from the importance of early diagnosis to digital solutions

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’m a neurology consultant. I’ve been a consultant for 17 years. I work in the Oxford University Hospital’s NHS Trust or John Radcliffe Hospital. 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.

About 12 years ago, Oxford was awarded five million pound research grant from Parkinson’s UK, and we set up the Oxford Parkinson’s Disease Center, which has become an amazing interdisciplinary research center for Parkinson’s, now recognized worldwide.

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 happens over the 20 years before diagnosis. They start with early changes in sleep patterns and losing the ability to smell particular herbs.

Parkinson’s is not just a brain disorder; it affects parts of the peripheral body, like the motility of the gut. We also can see changes in sleep, where people may start to act out dreams in rapid eye movement sleep. People with a sleep disorder, rapid eye movement sleep behavior disorder (RBD), might kick a wall, but they’re dreaming they’re kicking a football.

In the five years before Parkinson’s is typically diagnosed, people can get very 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. Many people, when they first come to see me as a neurologist, have put these changes 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 these clumps deposit in cells, for example, in neurons. They may also deposit in microglia and astrocytes, which are reactive supporting cells that support the neurons. These deposits happen outside of the brain, and you can pick them up, for example, in the enteric nervous system of the skin.

How is PD currently diagnosed? What are the challenges associated with PD diagnosis?

Parkinson’s is what we call a clinical diagnosis. So if, for example, you had a prostate issue, we would be able to take a fine tissue biopsy of the prostate gland, look at it under a microscope, and tell you very definitively that that tissue has benign prostate hypertrophy or cancer. We can’t put somebody through a brain biopsy to diagnose Parkinson’s, so a Parkinson’s diagnosis is based on a clinical set of symptoms and signs when the clinician is talking to the individual.

When we correlate the accuracy of the clinical diagnosis with the actual diagnosis, which can only happen in people who’ve donated their brain after they die (a postmortem diagnosis), about one in 10 people given a label of Parkinson’s disease in life are misdiagnosed. They have what we call a mimic of Parkinson’s, which might be drug-induced Parkinson’s disease, vascular Parkinson’s, benign tremor syndromes, and also what we call Parkinson-plus conditions, which are forms of Parkinsonism, but without the typical pathological correlate.

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 be a CT scan or an MRI brain, which do not tell you if you have Parkinson’s. However, they are useful because they can show the downstream effect of this alpha-synuclein misfolded protein in the brain cells.

Ultimately, misfolded alpha-synuclein interferes with cell function, so cells can no longer recycle their rubbish effectively, can no longer generate sufficient energy to maintain their life, and are under a lot of oxidative stress. The end result of having Parkinson’s is cell death, which we can see on imaging if it’s quite pronounced as what’s called atrophy or loss of substance in the brain. But mainly, CT and MRI scans are done to exclude other pathologies that might be happening in somebody in their mid-60s to 70s.

We also have functional brain imaging, which allows us to estimate the brain neurotransmitters happening in an individual. These include a dopamine transporter single photon emission computerized tomography (SPECT) scan. It involves an injection of radioactive dye from an arm vein going to the brain, and then we can estimate how much dopamine your brain can produce. In Parkinson’s, dopamine is significantly reduced to 50% or less in the basal ganglia, where the dopamine neurons project.

Lastly, we have research brain imaging, which my team is involved with in 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 80 to 90% accuracy, which is as good as a good clinician.

What is prodromal PD?

Prodromal Parkinson’s is the stage that is 10 to 20 years before the motor symptoms manifest. It’s not when you are born or a genetic risk you might inherit for Parkinson’s. But prodromal Parkinson’s is when prodromal symptoms start to build up, but a patient has insufficient symptoms to make a clinical diagnosis.

What is the link between rapid eye movement (REM) sleep disorder and PD?

