Parkinson’s is the fastest growing neurological condition in the world and affects around 153,000 people in the UK. Yet despite decades of research, treatments that can stop, reverse, or prevent Parkinson’s remain out of reach.
Although inroads have been made in understanding the causes of the condition, a complete picture of how and why people develop Parkinson’s still eludes experts.
Now a groundbreaking study will investigate Parkinson’s disease in unprecedented detail, with the aim of discovering a cure for the condition. The Landmark programme will look at what causes Parkinson’s – a condition caused by a lack of dopamine in the brain with over 40 symptoms, from tremors and pain, to anxiety – and what triggers the spread through the brain to bring about the sequences of symptoms.
The project will analyse hundreds of tissue samples from the Parkinson’s UK Brain Bank in order to create a map of how genes are activated in Parkinson’s across different cell types. Researchers hope the findings will reveal the causes of Parkinson’s and Parkinson’s dementia, why some brain cells are more vulnerable to the condition than others, and potential targets for developing new treatments. They also hope to uncover new ways to measure the progression of the condition, and which genes or mutations in the body increase someone’s risk of developing Parkinson’s.
“At the moment we have good treatment for the symptoms of Parkinson’s in contrast to something like dementia, but what we’d really like is disease modifying therapy,” said Alastair Noyce, Professor in Neurology and Neuroepidemiology at Queen Mary University of London and Consultant Neurologist at Barts Health NHS Trust.
“The reasons why we don’t currently have those is that we make the diagnosis too late and that diagnosis is made based on the clinical signs of Parkinson’s rather than diagnostic tests.
“Data from UK primary care shows that people go and see their GP with a range of symptoms for a decade or more before they eventually get diagnosed with Parkinson’s: movement symptoms, such as a tremor or balance problems, some are mood symptoms, such as anxiety, depression or sleep/memory problems. There is also a long list of other symptoms, such as constipation and erectile dysfunction.”
One of the major breakthroughs over the last couple of years has been a potential new diagnostic test for Parkinson’s – a spinal fluid test. The lab test involves taking a sample of cerebrospinal fluid (CSF), a clear liquid that surrounds the brain and spinal cord, via an injection into the spine called a lumbar puncture.
The research team then uses this to look for a protein called alpha-synuclein. Lumps of a misfolded form of the alpha-synuclein protein can be found can be found in Parkinson’s patients and is attributed with the rapid progression of the condition. This toxic form of the protein can damage dopamine-producing cells and may be responsible for the development and spread of the condition in the brain.
Results from the study showed that the test was able to correctly show a diagnosis of Parkinson’s with 88 per cent accuracy overall. This included being able to diagnose Parkinson’s in people who had early symptoms but no diagnosis.
This suggests that the misfolded forms of alpha-synuclein are already present in the CSF before there is any observable damage to the brain cells that produce dopamine. This is exciting, as it could allow for earlier diagnosis and, in future, the opportunity to use treatments that can slow or stop the damage before it leads to significant symptoms. People may be diagnosed earlier and more accurately thanks to this new test.
Prof Noyce said: “What’s also exciting is that this may not be restricted to a sample of the spinal fluid. There’s pretty good evidence now that the same signature can be picked up with a peripheral skin biopsy and some evidence that this may also be possible to do in blood tests, but this has not been fully replicated.”
Experts believe all this means we are potentially shifting from a clinical diagnosis of a neurological disease like Parkinson’s to a biological definition. Parkinson’s develops over a 20-year period, spreading through the cortical regions of the brain, which give rise to other symptoms such as cognitive decline seen in dementia patients, which people with Parkinson’s are at greater risk of having
Professor Sonia Gandhi, MRC Senior Clinician Scientist at The Francis Crick Institute, said: “If we’re trying to understand the disease and find therapies, we need to find therapies that treat the early stages. But we also need to think about therapies that delay the spread into these other parts of the brain where the later complications can occur.”
The fact only three disease modification therapies are at late stage clinical trial for Parkinson’s highlights the difficulties scientists have.
Prof Gandhi said: “It’s very difficult to make a model of the human brain and human brain disease – and Parkinson’s is a uniquely human condition. It’s also very had to understand the cell diversity of the human brain.
