Preventive Neurology Unit Showcase

Yesterday alongside the launch of the second phase of PREDICT-PD (a new drive to recruit 10'000 participants to the study!) was the showcase of the Preventive Neurology Unit. The Preventive Neurology Unit is a new and exciting unit that is part of the Wolfson Institute at Queen Mary University London. The Wolfson Institute of Preventive Medicine has a proud history of leading the way in terms of cancer prevention and epidemiology with many high impact publications. Now, thanks to Barts Charity, we are trying to replicate some of the successful preventive techniques used in cancer and apply them to neurological diseases.

The showcase yesterday gave the three senior clinical lecturers the opportunity to explain some of their work and objectives as well as hearing from Professor Jack Cuzick and Professor Gavin Giovannoni about their hopes for this new unit.

The showcase began by Dr Charles Marshall explaining his work regarding the benefits and difficulties of diagnosing Alzheimer's disease as early as possible. Current research suggests that amyloid deposits can begin accumulating in patient's brains up to 20 years before they have any symptoms of dementia. This period before symptoms begin would be the ideal time to intervene with medications to prevent the onset of dementia but unfortunately there is no way to easily identify these people. Dr Marshall explained how the use of 'Brain Stress tests' could help to identify patients before they develop any symptoms of dementia and how his work will use these tests to see if people who will go onto develop Alzheimer's dementia can be identified earlier and therefore start treatments sooner.

Next up was Dr Alastair Noyce who explained the PREDICT-PD project which I am sure most readers of this blog are familiar with. Dr Noyce explained how the project evolved from a keyboard tapping test called the BRAIN test and now has 1000 participants who have been taking part over 5 years and will soon have 10'000 participants! The benefits of this research could be huge if we can begin to identify patients who are highly likely to develop Parkinson's before they suffer from any symptoms then we can begin to start trying to prevent Parkinson's in the first place. Dr Noyce also explained some fascinating results about Exenatide (a diabetes medication) which has recently been shown to potentially have some neuroprotective effect in Parkinson's and could be the first disease modifying medication for Parkinson's disease. Medications such as this would be ideal to use in further studies if PREDICT-PD can successfully identify those at high risk of Parkinson's.

The final talk about preventive approaches to Multiple Sclerosis was delivered by Dr Ruth Dobson. The complex links between EBV, childhood obesity and vitamin D levels were examined. Dr Dobson explained some of the intriguing results regarding EBV infection and Multiple Sclerosis and some of the difficulties of interpreting this relationship. The audience was also fascinated to hear about the links between foetal and neonatal vitamin D levels and MS. The main point that Dr Dobson emphasised is that a preventive approach to MS has to happen much earlier than the couple of years prior to diagnosis; the most important potential modifiable risk factors are all in early childhood or potentially in-utero!

Overall the showcase was very successful and the audience provided lots of insightful questions and interesting discussion. It is an exciting time to be working on preventive approaches to neurological disease and yesterday definitely highlighted that.

We have lift-off

PREDICT-PD has been going since 2011, and during that time we have had around 1,300 participants complete annual surveys, and we have done around 500 in-person assessments all around the UK.

This year we have also started our imaging project, where we are using the PREDICT-PD model with cutting edge MRI and ultrasound techniques to 'see' Parkinson's at the very earliest stages.

We have also been paying special attention to two special groups within PREDICT-PD: people who have lost their sense of smell, and people with a certain kind of sleep disorder. We have been seeing individuals who have been referred to us from specialist clinics, and doing in-person assessments with them to see if we can tease out what features put some people in these groups at increased risk of Parkinson's.

All of this has been taking place while we have been working tirelessly to create a new online platform on which to continue the study. The website has an entirely new design and set up, with a really robust 'back end' to safely and securely store participants data. This has come during the implementation of GDPR, to add to the complexity.

However, the exciting news of the day is that we have officially launched the second phase of PREDICT-PD!! We are now aiming to recruit at least TEN THOUSAND new participants.

So if you have not been part of this journey, please visit www.predictpd.com to find out more, and when you're ready, press 'TAKE PART'. It takes about 20 minutes to register, and go through the questionnaires and assessments. Now is your chance to join in with a truly groundbreaking research study, from the comfort of your own home. If you have already joined us, thank you. Please talk about it with friends and neighbours, encourage as many people as you can to join in. We take all comers (as long as they're between 60-80, and do not have Parkinson's disease (to their knowledge).

