects, and I was more likely to feel nausea.

After taking my new drugs, my behaviour started to change – I began to place small bets on the internet.

Eye-catching ‘pop-ups’ advertising gambling websites would appear and I’d find myself clicking onto the links and betting money. Before I knew it, I became a regular user of more and more websites. Strangely, if I lost money, I wasn’t bothered – I felt compelled to carry on and on.

A couple of years later, I visited my neurologist. I remember telling him that although my Parkinson’s symptoms were very well controlled, I was worried, as I felt something wasn’t quite right. I clearly recall asking him if there was a possibility that my behaviour had anything to do with my medication or my condition.

But my neurologist said no and nothing was done.

As time went on, my behaviour worsened. I feel bad to say this, but I found myself becoming more and more devious. I even used my daughter’s credit card without her knowing and took out loans behind my husband’s back. Slowly but surely, my debts piled up, till I could no longer ignore the alarm bell ringing loudly in my head.

My Parkinson’s was diagnosed 12 years ago, when I was in my early 40s.

At first, I was prescribed bromocriptine and levodopa, but really struggled to control my movements. So my consultant changed my medication regimen, putting me on a dopamine agonist. I was warned that I might experience hallucinations as a side effect and this concerned me. I remember that when I picked up my drugs, I talked to the pharmacist about my fear of

20 I Progress

© Trevor Goodwin

money © Christopher Hall

Finally, I shared my fears and problems with my Parkinson’s nurse. She was great and linked my obsession with gambling to my medication. So I have now changed my drugs. I feel like a great weight has been lifted from my shoulders, and my behaviour is getting better.

Summer 2008 :Issue 4

Compulsive gambling has had a truly devastating effect on my life – as well as the lives of those I love. Without knowing it, and without anyone recognising it - I turned from a person who enjoyed the occasional game of bingo, to an addict who gambled in secret and mounted many thousands of pounds of debt.

PDS funding the research gap So far, research into compulsive behaviours has focused on describing the different types of behaviours and their effect on people with Parkinson’s. However, many people with these problems do not receive proper help.

One reason might be that people are unaware that their changes in behaviour are related to their medication.

Alternatively, they might be too embarrassed to mention it to their doctors. Also, some doctors might not be aware of how common these behaviours are, so do not ask their patients if they are experiencing such side effects.

Now is the time to raise awareness of this condition among healthcare professionals, and people with Parkinson’s and their families. For this reason, the PDS is bridging the knowlege gap by investing £640,000 in a large-scale research programme. It will investigate compulsive behaviours in people with Parkinson’s who are taking dopamine agonists. The programme consists of two parallel and complementary studies carried out

by Dr Paola Piccini from Hammersmith Hospital and Professor Anthony David from King’s College London.

PDS-funded research into compulsive behaviours aims to answer questions like: • why certain people are affected • what is happening in the brain • what is the best way to treat the problem

Doctors Kit Wu (left), Marios Politis, Paola Piccini and Sean O’Sullivan

What risk factors cause compulsive behaviours?

Lead researcher: Dr Paola Piccini Institution: Imperial College London Cost: £310,319 over 36 months Our research group is trying to uncover what risk factors make some people more prone to compulsive behaviours than others.

We believe that a person’s personality and their attitude towards risk and reward are very important. Also, we think that compulsions are triggered when the brain’s pleasure centres are stimulated too much and become over-excited.

To test this, the first part of our study investigates the psychological factors associated with compulsive behaviours. We are doing this by using questionnaires to ask around 100 people with and without Parkinson’s about their attitudes towards gambling, spending, medication-taking, sexual activity and binge eating.

After we collect and analyse this data, we will see if there are certain personality traits that are more common in people with Parkinson’s who either have or go on to develop compulsions. In the future, we might be able to use these traits to identify those who may have a higher risk of developing the behaviours.

During the second part of our study, we plan to compare the activity of the brain in people with Parkinson’s who do and do not display compulsive behaviours. To do this, we will use modern imaging technologies to look at the brain. As we scan the brains, we will show people rewarding or pleasurable images, such as money, appetising foods and dopamine medications. We will then look at the areas of the brain thought to be responsible for addiction and see if there is any difference.

