Despite 30 years of research, not a single therapy has been found to successfully delay or stop the progression of Parkinson’s Disease (PD), a slowly progressive disorder that affects movement, muscle control and balance.
It is the second most common age-related neurodegenerative disorder affecting about three per cent of the population by age 65, and up to 5 per cent of individuals over the age of 85.
Each potential cure for PD has to go through three clinical trial phases to test its safety, whether it shows signs of improving PD, and whether there is any meaningful benefit to people with PD.
Running a clinical trial is a huge logistical, costly, and time-consuming undertaking. For a single new therapy this process can take the best part of a decade.
“The current way we do trials in Parkinson’s is too slow and inefficient,” explained Camille Buchholz Carroll from the Applied Parkinson’s Research Group at the University of Plymouth.
“We need to develop new ways of doing trials such as the Multi Arm Multi Stage (MAMS) trial platform, which will speed up the process and bring us closer to finding a cure, faster. We have the opportunity to learn from the experience in these other conditions and design a new trial that will work for people with Parkinson’s.”
MAMS trial platforms already exist for prostate, renal, and oropharyngeal cancer and are currently being developed within the UK for other neurogenerative disorders such as progressive multiple sclerosis (PMS) and motor neuron disease (MND).
MAMS trials test many potential therapies in parallel (multi-arm), transitioning seamlessly through various phases (multi-stage), i.e., from a phase II safety and efficacy study to a phase III trial.
Early analyses allow unsuccessful therapies to be replaced. At the interim checkpoint, ineffective arms can be dropped and replaced by new treatment arms, thereby allowing for the continuous evaluation of interventions.
Dr. Carroll and colleagues explore how the challenges of drug selection, trial design, stratification and outcome measures, type and stage of PD to be tested have been met in promising MAMS trials instituted to address other diseases including the STAMPEDE trial; Motor Neuron Disease Systematic Multi-Arm Adaptive Randomized Trial (MND SMART]; and UK MS Society’s 2018-2022 Research Strategy.
“There are many promising drugs in the pipeline that have potential to slow down the progression of PD but taking that hypothesis to the test is still a long and cumbersome process,” notes Prof. Bas Bloem, co-editor-in-chief of the Journal of Parkinson’s Disease.
“The new approach described holds great promise for facilitating this complex procedure, so that we can gather the necessary evidence for new treatments much quicker than before. Patients will certainly applaud this development as well!”
The authors stress that to maximise the potential of a MAMS platform trial running over many years and interrogating many research questions, it is crucial that there is a pipeline in place that will continuously identify and evaluate suitable drug candidates.
Furthermore, outcome measures have to be chosen that are sensitive enough to changes in disease progression over interim stages as well as the full duration of the trial.
Other studies are taking different approaches to relieve the symptoms of Parkinson’s disease. For example, biomedical engineers at Duke University have used deep brain stimulation based on light to treat motor dysfunction in an animal model of the disease.
Succeeding where earlier attempts have failed, the method promises to provide new insights into why deep brain stimulation works and ways in which it can be improved on a patient-by-patient basis.
“If you think of the area of the brain being treated in deep brain stimulation as a plate of spaghetti, with the meatballs representing nerve cell bodies and the spaghetti representing nerve cell axons, there’s a longstanding debate about whether the treatment is affecting the spaghetti, the meatballs or some combination of the two,” said Warren Grill, the Edmund T. Pratt, Jr, school distinguished professor of biomedical engineering at Duke.
“But it’s an impossible question to answer using traditional methods because electrical deep brain stimulation affects them both as well as the peppers, onions and everything else in the dish. Our new light-based method, however, is capable of targeting just a single ingredient, so we can now begin teasing out the individual effects of activating different neural elements.”
“Neurons being stimulated with optogenetics don’t generally respond very quickly, and it seemed to me that the researchers [in a previous study] were flashing their lights faster than the neurons could keep up with,” said Grill. “The data bore this out, as the neurons appeared to be responding randomly rather than in sync with the flashes. And previous research that we conducted showed that random patterns of deep brain stimulation are not effective at relieving symptoms.”
It took more than a decade for Grill to be able to test his theory, but two recent developments allowed him to follow his hunch. Researchers developed a faster form of optogenetics called Chronos that could keep up with the speeds traditionally used in deep brain stimulation.
And Chunxiu Yu, a research scientist with expertise in optogenetics, joined Grill’s laboratory. Also contributing to the work in Grill’s laboratory were Isaac Cassar, a biomedical engineering doctoral student, and Jaydeep Sambangi, a biomedical engineering undergraduate.