Flying the flag, and raising support

At PREDICT-PD nothing we do would be possible without our funding from Parkinson's UK. In clinic, we know how invaluable the support they give to people with Parkinson's all over the UK.

I have just received a wonderful phone call from Parkinson's UK, offering me one of their places in the London Marathon 2019. 

Please help me make groundbreaking research a reality, bring us closer to a cure, and provide life changing support to people with Parkinson's, by sponsoring me at here 

I'm aiming for a Good For Age time of under 3 hours, smashing over 20 minutes from my previous record. Every donation will spur me on through training in the long winter months between now and April. Follow my progress on Strava. Last weekend was my first 20 miler since the 2015 London marathon, and this Sunday I'm running in the Wimbledon Half marathon.

Wish me luck!

RNR

Why more Parkinson's might not be such a bad thing

This week, the Lancet Neurology have published the "Global, regional, and national burden of Parkinson’s disease, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016", a very large and very complex analysis of the amount of Parkinson's all over the world.

As can be seen from the map below, there are huge differences in the rate of Parkinson's. Some of the reasons for this are clear, and some are less well understood.

Worldwide rates of people with Parkinson's (age-standardised prevalence per 100,000 population in 2016)

What is more interesting is the rates of change. Parkinson’s was the fastest growing condition in terms of prevalence, disability and death of all neurological conditions. Since 1990, the prevalence (number of people with a condition), mortality, and disability-adjusted life-years (One DALY can be thought of as one lost year of "healthy" life. Read more about DALYs here), have more than doubled. In part this is because of the population of the world getting older. This figure shows the rates of Parkinson’s for men and women at different ages.

The percentage of men (red) and women (blue) with Parkinson's by age. The line is  the current estimate, with the shaded area being the region of uncertainty in which the 'true' figure lies.

Although there are many reasons why this increase is being seen, one reason is that the prevalence is related to two things: how many people receive a new diagnosis, but also how long people with a condition live with it. If the rate of new diagnoses has not significantly changed (the evidence remains unclear), in a generation we have enabled people with Parkinson’s to live longer. The authors remind us that this is only partly due to drugs like levodopa, and also due to the general increase in sanitation, food security, general health improvement, vaccination etc. as well as attention to things like physiotherapy, speech and language therapy etc.

So as we go forward, lets hope that the number of people with Parkinson’s continues to increase, but the DALYs decrease. And lets continue to work hard so we can at last make a real change to the incidence of Parkinson’s.

RNR

GBD 2016 Parkinson's Disease Collaborators. Global, regional, and national burden of Parkinson's disease, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet Neurology. 2018 Oct 1;17(11):939–53. 

What does ethnicity have to do with Parkinson's disease?

I have recently started working at the Preventive Neurology Unit (QMUL) on a new project called the East London Parkinson’s Project. It has been exciting to be starting a new project, especially when the subject is so interesting; the way that ethnicity can affect Parkinson’s disease (PD). This is really important to study because up until now most studies of PD have been based on white participants or a single ethnic group that does not allow us to compare any differences between different ethnicities. Unfortunately due to the lack of research in this area we know very little about even some of the most basic information regarding PD and ethnicity.

For example there is not even a consensus as to whether people from different ethnicities have a different chance of developing PD. This is usually one of the first things that we learn about any condition. Previously PD was thought of as more common in white people and some studies have confirmed this, however other studies have found that people of all ethnicities have similar rates of PD. The results seem to vary depending on the way the study was carried out and there is a distinct lack of large scale multi-centre studies to more accurately answer this question.

If we are still struggling to determine something as simple as the rates of PD in different ethnicities then you can imagine how difficult is to work out more complicated relationships between ethnicity and PD. For example a study in Israel looked at differences in PD between Ashkenazi Jews (a distinct group of Jews who have lived throughout Europe since the 7^th/8^th century) and Yemenite Jews (a group of Jews who evolved completely separately to the rest of the Jewish population after arriving in Yemen around the second century). The study showed that Yemenite Jews with PD had more severe symptoms and the PD progressed faster than in Ashkenazi Jews. This is interesting because all the participants live in Israel now so have a relatively similar environment raising the possibility that the differences observed are genetic. Having said that Yemenite and Ashkenazi Jews have different diets and lifestyles to each other and it is possible that this could be having an effect. This is just one study out of hundreds I could have discussed but I think it demonstrates some of the interesting trends we notice between ethnicity and PD but also some of the complications when trying to analyse these differences.