We are optimistic that our research will provide a better understanding of why some people with Parkinson’s develop compulsive behaviours. By investigating potential causes for these problems, it will help doctors identify at-risk people, and tailor their advice about medications. It may also lead to ways of stopping these problems getting worse or even preventing them.

Progress I 21

Issue 4: Summer 2008

How can we manage compulsive behaviours?

Lead researcher: Professor Anthony David Institution: King’s College London Cost: £333,333 over 36 months Our part of the research programme investigates different ways in which people with Parkinson’s and their carers can manage their compulsive

PDS-funded Senior Research Fellowship Complementing the new research programme, the PDS has already awarded a Senior Research Fellowship to Dr Iracema Leroi, a consultant in old age psychiatry and specialist in the mental health of people with Parkinson’s.

Dr Leroi is also trying to determine which risk

behaviours more effectively.

factors might predispose someone with Parkinson’s

One thing that we often hear is that people with Parkinson’s and their carers find it difficult to ask for the help they need. We think that having an ‘advocate’, whose role is to do this, might be very beneficial. We

is using laboratory-based behavioural tasks on

would like to see if the Parkinson’s Disease Nurse Specialist (PDNS) can fulfil this role.

to develop compulsive behaviour. However, she people with Parkinson’s that either have compulsive behaviours or apathy.

Dr Leroi will see how being ‘on’ and ‘off’ Parkinson’s medications might affect decision-making and risk taking during certain thinking tasks.

In our project, around 40 people with Parkinson’s and their carers will have a dedicated PDNS, who has experience and skills in mental health, allocated to them. Our research will compare people with Parkinson’s who have access to a dedicated PDNS with those who don’t.

The PDNS will work with them to find better ways of managing their behavioural problem using existing services such as the local community mental health team, the GP and social services.

The PDNS will also carry out a nurse-led psychosocial treatment to help manage the person’s compulsive behaviour and improve the burden on their carer. This includes optimising medication, looking at beliefs and attitudes, things that seem to ‘trigger’ compulsions, and working out coping strategies for both the person with Parkinson’s and their carer.

If such a treatment does prove to be valuable, it will have implications for broadening the training of PDNSs. It will also support the case for having more PDNSs working with clinical teams looking after people with Parkinson’s throughout the country.

Dr Iracema Leroi 22 I Progress

Summer 2008 :Issue 4

Research Equipment

Shopping List

How PDS branches and support groups are helping researchers

What is the Shopping List?

Running for 15 years, the Research Equipment Shopping List has grown in popularity with researchers and branches alike. PDS-funded scientists, who require extra equipment for their projects, apply to place items on the scheme.

Requested items can range from £50 all the way up to £5,000. The Shopping List is circulated to over 330 PDS branches and support groups throughout the UK. Each branch then decides if they would like to take part. If so, they can choose which research project to support and what piece of equipment to buy. This is just one of the many ways that branches can support researchers.

“It is a way for PDS branches and support groups to get involved in research. They help by raising money to buy much-needed equipment for scientists to carry out their everyday work.”

Trish Hadfield, Research Grants Officer Last year, the Shopping List helped 30 different research groups across Scotland, England, Wales and Northern Ireland. Collectively, branches and support groups kindly donated over £71,000 worth of equipment to laboratories.

PDS Edinburgh Branch supports local research One scientist who has benefited from this generosity is Dr Tilo Kunath, a PDS Research Fellow, at the University of Edinburgh. Dr Kunath and his team are studying how certain genes and chemicals can turn embryonic stem cells into nerve cells and tissue. After requesting an electrophoresis tank, the PDS Branch in Edinburgh stepped in to help.

“People like to see that something positive is being done – it’s good for people in Scotland to give to research in Scotland. It gives a sense of ownership and an opportunity to engage with the researchers.”

Patrick Mark, Chairman of the PDS Edinburgh Branch The new tank is already being put to good use by the team:

“We use the tank on a daily basis to separate bits of DNA on a gel with an electric current.

“The DNA contains the genes we are interested in. They appear as bright fluorescent bands, which we cut out of the gel.

“We then separate the DNA from the gel and eventually put the pure DNA into embryonic stem cells.

“This is a vital procedure in our research programme. By doing this, we hope to find genes that instruct stem cells to turn into nerve cells.”