In my experience, the strongest known risk factor for future Parkinson’s, i.e., in the prodromal Parkinson’s stage, is RBD or rapid eye movement sleep behavior disorder. If you have a confirmed diagnosis of RBD on a hospital sleep study where you are wired up and your sleep is monitored, you have a six percent per year chance of developing either future Parkinson’s or very related alpha-synuclein disorders, including dementia with Lewy body.

If you have had RBD for ten years, your risk of future Parkinson’s is 60%. This is the strongest known risk factor for future Parkinson’s, greater than genetic forms or the forms that come from idiopathic hyposomnia, which is loss of sense of smell that we cannot relate to head trauma, sinusitis, or other problems.

How can wearable technologies impact the diagnosis of RBD?

When I started working with individuals with RBD, it was quite frustrating because many people live out in the general community without a diagnosis. They may have episodes at night that their partner’s aware of. We know from population sleep studies that around one to three percent of people over 55 or 60 have RBD.

But the tip of the iceberg effect means that people with the more severe forms who are perhaps hitting their spouse in their dreams are the ones that go and have a sleep clinic. The problem is often a waiting list of six to 12 months to be admitted to a hospital for two nights to have that sleep study.

Analyzing the data generated from sleep studies is very time-consuming because sleep has multiple channels being investigated. Each channel is 90 seconds, and the sleep technician is looking at perhaps an average recording of 16 hours, and we have no automated diagnosis for RBD.

My research looks at ways to diagnose a person with RBD at home. That is much more representative of a typical night’s sleep. Many people go to the hospital, and they don’t sleep normally. Secondly, home recordings are a lot cheaper. Furthermore, we think we can get as much information from a limited sleep study at home to get the diagnosis.

Digital technology can help us. The sleep kit we have 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 that. A wrist accelerometry, like a Fitbit, is increasingly being looked at for its accuracy in diagnosing RBD.

For example, the UK Biobank study has received accelerometry from over 15,000 individuals over 55. Preliminary analysis suggests diagnosing RBD just from wrist accelerometry over seven days is possible. However, we need more studies and analysis to look at the accuracy and ability to distinguish other sleep conditions from RBD.

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 is individuals put their physical state down to getting older. There’s often quite a blurred margin where it’s quite hard to know at the first or second visit if the symptoms the person has could simply be related to getting older.

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 NHS crisis of care. Over the last five years, there’s been a 15% average increase year-on-year in new Parkinson’s referrals. This is consistent with population predictions that the prevalence of Parkinson’s will double or triple in the next 20 years because people are living longer. Still, it seems to be getting more common than we would predict from the aging population alone.

My group has developed an eight-minute smartphone test. This smartphone test is very 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.

We now use this 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 and that we can also develop a composite score, which gives us an overall measure of that individual’s Parkinson’s motor severity.

We’ve also shown that this smartphone test can predict the onset of milestones for people with Parkinson’s, but it can predict 18 months or three years before this milestone has happened. These milestones might include going from normal walking to falling. These tests might be used, for example, by physiotherapists, to stratify or categorize individuals at higher risk of these future outcomes so they can intervene. If you can prevent falls, you will prevent hip fractures, emergency department admissions, cost to the taxpayer, and hospital bed blocking because a person is falling at home and not coping.

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 an infectious disease like COVID-19, if you were to model the increase in people living with Parkinson’s and the projected increase over the next 20 years, it would behave like a pandemic. We need people to recognize the symptoms earlier so that they seek earlier help, and we need more information on 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 the first-ever randomized placebo-controlled trial in patients with prodromal Parkinson’s who have RBD. The endpoint of the trial will be a change in brain imaging for inflammation, as inflammation in the brain may be a very early feature of prodromal Parkinson’s that could be disease-modified by anti-inflammatory medications.

We also have a new website. We’ve recognized that people with Parkinson’s have a good media presence and websites through Parkinson’s UK, Michael J. Fox Foundation, and Cure Parkinson’s Trust, for example. 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 website for people with RBD. We have other initiatives happening through the North American Prodromal Synucleinopathy.

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.