To commemorate World Parkinson's Day, we spoke to Michele Hu, Consultant Neurologist at Oxford University Hospitals and Professor of Clinical Neuroscience at the Nuffield Department of Clinical Neurosciences, University of Oxford, about prodromal Parkinson's, and what the future looks like for this neurological disease.
Please can you introduce yourself and tell us about your professional background?
My name is Michele Hu, and I’ve been a UK-based neurology consultant for the past 17 years. I work at the John Radcliffe Hospital, part of the Oxford University Hospital's NHS Trust where I lead medical therapies for Parkinson’s. I'm also a Professor of Clinical Neuroscience at Oxford University in the Nuffield Department of Clinical Neuroscience.
I've been interested in Parkinson's and earlier forms of Parkinson's, which I'll refer to as prodromal Parkinson's, for about 15 years. I'm particularly interested in sleep and how sleep disorders interplay with Parkinson's and related neurodegenerative conditions.
In 2010 Oxford was awarded a five million pound research grant from Parkinson's UK, and we set up the Oxford Parkinson's Disease Center, now recognized worldwide as a leading interdisciplinary research center for Parkinson's.
What are the clinical manifestations of PD? What is happening in the brain during PD on a pathophysiological level?
We now recognize that the process that leads to motor symptoms of Parkinson's has been happening over the past 20 years before diagnosis. They start with early changes in sleep patterns and losing the ability to smell particular herbs.
Its increasingly recognized that Parkinson's is not just a brain disorder; it affects other parts of the body, including the skin, heart, and gut. We also see early changes in sleep 20 years before Parkinson’s is diagnosed, where people may start to act out their dreams in rapid eye movement (REM) sleep. People with this sleep disorder may dream that they kicking a football but actually kick the wall next to their bed or dream that they are being attacked and may hit or injure their bed partner while asleep.
In the five years before Parkinson's is typically diagnosed, people develop subtle motor symptoms. They might be aware of a very intermittent tremor in their hand but think it might be due to a frozen shoulder or repetitive strain injury. Subtle changes in manual dexterity and typing ability occur, which many people, when they first come to see me as a neurologist, have put down to normal aging.
Parkinson's, like many degenerative conditions, is a protein-misfolding disorder. Proteins, in particular alpha-synuclein, form clumps of insoluble protein, and deposit into clumps in cells, for example, in brain neurons. In the brain, alpha-synuclein may also deposit in other cells including microglia and astrocytes, which are reactive supporting cells that support the neurons. These deposits also happen outside of the brain, and you can pick them up, for example, in the skin or gut nervous system.
How is PD currently diagnosed? What are the challenges associated with PD diagnosis?
Parkinson's is what we call a clinical diagnosis. If, for example, you had a prostate issue, we would be able to take a tissue biopsy of the prostate gland, look at it under a microscope, and tell you very definitively that your tissue biopsy shows benign prostate hypertrophy or cancer. We can't put somebody through a brain biopsy to diagnose their Parkinson's, so diagnosis is based on a clinical set of symptoms and signs elicited when the clinician is talking with and examining the individual.
If we compare the accuracy of Parkinson’s clinical diagnosis during life with the actual diagnosis found by looking at their brain under a microscope afted death, we know that about one in 10 people given a diagnosis of Parkinson's in life are misdiagnosed. Typically, this will be with a condition that mimics Parkinson's symptoms, including drug-induced Parkinson's disease, vascular Parkinson's, benign tremor syndromes, and Parkinson-plus conditions, which are forms of Parkinsonism, but with different pathological features.
How can brain imaging impact the diagnosis and prognostication of Parkinson's?
There are different types of brain imaging. If we start with what is routinely available in the UK on the NHS, that would include a CT or MRI brain scan, which do not tell you the doctor if their patient has Parkinson's. These structural scans are usually done to exclude other conditions, such as stroke or tumour. However, they are useful because they can show the downstream effect of alpha-synuclein misfolded protein in the brain cells.
Misfolded alpha-synuclein deposits interfere with critical cell function, including the ability to recycle their rubbish effectively, exliminate toxins and generate sufficient energy to maintain cell life. This leads to accelerated death of brain neurons, which we can see on imaging if it's quite pronounced as atrophy or loss of brain substance.