Dr Tilo Kunath

Dr Kunath (right) with his research team Progress I 23

Issue 4: Summer 2008

Electrophoresis tank

This is the second item to be donated to the team by the PDS Edinburgh Branch. Earlier last year, they received a brand new centrifuge. What’s more, these generous donations have come at an ideal time for Dr Kunath…

“Now we have two modern pieces of equipment that really make a difference. Our research moves much faster – the team can work more quickly and efficiently.”

© Danielle Bonardelle

“I’ve just started my own research group, so suddenly there were four people trying to use one very old electrophoresis tank and a centrifuge borrowed from another laboratory.

Bands of DNA (orange) on a gel

Dr Kunath Although a single item may not cost a great deal, it can make a huge difference to the researchers.

Dr Kunath and his team will no longer have to queue to use equipment shared with other laboratories. Also, the research apparatus is good value – it lasts for many years and can be used in hundreds of projects.

“The Shopping List is great because it allows members to see where their money is going and how much of a difference it makes to research into Parkinson’s.”

Patrick Mark Not only does the Shopping List provide important equipment for PDS-funded projects, it also helps build relationships between scientists and people with Parkinson’s.

24 I Progress

“For us, it’s a two-way process that nurtures links with local researchers.

“It’s important for researchers to meet and learn from people living with Parkinson’s, as well as providing opportunities for the scientists to explain their research and how the project is progressing.”

Patrick Mark

Get involved!

To find out more about how you and your branch or support group can help researchers like Dr Kunath, please contact the PDS Research & Development team.

Summer 2008 :Issue 4

Site visit

Tackling speech problems in Parkinson’s What’s it all about?

In Parkinson’s, the ability to speak clearly and fluently is often affected at some stage as the condition progresses.

“We know that around 75% of people with Parkinson’s struggle with their speech.

Problems include vocal blocks, difficulty in starting speaking, syllable repetition and acceleration of speech rate once they get going.

with Dr Ho and her team, who gave them a tour of their research facility, a presentation about their work so far, and an opportunity to ask lots of questions.

Can hearing your own voice differently help with speech problems?

In this study, Dr Ho wants to know if changing how a person with Parkinson’s hears their voice while they speak has any impact on their speech problems.

“At the moment, treatment options such as medicines and surgery are very limited. And unfortunately, they often don’t work.

“My research team is keen to find other ways of tackling speech problems in Parkinson’s.

“We know that techniques that use the senses, like touch, vision and hearing, have worked in people who stutter.

“Our project looks at using similar techniques to help people with Parkinson’s.”

Dr Aileen Ho, Lead Researcher The PDS awarded Dr Aileen Ho £121,512 to carry out a three-year project on speech problems in Parkinson’s.

One year into the research, a group of Research Network members and PDS staff went to visit the University of Reading to find out more about the project and how it’s going. They spent the afternoon

This approach has proved successful in treating people who stutter, but researchers are not sure how it works.

They think it may involve the area of the brain called the basal ganglia. It is the main part of the brain affected in Parkinson’s, and is primarily responsible for the timing and control of movement.

Dr Ho’s team are using special computer software to manipulate the pitch and/or timing of how people hear their voices as they are speaking. To do this, research participants read a variety of different passages into a microphone. The sounds are fed into a computer programme which either delays the vocal feedback (giving an echo effect), or adjusts the pitch to produce a high squeaky or deepened version. This computer Progress I 25

Issue 4: Summer 2008

modified version is then played back through the participant’s headphones while they continue to read.

One of the research participants, Ann, who also attended the site visit, recalled “the funny sensation of perceiving the delay” in her hearing. By analysing the recordings, the researchers hope to reveal the best levels of pitch and delay to control speech.

Results so far “We are still assessing if these techniques could help control speech problems for some people with Parkinson’s.

“Like Parkinson’s itself, speech control varies hugely from person to person. We are finding that different people respond to individual sound stimuli.”

“Because I have Parkinson’s, my voice has recently become quieter, I have been referred for speech therapy and am interested in understanding what can be done to improve voice volume and intelligibility.”

Terry, Research Network member Although this research is still in the early stages, the preliminary findings and the potential for the future were discussed.