To make any headway with this difficult issue we need more studies that explore this tangled relationship between PD and ethnicity.

J Neural Transm (Vienna). 2008 Sep;115(9):1279-84. doi: 10.1007/s00702-008-0074-z. Epub 2008 Jul 30.

Clinical characteristics of Parkinson's disease among Jewish Ethnic groups in Israel.

Djaldetti R, Hassin-Baer S, Farrer MJ, Vilariño-Güell C, Ross OA, Kolianov V, Yust-Katz S, Treves TA, Barhum Y, Hulihan M, Melamed E.

Yemenite Jews in Israel are a distinctive ethnic division of the Jewish diaspora. Clinical findings, disease course and genetic tests for the LRRK2 6055G > A (G2019S) mutation were compared between Ashkenazi and Yemenite Israeli patients with Parkinson's disease (PD). Age of onset was significantly younger in the Yemenites (P < 0.001). There were no differences in the distribution of initial symptoms, environmental risk factors or rate of motor/non-motor phenomena. The Yemenite group had a more severe disease (P < 0.001), and a more rapid disease course (P = 0.006). The frequency of Lrrk2 substitution was 12.7% in the Ashkenazi group and was not observed in the Yemenites. These results show that there are differences between Israeli Jewish ethnic groups in the severity and progression of PD, but not in clinical symptoms. The high frequency of Lrrk2 G2019S in the Ashkenazi and its absence in the Yemenite Jews suggests a specific ancestral pattern of inheritance in Ashkenazi Jews.

Why gout might be surprisingly good for the brain

There has been quite a lot of interest in the role of uric acid in Parkinson's Disease. Uric acid is a by-product of normal cell function, and a normal part of urine. In medicine uric acid is well recognised for its role in gout, where high levels in the blood lead to joint swelling and pain.

However, in Parkinson's Disease, uric acid seems to have a protective value. The study I've looked at here took 200 Koreans who had newly been diagnosed with Parkinson's, testing their thought processes as well as smell and uric acid levels in the blood. They found that there was a significant link with uric acid - higher levels were associated with better scores on tests of cognitive function.

from nhsdirect.wales.nhs.uk 

from memorangapp.com

vs

Does this mean that uric acid is somehow neurologically protective? This study looks at one point in time, but in large groups where uric acid has been measured and the participants followed up for diagnosis of Parkinson's, those with higher levels are less likely to go on to develop the disease. Recent findings have suggested that uric acid is particularly associated with those who have cognitive problems, who tend to have more severe disease.

Other possibilities are that there are other factors related to both urate levels and risk of parkinson's - for example diet or smoking, or that lower urate levels could be caused by the disease itself.

However, this is a promising avenue and a good example of how potential treatments can result from studies looking at risk factors. A trial with a drug designed to increase urate levels, Inosine, has so far shown that it is effective and safe, although will require close monitoring for the known side effects of high urate.  I will be particularly interested to see how this drug affects thought processes as it is studied further.

-Anna

 https://www.researchgate.net/publication/328022951_Cognition_Olfaction_and_Uric_Acid_in_Early_de_novo_Parkinson's_Disease

Cognition, Olfaction and Uric Acid in Early de novo Parkinson's Disease.

Lee HR, Park JH, Han SW, Baik JS

OBJECTIVE: Cognitive impairment is one of the nonmotor symptoms in Parkinson's disease (PD), and olfactory dysfunction is used as a marker to detect premotor stages of PD. Serum uric acid (sUA) levels have been found to be a risk factor for PD. Our objective in this study was to examine whether sUA levels are associated with cognitive changes and olfactory dysfunction in early de novo PD patients.

METHODS: The study participants included 196 de novo PD patients. We assessed cognitive function by the Korean versions of the Mini-Mental State Examination and the Montreal Cognitive Assessment and assessed olfactory function by the Korean version of the Sniffin' Sticks test.

RESULTS: The mean sUA level was 4.7 mg/dL and was significantly lower in women than in men. Cognitive scores were lower in women, suggesting that sUA levels were related to cognitive function. The olfactory functions were not related to sUA level but were clearly associated with cognitive scores. Olfactory threshold, odor discrimination, and odor identification were all significantly related to cognitive scores.

CONCLUSION: We conclude that lower sUA levels were associated with cognitive impairment, not olfactory dysfunction, in de novo PD patients. This finding suggests that UA is neuroprotective as an antioxidant in the cognitive function of PD patients.