In the new paper, Yu embedded the Chronos optogenetics machinery into the subthalamic nucleus neurons of rats that have been given Parkinson’s disease-like conditions in one-half of their brains. This model helps researchers determine when a treatment is successful because the resulting physical movement symptoms only occur on one side of the rat’s body.
They then delivered deep brain stimulation using light flashes at the standard 130 flashes per second.
As Grill first suspected nearly 15 years ago, the technique worked, and the rats’ physical symptoms were substantially alleviated.
Perhaps the most important result is simply that the technique worked at all. Besides offering a much clearer look at neural activity by removing electrical artifacts, the ability to deliver deep brain stimulation to precise subsets of neurons should allow researchers to begin probing exactly which parts of the brain need to be stimulated and how therapies might be tailored to treat different motor control symptoms on a case-by-case basis.
As their next experiment in this line of research, Grill and his colleagues plan to recreate this same study but in the hyperdirect pathway – the spaghetti instead of the meatballs – to see what its individual contribution to relieving symptoms might be.
Elsewhere, Parkinson’s disease researchers have used gene-editing tools to introduce the disorder’s most common genetic mutation into marmoset monkey stem cells and to successfully tamp down cellular chemistry that often goes awry in Parkinson’s patients.
The researchers used a version of the gene-editing technology CRISPR to change a single nucleotide – one molecule among more than 2.8 billion pairs of them found in a common marmoset’s DNA – in the cells’ genetic code and give them a mutation called G2019S.
In human Parkinson’s patients, the mutation causes abnormal over-activity of an enzyme, a kinase called LRRK2, involved in a cell’s metabolism. Other gene-editing studies have employed methods in which the cells produced both normal and mutated enzymes at the same time. The new study is the first to result in cells that make only enzymes with the G2019S mutation, which makes it easier to study what role this mutation plays in the disease.
“The metabolism inside our stem cells with the mutation was not as efficient as a normal cell, just as we see in Parkinson’s,” says Marina Emborg, professor of medical physics and leader of University of Wisconsin-Madison scientists , whose work is supported by the National Institutes of Health.
“Our cells had a shorter life in a dish. And when they were exposed to oxidative stress, they were less resilient to that.”
The mutated cells shared another shortcoming of Parkinson’s: lacklustre connections to other cells. Stem cells are an especially powerful research tool because they can develop into many different types of cells found throughout the body.
When the researchers spurred their mutated stem cells to differentiate into neurons, they developed fewer branches to connect and communicate with neighboring neurons.
Scientists have long known that clumps of a damaged protein called alpha-synuclein build up in the dopamine-producing brain cells of patients with Parkinson’s disease. These clumps eventually lead to cell death, causing motor symptoms and cognitive decline.
“Once these cells are gone, they’re gone. So if you are able to diagnose the disease as early as possible, it could make a huge difference,” says LJI research assistant professor Cecilia Lindestam Arlehamn, Ph.D., who served as first author of a new study co-led by scientists at the La Jolla Institute for Immunology (LJI) which adds increasing evidence that Parkinson’s disease is partly an autoimmune disease.
The research could make it possible to someday detect Parkinson’s disease before the onset of debilitating motor symptoms–and potentially intervene with therapies to slow the disease progression.
The new findings shed light on the timeline of T cell reactivity and disease progression. The researchers looked at blood samples from a large group of Parkinson’s disease patients and compared their T cells to a healthy, age-matched control group.
They found that the T cells that react to alpha-synuclein are most abundant when patients are first diagnosed with the disease.
These T cells tend to disappear as the disease progresses, and few patients still have them ten years after diagnosis.
The researchers also did an in-depth analysis of one Parkinson’s disease patient who happened to have blood samples preserved going back long before his diagnosis.
This case study showed that the patient had a strong T cell response to alpha-synuclein ten years before he was diagnosed with Parkinson’s disease. Again, these T cells faded away in the years following diagnosis.
“This tells us that detection of T cell responses could help in the diagnosis of people at risk or in early stages of disease development, when many of the symptoms have not been detected yet,” says professor Alessandro Sette who co-led the study.
“Importantly, we could dream of a scenario where early interference with T cell responses could prevent the disease from manifesting itself or progressing.”
Sulzer added: “One of the most important findings is that the flavour of the T cells changes during the course of the disease, starting with more aggressive cells, moving to less aggressive cells that may inhibit the immune response, and after about 10 years, disappearing altogether.