“I learnt that some treatments help voice production. In particular, frequency-altered feedback, where the voice can reach high ‘Mickey Mouse’ sounding levels, worked for some people.”

Will, Research Network member

Dr Ho

Looking to the future The researchers hope that the outcomes from this project may eventually contribute to the development of a novel hearing-aid type of device. By altering how people hear themselves, it would take all the strenuous work out of speech. So instead of having to concentrate extremely hard to overcome speech difficulties, simply hearing your own voice in a different way may improve speaking.

Who went and what they said Site visits play a crucial role in helping us build relationships between PDS members and researchers.

They also provide an excellent opportunity for everyone to share experiences and ideas.

“Like all the other visits I have attended, it was an enjoyable day. It provided an opportunity to meet some very interesting people and visit a grant-assisted research facility.

“It is good to see, at first hand, the practical work the Society initiates for the benefit of its members.”

Graham, Research Network member 26 I Progress

Dr Ho (centre) with PDS members on the site visit

“Obviously we hope this work will lead to some form of device, which will help those whose voice-brain hearing loop is not functioning properly.”

Len, Research Network member

Get involved!

To find out what PDS-funded research is going on near you and get involved in a site visit, please contact the Research & Development team.

Please note that places on site visits are limited and allocated on a first come, first served basis.

Summer 2008 :Issue 4

Completed research

Cueing helps walking in Parkinson’s

Does cueing improve walking in people with Parkinson’s with cognitive problems or dementia?

Lead researcher: Professor Lynn Rochester, Glasgow Caledonian University Cost: £8,184 over six months

What it’s all about Despite current drugs and surgical treatments, Parkinson’s will eventually lead to problems in movement. People develop stooped posture and rigid muscle tone which have a huge impact on everyday activities such as walking, turning in bed and rising from a chair.

If left unmanaged, these mobility problems can worsen and increase the likelihood of falling and serious injury.

They can affect people’s physical, emotional and social well-being. Someone with Parkinson’s can end up losing their confidence and independence. This, in turn, increases the burden and strain on carers.

One way of managing walking problems is by physiotherapy. In particular, responding to sound or image prompts can help overcome mobility issues.

Research has shown that these cueing techniques can benefit people with Parkinson’s in the short term by improving the pattern of how they walk (this is also known as gait). Cues can help to start walking, and improve the speed of walking, by influencing step length and step number.

The point of our study Alongside the physical changes in movement, Parkinson’s may also lead to a variety of other symptoms, such as changes in cognition or one’s ability to think, reason and remember. Cognitive problems mean that a person may: • think slower • take longer to make sense of information or problem solve • find it difficult remembering where and when particular events occurred When cognitive problems become very severe, they can lead to dementia.

Our research group wanted to investigate whether cueing was a feasible option for a specific group of people with Parkinson’s – those who also have cognitive problems or dementia. We wanted to test if listening to an auditory cue could improve walking in participants who also have trouble thinking, reasoning and remembering, or dementia.

Progress I 27

Issue 4: Summer 2008

What we did Our team carried out a small study on nine individuals with Parkinson’s who also had mild cognitive problems or mild dementia. We looked at how these people walked with and without auditory cues during two different tasks.

The first task involved the person walking in a straight line. In the second task, the participant did the same thing as before but had to carry a tray with two cups of water while walking.

The two tasks were carried out with and without auditory cues. A metronome – a device that makes a rhythmical clicking sound – was used to produce the auditory cue. It provided a steady beat for stepping.

The participants were asked to use the cues in two different ways when they were walking. They were asked to: • walk with the cue by stepping in time to the beat • walk with the cue while hearing the command ‘take a big step in time to the beat’ A long carpet that records footsteps was used to record the walking speed, step length and step frequency. Our team compared and analysed the walking pattern of each participant.

What we discovered Our results show that auditory cues improved walking for individuals with Parkinson’s who have mild cognitive problems or dementia in both tasks. We also found that people were also able to use the cues easily. What’s more, the participants who followed the rhythm of the cue and heard the command ‘take a big step in time to the beat’ had the greatest improvement.

What happens next…

PDS Innovation Grants are designed to support small studies that open up new research avenues in Parkinson’s – so if the results are positive, the researchers can apply for more funding to carry out bigger trials.