Cognitive decline in Parkinson's disease: the impact of the motor phenotype on cognition

This is a nice large study looking at the relationship between different motor features of Parkinson's and having more severe cognitive features.

We already know that patients with a mainly shaky (tremulous) form of Parkinson's tend a run a milder course compared to those patients that have a very slow & stiff (akinetic rigid) form of Parkinson's. For example, patients with the tremulous form of Parkinson's also seem to live for longer than those with the akinetic rigid form. Of course these categories overlap substantially but they are generally well recognised.

Here the researchers show that in patients who tended to be more slow and stiff, scores on a variety of cognitive tests were worse than in the patients that had predominant tremor.

The study design was cross-sectional, which means that movement and cognition were measured at the same time. This means that strict conclusions cannot be drawn about the progression of movement or cognitive abnormalities either separately or together. The explanation for the association between akinetic-rigidity and worse cognition is likely due to involvement of common structures brain (more so than the structures that are involved in tremor), the overall burden of disease (likely to be less in those with predominant tremor), and shared risk factors (including genetic determinants).

- Alastair Noyce

J Neurol Neurosurg Psychiatry. 2018 Oct 8. pii: jnnp-2018-319008. doi: 10.1136/jnnp-2018-319008.

Wojtala J, Heber IA, Neuser P, Heller J, Kalbe E, Rehberg SP, Storch A, Linse K, Schneider C, Gräber S, Berg D, Dams J, Balzer-Geldsetzer M, Hilker-Roggendorf R, Oberschmidt C, Baudrexel S, Witt K, Schmidt N, Deuschl G, Mollenhauer B, Trenkwalder C, Liepelt-Scarfone I, Spottke A, Roeske S, Wüllner U, Wittchen HU, Riedel O, Dodel R, Schulz JB, Reetz K.

https://jnnp.bmj.com/content/early/2018/10/07/jnnp-2018-319008.long

OBJECTIVES: Parkinson's disease (PD) is the second most common neurodegenerative disorder and is further associated with progressive cognitive decline. In respect to motor phenotype, there is some evidence that akinetic-rigid PD is associated with a faster rate of cognitive decline in general and a greater risk of developing dementia.The objective of this study was to examine cognitive profiles among patients with PD by motor phenotypes and its relation to cognitive function.

METHODS: Demographic, clinical and neuropsychological cross-sectional baseline data of the DEMPARK/LANDSCAPE study, a multicentre longitudinal cohort study of 538 patients with PD were analysed, stratified by motor phenotype and cognitive syndrome. Analyses were performed for all patients and for each diagnostic group separately, controlling for age, gender, education and disease duration.

RESULTS: Compared with the tremor-dominant phenotype, akinetic-rigid patients performed worse in executive functions such as working memory (Wechsler Memory Scale-Revised backward; p=0.012), formal-lexical word fluency (p=0.043), card sorting (p=0.006), attention (Trail Making Test version A; p=0.024) and visuospatial abilities (Leistungsprüfungssystem test 9; p=0.006). Akinetic-rigid neuropsychological test scores for the executive and attentive domain correlated negatively with non-tremor motor scores. Covariate-adjusted binary logistic regression analyses showed significant odds for PD-mild cognitive impairment for not-determined as compared with tremor-dominant (OR=3.198) and akinetic-rigid PD (OR=2.059). The odds for PD-dementia were significant for akinetic-rigid as compared with tremor-dominant phenotype (OR=8.314).

CONCLUSION: The three motor phenotypes of PD differ in cognitive performance, showing that cognitive deficits seem to be less severe in tremor-dominant PD. While these data are cross-sectional, longitudinal data are needed to shed more light on these differential findings.

Real life: Parkinson's and relationships

Warning: this post contains no statistics.

Several friends have recently suggested I listen to a podcast series, "Where should we begin, with Esther Perel". It is a podcast of relationship therapy sessions between couples and the host. The very last episode of the series (series 2 episode 8) is about a couple where the husband has early onset Parkinson's.

In clinic we see patient's for as much as an hour and a half (if they're lucky) per year, leaving the other 8,760 hours per year without our support. In the time with us we focus on their agenda and our agenda - tremor, swallowing, falls, cognition, stiffness, slowness: the list goes on.

The minefields we don't (and probably can't) help them navigate though are vast. From the existential to the personal. Love, sexuality, closeness, meaning - these are not problems we can address in five minutes on a Tuesday afternoon in clinic.