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Functional brain imaging allows us to estimate brain neurotransmitter levels on an individual basis. These include a dopamine transporter single photon emission computerized tomography (SPECT) and positron emission tomography (PET) scans. They involve an injection of radioactive dye into an arm vein followed by a nuclear medicine brain scan, allowing estimation of how much dopamine your brain can produce. In Parkinson's, dopamine levels are significantly reduced to 50% or less in the basal ganglia, where the dopamine neurons project.
Lastly, we have experimental research brain imaging, which my team is involved with at Oxford. Our work involves developing sensitive sequences to image deep structures in the brainstem, including the substantia nigra, which are affected by alpha-synuclein, and other pathology, including iron deposition. We think that, with these higher resolution scans, we can separate somebody with Parkinson's from somebody without, of the same age and gender, with around 90% accuracy, which is as good or even better than an experienced clinician.
What is prodromal PD?
Prodromal Parkinson's refers to the stage wherein early symptoms or signs of Parkinson’s neurodegeneration are present, but classical clinical diagnosis based fully evolved motor parkinsonism is not yet possible. Prodroma Parkinson’s typically starts up to 20 years before clinical diagnosis. Symptoms can include sleep and memory disturbance, anxiety, depression, bladder and erectile dysfunction, reduced ability to smell and taste, constipation, REM sleep behavior disorder and subtle motor symptoms. Prodromal Parkinson's occurs as prodromal symptoms gradually build up, but are insufficient to make a clinical diagnosis. Currently a significant debate exists about the best way to diagnose Parkinson’s earlier in a consistent way. Biomarkers might help earlier, prodromal PD diagnosis, allowing therapies to be started earlier on in the disease course, and a greater chance of disease modification.
What is the link between rapid eye movement (REM) sleep disorder and PD?
Currently, the strongest known risk factor for future Parkinson's, i.e prodromal Parkinson's, is having rapid eye movement sleep behavior disorder (RBD). If you have a confirmed diagnosis of RBD on an overnight sleep study where you are wired up with electrodes, you have a six percent per year chance of developing future Parkinson's or a related alpha-synuclein disorder, including dementia with Lewy body.
Therefore, if you have had RBD for ten years, your risk of future Parkinson's is 60%. RBD is the strongest known risk factor for future Parkinson's, in excess of genetic forms of Parkinson’s or the future risk arising from hyposmia- a loss of the ability to smell different odours- that isi unrelated to head injury, sinusitis, or related causes.
How can wearable technologies impact the diagnosis of RBD?
When we started the Oxford Discovery RBD cohort, we had to recruit sleep study RBD participants from 4 UK sleep centres. It can be difficult to find RBD individuals, because many people live in the general community without a formal diagnosis, and no explanation for their sleep symptoms. General Practitioners and other doctors may not be aware of the typical symptoms someone with RBD experiences. We know from population sleep studies that around one to three percent of people over the age 55-60 years have RBD.
A potential iceberg effect means that it is people with the more severe forms of RBD, who are perhaps hitting their bedpartner in their dreams, are the ones more likely to be referred to a local sleep clinic. The problem is that a waiting list of six to 12 months to be admitted to hospital overnight for a sleep study is common. People who sleep alone are less likely to be aware of symptoms or reach a diagnosis.
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Analyzing the data generated from sleep studies is very time-consuming, because each study collects large amounts of data over 12-24 hours recording, from multiple channels (ie EEG, muscle EMG, EOG, video). Currently RBD diagnosis is not automated, hence the sleep technician will look over 10-24 hours of sleep recording to capture typical episodes, which then require sleep specialist input for formal diagnosis.
My research looks at ways to diagnose a person with RBD through home sleep studies. That is much more representative of a typical night's sleep. Many people go to the hospital, and they don't sleep normally in a foreign environment. Secondly, home recordings are a lot cheaper, and have opportunity to capture more nights sleep at a time. Furthermore, we think we can collect sufficient information from a limited sleep study performed at home to get an accurate diagnosis.
Digital technology can help us in this aim of developing automated sleep staging and RBD diagnosis. The sleep kit we use allows us to take a home video. We ask the participant and their carer to put on brain electrodes and sticky sensors onto their arms and legs, and then we analyze overnight recordings. A wrist accelerometry, like a Fitbit, is also increasingly being looked at for its accuracy in diagnosing RBD alone compared to more extensive equipment.
The UK Biobank study has received accelerometry from over 15,000 individuals over 55 years. Preliminary analysis suggests that reasonably accurate RBD diagnosis can be achieved just from wrist accelerometry recordings alone, taken over seven days. However, we need more studies and analysis to look at the accuracy and ability of accelerometry and other approaches to distinguish other sleep conditions from RBD that are common in the over 50 years age group.