“It is almost as if immune responses in Parkinson’s disease are like those that occur during seasonal flu, except that the changes take place over ten years instead of a week.”
Here in the UK, neuroscientists at York University have found five different models that use types of non-motor clinical – such as sense of smell, frequently dozing off or thrashing about during dreams – as well as biological variables to more accurately predict early-stage Parkinson’s disease.
Their five-model analysis is one of the first utilising only non-motor clinical and biologic variables. Some models performed better than others but all distinguished early stage (preclinical) Parkinson’s disease from healthy, age-matched controls, with better than 80 per cent accuracy.
The models may assist in more timely administration of future treatments as they become available, according to the study published in Frontiers in Neurology today.
In the study, two separate analyses were conducted: one for the classification of early Parkinson’s disease versus controls, and the other for classification of early Parkinson’s versus SWEDD (scans without evidence of dopamine deficit).
The term SWEDD refers to the absence, rather than the presence, of an imaging abnormality in patients clinically presumed to have Parkinson’s disease.
Facilitated and more accurate prediction of early-stage, de novo Parkinson’s can allow those positively diagnosed to adopt lifestyle changes such as regular physical exercise early on that can improve mobility and balance, says Joseph DeSouza, associate professor of the Department of Psychology at York University.
Researchers used cross-sectional, baseline data from the Parkinson’s Progressive Markers Initiative (PPMI).
The PPMI data used was confined to non-motor clinical variables (e.g. sense of smell, daytime sleepiness, presence of rapid eye movement behaviour disorder, age, etc.) and biologic variables (e.g. cerebral spinal fluid alpha-synuclein, tau protein, beta-amyloid-142, etc.)
Five different model types were “trained” models that could prove useful in helping to differentiate early stage Parkinson’s pathology.
New tech start-up supports those living with dementia
MOJO (Moments of Joy) is a new dementia portal and app connecting everybody involved in the care of a loved one.
The MOJO platform aims to share the load, reduce stress and uncover more crucial opportunities for moments of joy.
MOJO launched the #MomentsOfJoy movement last week, which aims to raise awareness of people affected by dementia, both directly and indirectly.
Dementia is the biggest cause of death in the UK today, with over 850,000 currently diagnosed cases. Unlike many other illnesses however, it is the wider family who often bear the burden of primary care, and there has been very little support available for them during this incredibly challenging journey. MOJO aims to change this with a combination of accessible technical innovation, helpful online resources and real-time support workshops.
Founded by UK-based entrepreneurs John Thornhill and Sasha Cole, MOJO helps families and their loved ones by reducing the stigma around dementia through a holistic support platform and positive philosophy.
The MOJO platform and app provide practical tools to ensure that medical treatment is monitored and reported in a simple way, and imaginative features to create a more comfortable care environment for the whole family.
The suite of tools, includes, ‘MOJO Manager’, which uses imaginative new features to share the practical elements of care amongst the wider family, whilst creating moments of joy during times spent together. MOJO Mentoring, which provides live workshops, advice sessions, and online resources, while MOJO Monitoring is an alert system for situations of disorientation or wandering.
John Thornhill, co-founder of MOJO, realised that technology could revolutionise dementia support. “Most of us have seen the effect of dementia on the patient, but MOJO is for the family. For those whose daily lives are dramatically altered by the practical responsibility and emotional impact of a loved one’s dementia diagnosis.
“Until now there has been little help available for them. We believe our philosophy, ongoing support and technology will make that difficult journey less challenging and more joyful for everybody involved. “
Sasha Cole, co-founder of MOJO adds: “Having worked in dementia-related fields for over ten years, I am acutely aware of the lack of support for patients’ families who are often obliged to provide primary care. The burden of responsibility can be overwhelming. Our aim is to share the load, reduce stress and uncover more crucial opportunities for moments of joy. In this context, what could be more important?
“Philosophically, it’s about going with the flow. It’s easier for us to think like a person who has dementia, than for your loved to think like a person who hasn’t. Although our realities might not always align, the emotional response is what counts. After all, laughter is the best medicine.”
Could female footballers face greater dementia risk?
Female footballers heading the ball could be putting themselves at even greater risk of dementia than male players according to experts at the University of East Anglia.
Dr Michael Grey is running a project to monitor ex-footballers for early signs of dementia.
More than 35 former professional players have now signed up including former Norwich City stars Iwan Roberts and Jeremy Goss, and Crystal Palace hero Mark Bright.
But the research team are urgently looking for amateur and professional female players to take part too.