“We have an incredibly complex brain structure: we have 80 billion neurons, we have far more other non-neuronal cell types as well, so resolving complexities are very difficult problems for neuroscientists. Finally, finding these hallmarks [of the disease] is also difficult in complex biological systems like the human brain.”
Landmark, which launched this week, is a three-year research partnership that aims to understand Parkinson’s disease in unprecedented detail. It brings together Parkinson’s UK, Imperial College London, GSK, Novartis, Roche and UCB for the first time, and has been made possible by a founding gift of £4m from the Gatsby Charitable Foundation.
The project is based on original work carried out by Professor Michael Johnson in Imperial’s Department of Brain Sciences, who will be its principal investigator. The university’s scientists will sequence hundreds of tissue samples from the Parkinson’s UK Brain Bank, based at the university, in order to build up a map of gene expression caused by Parkinsons across different cell types. The resulting global resource of data will identify predictive biomarkers for Parkinson’s disease and will ultimately help to discover new drug targets.
“The Landmark project will produce state-of-the-art datasets that will enable scientists to fully understand the biological ways in which Parkinson’s takes hold and progresses in the brain. But alongside that, our overarching aim is to find new potential drugs that can help us tackle the condition,” Prof Johnson said.
“By identifying the predictive biomarkers involved in Parkinson’s, we hope to speed up the eventual journey of these drugs to patients.”
Although risk genes for Parkinson’s have been identified, scientists really don’t know which genes are actually “controlling” the disease and triggering its spread through the brain.
The Landmark team is going to be using Mendelian randomisation (commonly abbreviated to MR), a method using measured variation in genes to examine the causal effect of an exposure on an outcome, to understand how those cells are talking to each other in the brain and how they are being effected by the disease.
What is Parkinson’s disease?
Parkinson’s disease is a brain disease that affects around 145,000 people in the UK.
At first it mainly causes problems with movement. However, after a few years some people also start to have problems with thinking, memory and perception.
These symptoms are mild at first and for many people they do not get much worse. However, around a third of people with Parkinson’s eventually develop dementia.
Symptoms of Parkinson’s dementia
Symptoms vary and can change quickly from hour to hour. However, most people have symptoms very similar to those of dementia with Lewy bodies. These include:
- problems with staying focused
- difficulties with making decisions
- memory loss and forgetfulness
- problems with the way the person sees things around them.
As well as problems with memory and thinking, Parkinson’s dementia also often causes:
“For the first time, we’ll be able to understand the true causal risks of Parkinson’s,” Professor David Dexter, director of research at Parkinson’s UK, said. “Landmark will be able to say to us why some of those brain cells are susceptible to the pathology. We’ll be able to identify for the first time the causal risk genes for Parkinson’s. If you know a gene that’s implicated in risk, it’s far easier to develop therapies to stop the condition.
“It will give us an unparalleled depth of information into what causes Parkinson’s, and what triggers the spread of the pathology through the brain and then causes the sequences of symptoms, culminating in dementia in quite a high percentage of people with Parkinson’s. It will give us that unique insight into why some people develop dementia and others don’t.”
The new insights gained will also feed directly into Parkinson’s Virtual Biotech – the drug development arm of Parkinson’s UK, in partnership with the Parkinson’s Foundation – to power the creation of new treatments for the community. Ultimately, however, the unique datasets will be made freely and openly available to the global research community.
Prof Johnson said: “There is lots of excitement around the use of machine learning and artificial intelligence for drug target discovery. The problem is, without high quality data these computational models still end up with the wrong answer. Landmark will become a globally important resource, establishing the standardised genomic data at scale that these models require to come up with the right answers.”
Prof Dexter called Landmark “a highlight of my career”.
He said: “I set up the Brain Bank 22 years ago because I knew that one day techniques like these would be possible, allowing us to unlock the secrets held in the brains of people with Parkinson’s. We are delighted to be bringing together charities, academia and pharmaceutical partners for the first time on this project. To see it launch and know of the potential it has to ultimately change the lives of people living with Parkinson’s is incredible.”