28 I Progress

Our project has produced very good data, which we are going to use to support another grant application.

We would now like to carry out a larger trial to test if auditory cues can improve walking in a larger group of people with Parkinson’s who have cognitive problems or dementia. This will offer the potential to develop cueing guidelines and specific exercises that people can practice in their own homes.

How this helps people with Parkinson’s Our research has the potential to greatly increase the physical, emotional and social wellbeing of people with Parkinson’s by improving their walking and reducing falls. This would have a major effect on their quality of life – allowing individuals to carry out everyday activities and lessening the load on carers.

Unfortunately, there are currently no cueing guidelines for therapists who treat people with Parkinson’s that also have cognitive problems or dementia.

Professor Lynn Rochester added:

“Little work has been done to develop therapies that improve or maintain safe and independent mobility for people with cognitive problems or dementia.

“We are very keen to address this gap by applying our considerable research experience.

“Simple easy-to-use techniques, such as cues, are particularly beneficial. This is because people can use cues in their homes and tailor them to meet their own needs.”

Summer 2008 :Issue 4

Meet…

Professor Paul Bolam

Chair of the Research Advisory Panel The Research Advisory Panel (RAP), a diverse group of 36 research experts and members of the Research Network, helps the PDS decide which projects to fund. We recently caught up with the Chair, Professor Paul Bolam, for an insight into his role and how it all works.

Getting to know you As a child, what was your dream job?

Well, I started off wanting to be a tram driver!

And, if you could go back in time?

I would like to see dinosaurs ... I could just watch Jurassic Park ... but real dinosaurs would be pretty good.

If you went into space what would you take?

I would take my garden – so it would have to be a big spaceship!

Do members of the PDS get involved?

Members are involved through the Research Network.

When RAP meets, someone from the Research Network talks about each project application, and tells us if they think it’s value for money. For me, this is very important – hearing what the PDS membership would like funded.

Also, I get to meet people with Parkinson’s and their carers. It’s very important for scientists to meet the people who inspire the research, as they are what it’s all about.

The PDS funding process PDS advertises for research proposals

 Applications evaluated Stage 1: International peer review Stage 2: RAP assessment

 What drew you to research?

Ever since I was a schoolboy, I remember wanting to be a scientist. I can actually recall telling a friend, while we were walking to the rugby field, that I was going to be a research scientist when I grew up! Many years later, at university, I developed a real passion for pharmacology – that’s understanding how drugs work.

Why is it important to have a RAP? Well, the PDS is the leading non-commercial funder of Parkinson’s research in the UK. Since the Society gives so much money, we must make sure that it’s going to the right places. It’s important to have a strict peer review system with independent experts. They can help assess whether an application is good quality research and whether the PDS should fund it.

PDS Board of Trustees approve

 New research is funded

How does the PDS decide which projects to fund?

The proposals need to stand out – it needs to be a strong idea. New projects have to fit in with the priorities of the PDS. The science must be high quality and really benefit people with Parkinson’s, either in the shorter or longer term. It has to be right. If it’s not right, then we just don’t fund it.

Progress I 29

Issue 4: Summer 2008

Last year, the PDS invested £4.2million in high-quality innovative research. We fund projects in five ways: • Themed Research – research programmes that investigate a critical topic for people with Parkinson’s on which there is little current research • Project Grants – new projects that tackle specific problems in Parkinson’s • Innovation Grants – high-risk, high-reward projects to open new research avenues in the study of Parkinson’s • Prize PhD Studentships – attract outstanding graduates to the field of Parkinson’s research • Career Development Awards – encourage talented researchers to start their own groups to investigate Parkinson’s

Are there ever differences of opinion between the scientists and Research Network members?

Sometimes – the Research Network may look at a grant and decide that the topic is important to people with Parkinson’s. Then the researchers might assess the same grant and say the research plan is poor. It’s a good thing to hear what’s very important to people with Parkinson’s. However, it’s also important to look at the project plan and design. We cannot fund the project if it’s not well constructed and we do not believe the people can do it.

What does a Chair do?

I’m like an enabler; I facilitate discussion and ensure there is fair play at all times. So that means everybody in the meeting has an opportunity to speak about the project applications and feel confident that their opinion is taken into account. I then make sure that the recommendations put forward to the Board of Trustees reflect the true wishes of RAP.