Research from the University of Glasgow has shown that retired male players are around five times more likely to suffer from Alzheimer’s disease compared with the average person.
But little is known about when players start to show signs of the deteriorating brain health and even less about the effects in women as the majority of research has focussed on men.
Dr Grey, from UEA’s School of Health Sciences, said: “We know that there is greater risk of dementia in former professional footballers, and we think this is related to repetitive heading of the ball.
“We know very little about how this affects female players, but we think female players are at even greater risk of developing sport-related dementia than male players.
“We know there are physical and physiological differences between male and female players and this could be important when it comes to the impact of repeatedly heading the ball.
“But we don’t fully understand the impact these differences could have, so we are encouraging former amateur and professional female players to come forward to help us with our project.”
The team will use cutting-edge technology to test for early signs of cognitive decline in men and women, that are identifiable long before any memory problems or other noticeable symptoms become apparent.
Dr Grey said: “We have already signed up more than 35 professional male players but we have very few women footballers in the study so far. We are looking for women and men over 40, who live in the UK and do not have a diagnosis of dementia. Testing is conducted on a computer or tablet from the comfort of their own homes and takes around 30 minutes, four times per year.
“We are tracking their brain health over time. And we hope to follow these footballers for many years to come.”
The project is among a number of pieces of work in the Concussion Action Programme, a research group within UEA Health and Social Care Partners.
Want to take part?
The research team are looking for former professional football players, both men and women, who are aged over 40 to take part in the study. Amateur footballers and active non-footballers aged over 40 can also take part.
The research will see a small group of participants coming into the lab, but the majority of the testing will be done online at home.
Magnetic sensor could detect early signs of TBI
Signs of traumatic brain injury, dementia and schizophrenia could be detected at an earlier stage as a result of the development of a new sensor which measures weak magnetic signals in the brain.
Through the development of the new Optically Pumped Magnetometer (OPM) sensor, scientists are hopeful of enabling a greater understanding of connectivity in the brain, which could have significant benefits in the chances of early diagnosis.
The device, developed by teams of scientists at the University of Birmingham, is currently in trail stage and clinicians at the Queen Elizabeth Hospital Birmingham are involved in its use in pinpointing the site of TBIs.
Its potential to increase diagnostics for neurological injury, neurological disorders such as dementia, and psychiatric disorders such as schizophrenia, has been widely recognised, and the team are now seeking commercial and research partnerships to help advance its development further.
The new sensor has enabled advances in detecting brain signals and distinguishing them from background magnetic noise, when compared to commercially available sensors. By using polarised light, the device can detect changes in the orientation of spin atoms when exposed to a magnetic field.
The team was also able to reduce the sensor size by removing the laser from the sensor head, and made further adjustments to decrease the number of electronic components, in a move that will reduce interference between sensors.
Benchmarking tests have taken place at the University’s Centre for Human Brain Health, and has reported “good” performance in environmental conditions where other sensors do not work.
Specifically, the researchers showed that the new sensor is able to detect brain signals against background magnetic noise, raising the possibility of magnetoencephalography (MEG) testing outside a specialised unit or in a hospital ward.
The research – published in the ‘Detection of human auditory evoked brain signals with a resilient non linear optically pumped magnetometer’ report, Kowalczyk et al (2020) – was led by physicist Dr Anna Kowalczyk.
“Existing MEG sensors need to be at a constant, cool temperature and this requires a bulky helium-cooling system, which means they have to be arranged in a rigid helmet that will not fit every head size and shape,” she says.
“They also require a zero-magnetic field environment to pick up the brain signals. The testing demonstrated that our stand-alone sensor does not require these conditions.
“Its performance surpasses existing sensors, and it can discriminate between background magnetic fields and brain activity.”
The researchers expect these more robust sensors will extend the use of MEG for diagnosis and treatment, and they are working with other institutes at the University to determine which therapeutic areas will benefit most from this new approach.
Neuroscientist Professor Ole Jensen, who is co-director of the Centre for Human Brain Health (CHBH), highlighted the potential of the sensor.
“We know that early diagnosis improves outcomes and this technology could provide the sensitivity to detect the earliest changes in brain activity in conditions like schizophrenia, dementia and ADHD,” he says.
“It also has immediate clinical relevance, and we are already working with clinicians at the Queen Elizabeth Hospital to investigate its use in pinpointing the site of traumatic brain injuries.”
The team at the CHBH has also recently been awarded Partnership Resource Funding from the UK Quantum Technology Hub Sensors and Timing to further develop new OPM sensors.
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