Update on Prodromal Parkinson’s
What is prodromal Parkinson’s?
Prodromal Parkinson's refers to the stage wherein early symptoms or signs of Parkinson’s neurodegeneration are present, but classical clinical diagnosis based on fully evolved motor parkinsonism is not yet possible. Prodromal 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 (RBD) and subtle motor symptoms. Prodromal Parkinson's occurs as prodromal symptoms gradually build up, but are insufficient to make a clinical diagnosis. Currently 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.
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 skin or gut nervous system biopsies.
What is the link between rapid eye movement sleep disorder (RBD) and PD?
Currently, the strongest known risk factor for future Parkinson's, or for having prodromal Parkinson's, is a diagnosis of rapid eye movement sleep behavior disorder (RBD). During RBD episodes, people act out their dreams in rapid eye movement (REM) sleep. They 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 bedpartner while asleep. Shouting, talking or mumbling are also common during RBD. If you have a confirmed diagnosis of RBD via an overnight sleep study, you have a six percent per year chance of developing future Parkinson's or a related alpha-synuclein disorder, including dementia with Lewy bodies.
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.
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 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.
How can wearable technologies impact the management of prodromal PD and RBD?
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 Neurology referrals for suspected new onset 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, and can be used to track progression in response to clinical trial medications, exercise or dopaminergic therapies.
We have also 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.
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?
https://www.opdc.ox.ac.uk
https://www.ppmi-info.org
https://www.naps-rbd.org
Related publications: https://www.dpag.ox.ac.uk/opdc/publications and Michele Hu - Google Scholar
Michele Hu, PhD, MBBS, FRCP is leading medical therapies for Parkinson’s and atypical Parkinson’s at the John Radcliffe Hospital, Oxford University Hospital's NHS Trust. Also she is a Professor of Clinical Neuroscience at Oxford University in the Nuffield Department of Clinical Neuroscience.
She will be presenting at the WPC 2023 in Barcelona on the subject of “Disease-modification trials in prodromal PD – hopes and barriers”. View the Scientific Program here.
Twitter: @ProfMicheleHu
Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not necessarily reflect the opinions or positions of the World Parkinson Coalition®