What have been the most exciting recent developments in Parkinson’s research?

I think a major development has been deep brain stimulation (DBS). That was really a fantastic thing to see – all these different strands of research coming together and leading to a therapy which has benefited around 40,000 people across the world.

30 I Progress

The other big thing is the work on genetics, where several rare types of inherited Parkinson’s have now been identified. Although this only affects a tiny proportion of people with Parkinson’s (up to 5%), knowing how molecules are changing may give us insights into what’s going wrong with the more common, non-inherited Parkinson’s. Professor Nick Wood at University College London has made a lot of those discoveries, including identifying the PINK1 gene, and is well supported by the PDS.

Which areas of Parkinson’s research are particularly promising at the moment?

Right now, the hot topics are genetics and stem cells – but it’s difficult to know what they will produce as they are both at an early stage. I actually think the most important thing is a neuroprotective therapy, but for this kind of therapy to be useful, we need an early diagnosis of Parkinson’s.

I believe you have to support a wide variety of research projects, which the PDS does. By doing that, it may lead to an exciting scientific breakthrough or it may simply add new grains of sand to the beach of knowledge.

What the PDS is doing DBS and the PDS DBS can hugely help certain people with Parkinson’s.

Unfortunately, access to funding varies across the UK. So the PDS is proactively campaigning for equal access regardless of where people live.

We have also invested £250,000 in a ten-year study called PD SURG which began in 2002. It is looking at the long-term benefits and safety of DBS for people with Parkinson’s.

Genetics and the PDS The PDS recognises that studying the contribution of genes to Parkinson’s is crucial for developing better ways of treating and new ways of preventing the condition.

Our researchers are working hard on all aspects of genetics. Today, we are running 22 research projects worth around £3million in this field.

Summer 2008 :Issue 4

60 seconds with…

Bunia Gorelick Research Grants Manager For one year now, Bunia Gorelick has been a member of the PDS Research & Development team. We grabbed 60 seconds to quiz her on who she is and what she does.

Getting to know you As a child I wanted to be…

national developments. Part of my role is to provide information to the Communications side of the team so that they can promote the research we fund and answer queries.

A member of Enid Blyton’s Famous Five!

If I could go back in time I would…

Meet my paternal grandmother – she died the year

What gets you out of bed in the morning?

My father has Parkinson’s so I have a personal interest in working for the Society.

before I was born and I’m named after her.

If I went into space I would take…

A thick book and my digital camera.

What did you do before you joined the PDS? I was the Research and Development Manager for an NHS trust in East London.

I really like going on site visits and meeting members of the Research Network. Also, I enjoy talking with people with Parkinson’s. Ultimately that’s why we’re here – to help and support people living with the condition.

And finally, what three words describe your life at the PDS? Challenging, rewarding and interesting!

What’s the best thing about working for the PDS? The great people I work with.

What does a Research Grants Manager do?

The Research & Development team is split into research operations and research communications.

I’m in research operations. I have overall responsibility for the Society’s various grant schemes, making sure they run smoothly and within budget. This means advertising the grants and ensuring that the applications we receive are reviewed.

I also organise the Research Advisory Panel (RAP), which is the committee that decides what research we fund.

Professor Paul Bolam, the Chair of RAP, gives a good snapshot of the PDS funding process in his interview on pages 29 and 30.

Another aspect of my job is my involvement with a number of panels, such as DeNDRoN (Dementias and Neurodegenerative Diseases Research Network) – to representing the PDS and keeping us up to date with

Bunia in Antarctica Progress I 31

Issue 4: Summer 2008

Help us make Progress magazine better! please complete this form Are you (tick the relevant box):  Someone with Parkinson’s

I have had Parkinson’s for_________years

 A carer or partner

I have been a carer for__________years

 A friend or relative

Please specify________________________________________

 Someone with a professional interest in Parkinson’s

Please specify________________________________________

How interesting did you find this issue? (tick the appropriate box: 1 = not very interesting, 5 = very interesting) 1