Parkinson's remains a somewhat unknown condition. What are some of the common misconceptions associated with PD, and what do you wish more people knew?
One of the commonest misperceptions about Parkinson’s is that individuals put their physical state down to simply getting older, or other conditions such as arthritis that commonly occur in this age group. Sometimes the clinician may find it hard to know at the first or second visit if the symptoms the person are simply related to getting older or that they have Parkinson’s disease, and further follow-up and investigations may be needed.
Parkinson's is the fastest-growing neurological condition in the world. What does the future of PD look like?
The way that we manage Parkinson's has to change. We are already in an crisis of care worldwide. Over the last five years in my hospital, we have experienced a 15% average increase year-on-year in General Practioner referrals to Neurology for suspected new diagnosis Parkinson's . This is consistent with global population predictions that the prevalence of Parkinson's will double or triple in the next 20 years because people are living longer, but also to unexplored factors that increase its prevalence.
My group has developed an eight-minute smartphone test which we have researched and tested over the past decade. This smartphone test is simple and can be done at home on a person's phone. It tests speech, tremors in the hand, reaction time, manual dexterity, and walking ability, and has instructions for use in 12 languages.
We have piloted this OPDC smartphone app in Korea, Europe, North America, and Canada. We've been able to show that from this simple digital test, we can diagnose Parkinson's with 90% accuracy, without the person even going to see a specialist. We have now also developed a composite motor score, which gives us an overall measure of the person’s motor involvement from Parkinson’s.
We have shown that this smartphone test can predict the onset of milestones for people with Parkinson's, 18-36 months before onset. Milestones include going from having normal walking to experiencing gait freezing and falls. The smartphone test might be used, for example, by physiotherapists, to identify individuals at higher risk of these future outcomes so they can intervene earlier. If you can prevent falls, you will reduce emergency department admissions, related head injury and bone fractures, plus the cost to the taxpayer. This also reduces hospital bed blocking from people who are falling at home and not coping, who can benefit from community-based interventions earlier.
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Work Parkinson's Disease Day aims to raise awareness of Parkinson's. Why is it important to recognize this day, as well as the individuals and families affected by PD?
It's critical. We need to increase general awareness in the general public because we have effectively a Parkinson's pandemic happening. Although Parkinson's is not transmitted like an infectious disease (eg COVID-19 or prion disease), if you were to model the projected increase in people being diagnosed over the next 20 years based on the last three decades, this would behave like a pandemic. We need people to recognize the symptoms earlier so that they seek and receive help earlier. We need more information on diagnosis and treatment for earlier forms of Parkinson's, including prodromal Parkinson's with RBD.
What is next for you and your research?
I'm excited to announce that, this year, in Oxford and Sydney, we will conduct one of the first-ever randomized placebo-controlled trials in patients with prodromal Parkinson's who have the sleep disorder RBD. The endpoint of the trial will be a change in brain inflammation changes measured by imaging, as inflammation in the brain may be a very early feature of prodromal Parkinson's that could be modified by anti-inflammatory medications.
We will also develop a new website for people with RBD. We've recognized that people with Parkinson's have a good media presence and websites through charity support of Parkinson's UK, Michael J. Fox Foundation, and Cure Parkinson's Trust, for example. However, there's very little support for people with prodromal Parkinson's who have RBD. The Oxford Biomedical Research Center I am affiliated with will support me in developing a UK website for people with RBD. Other global initiatives are available through the North American Prodromal Synucleinopathy consortium (NAPS) and the international RBD study group.
Where can readers find more information?
About Professor Michele Hu
Michele is a Consultant Neurologist at Oxford University Hospitals, and Professor of Clinical Neuroscience at the Nuffield Department of Clinical Neurosciences, University of Oxford. Her clinical work focuses on Parkinson's disease and related movement disorders. Her research within the Oxford Parkinson's Disease Centre (website:www.opdc.ox.ac.uk) looks at longitudinal cohort studies and biomarkers for early and prodromal Parkinson’s disease, with particular focus on REM sleep behaviour disorder (RBD) and how sleep affects neurodegeneration. Interests include the delivery of tractable, low cost, wearable technology that has a real impact on patient’s daily lives, and imaging the human brain from prodromal to established Parkinson’s.
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