2

3

4

5

Spotlight on stem cells











New research projects











Themed research











Research equipment shopping list











Site visit











Completed research











Meet... Professor Paul Bolam











60 seconds with... Bunia Gorelick











Which article did you like most and why?_______________________________________________________________ ____________________________________________________________________________________________________ ____________________________________________________________________________________________________ Which article did you like least and why?_______________________________________________________________ ____________________________________________________________________________________________________ ____________________________________________________________________________________________________ Which research topics would you like to hear more about?________________________________________________ ____________________________________________________________________________________________________ ____________________________________________________________________________________________________

Is there a research-related question you would like to ask us?_____________________________________________ ____________________________________________________________________________________________________

Please cut out this form and post it to: PDS Research & Development team Parkinson’s Disease Society 215 Vauxhall Bridge Road London SW1V 1EJ



____________________________________________________________________________________________________

Summer 2008 :Issue 4

PDS Research & Development team

Dr Kieran Breen

Stacey Buckley

Bunia Gorelick

Director of Research & Development

Research & Development Administrator

Research Grants Manager

Trish Hadfield

Dr Lubna Arif

Claire Bale

Research Grants Officer (until July 2008)

Research Communications Manager

Research Communications Officer

Progress is produced by the PDS Research & Development team.

To contact us: Call

020 7963 9313 or 020 7931 8080

Email research@parkinsons.org.uk Visit www.parkinsons.org.uk/research Write PDS Research & Development team

Parkinson’s Disease Society 215 Vauxhall Bridge Road

London SW1V 1EJ Progress I 33

As little as £5 a month can help us find a cure for Parkinson’s You can play a major part in the fight against Parkinson’s.

‘The next step’ is a new initiative that enables people to donate directly to research. By agreeing to make monthly or annual gift, you’ll be playing a vital role in making the next breakthrough.

Download a Direct Debit form at www.parkinsons.org.uk/donate or call 01753 688 687 (quoting reference Progress).

A vital gift

Help us cure Parkinson’s

The PDS Tissue Bank collects brain tissue generously donated by people with and without Parkinson’s. We provide this tissue to researchers around the world who are working hard to find:

• what causes Parkinson’s • a cure and better treatments Help us continue this essential research and drive towards a cure for Parkinson’s. Register with us today and donate your brain as a vital gift when you die.

Call 020 7594 9732 Email pdbank@imperial.ac.uk Visit www.parkinsonstissuebank.org.uk Write PDS Tissue Bank at Imperial College

Division of Neuroscience and Mental Health Burlington Danes Building

Imperial College London

160 Du Cane Road

London W12 0NN

©Parkinson’s Disease Society of the United Kingdom (2008) Charity registered in England and Wales No.258197 and in Scotland No.SCO37554 A company limited by guarantee Registered No. 948776 Registered Office: 215 Vauxhall Bridge Road, London SW1V 1EJ

The Parkinson’s Disease Society (PDS) works with people with Parkinson’s, their carers, families and friends, and health and social care professionals to provide support, information and advice. We are committed to investing in research, education and campaigning to improve the lives of people affected by the condition. The PDS has over 29,000 members, and more than 330 branches, support groups and special interest groups throughout the UK.

How you can help us We are totally dependent on voluntary donations so if you would like to make a contribution, it will be gratefully received and help us support people affected

by Parkinson’s through information, care and research.

To make a donation, please call 020 7931 0303 To discuss supporting a specific project please call 020 7932 1309 visit www.parkinsons.org.uk/donate write to Parkinson’s Disease Society, 215 Vauxhall Bridge Road, London SW1V 1EJ. Thank you.

Parkinson’s Disease Society of the United Kingdom 215 Vauxhall Bridge Road London SW1V 1EJ Tel: 020 7931 8080 Fax: 020 7233 9908 Free Phone Helpline: 0808 800 0303 (available Monday–Friday, 9.30am–9pm, Saturday, 9.30am–5.30pm) Email: enquiries@parkinsons.org.uk There are local PDS branches throughout the UK. Please call 0808 800 0303 for details. www.parkinsons.org.uk ©Parkinson’s Disease Society of the United Kingdom (2008) Charity registered in England and Wales No.258197 and in Scotland No.SCO37554 A company limited by guarantee Registered No. 948776 Registered Office: 215 Vauxhall Bridge Road, London SW1V 1EJ