Parkinson's specialist nurses are an invaluable bridge between specialist clinics and 'the big wide world'. Parkinson's UK provide excellent support around the UK to people with Parkinson's and their partners. But the greatest support we each have is those around us - if only we can develop the vocabulary and resources to engage with our families, our partners, our friends.

If you have Parkinson's, or if you know someone who has Parkinson's, I strongly recommend giving this a listen.

(also available on iTunes and other podcast providers)
 

To boldly go

An article on the BBC news website has prompted me to write a post that I’ve been considering for a while. 

Billy Connolly, the edgy and flamboyant comedian, has been an outspoken supporter of research for a cure for Parkinson’s. He was diagnosed with the condition five years ago. This week he has publicised that he is willing to be a ‘guinea pig’ for a stem cell trial.

Irony, foreshadowing or mere coincidence?
Picture from http://bit.ly/SundayPost100

I have been asked about my 'stance' on stem cell treatments for Parkinson's in clinic, and I confess to not having a 'stance'. The reason for this is that the state of the science is truly in its infancy, certainly in terms of deliverables for people with Parkinson's. This is not to diminish the decades of work that have led us to where we are, but even heroic gestures, such as Connolly's will only inch us forward in the marathon that lies between now and the New Era of stem cell treatments.

In preparation for this blog post I have read an update from the recently established GForce-PD network: a network of researchers from around the world who are working together to bring stem cell treatment closer to reality. An excellent (technically written) history of the subject can be found in a Nature Reviews article written by Prof Roger Barker from Cambridge.

Landmarks in the history of stem cell treatment of Parkinson's.
From Nat. Rev. Neurol.doi:10.1038/nrneurol.2015.123

As a brief overview, stem cells can be derived from a 'matched-donor' - in a similar way to  how organ donation works currently; from embryos, which has both ethical and immunological issues; and from the individual themselves.

Different sources of stem cells
from https://doi.org/10.1016/j.stem.2017.09.014

They are then surgically implanted into the area of the brain that is most affected by Parkinson's, where they grow and develop into (hopefully) fully functioning dopamine-producing cells. In essence, the aim is not just to mask the symptoms like current treatments do, but return the individual's brain to how it would be functioning without Parkinson's.

I want to focus attention on one aspect of the discussions of this group as it has particular resonance with PREDICT-PD. There is a very difficult decision regarding whom to choose as participants in a trial of stem-cell treatment. Do you choose participants who've only recently been diagnosed, or do you choose people in later stages of the condition?

Some arguments for 'earlier' intervention is that these individuals will be physically fitter so at less risk of the initial surgery, and be better able to tolerate the immunosuppression required. They would also have longer to reap the benefits of their investment, and given that this kind of intervention would be at great financial cost to a health system, the payer (be that the NHS or any other health system) would get the best bang for its buck.

However, these arguments only hold water on the assumption that it works. The flip side of the coin also applies. A big fear of stem cell technology from the early days of the field, is that the new cells go outside the normal control systems of cells and develop into cancer cells. This might prove worse for someone that the slow progress of Parkinson's left untreated by stem cells. The immunosuppression also has long term risks, with unusual infections, or usual infections presenting in unusual ways. 

What about the other option? Individuals with more advanced disease have more physically measurable symptoms, and so less time is needed for a (very expensive) clinical trial to show differences between treated and untreated (or sham procedures). Given the risks outlined above, it could be conceived that stem cell treatment is a 'last-chance saloon' treatment that should be embarked on only where more established treatments have failed. We have written about the personal costs Parkinson's on this blog, and that as the condition advances the costs spiral. If stem cell treatment is withheld until later in the condition, there is a greater chance that the cost will be offset by savings in other areas, as the need for more help reduces with a return of independence in multiple areas.

There are no perfect answers. It is essential that a global effort is sustained to get us safely, ethically and rigorously through the choppy waters that lie between now and a time when stem-cell treatments are as commonplace as other treatments for Parkinson's.

RNR

Parkinson's ex machina

Last week Anna talked about the need to ensure the 'human' is kept at the centre of drug design for Parkinson's treatments - "focussing on human cells, tissues and subjects". Today I also want to discuss the role of humans in Parkinson's and the role of machines.

Neurology (and neurologists) take pride from being a bastion of clinical medicine - the heart and soul of our practice is listening to our patient and observing their every movement. In some ways neurology has not moved on much (in spirit) from the historic view of 'physicians' portrayed so poignantly by Sir Luke Fields. Movement disorders, and the diagnosis and management of Parkinson's are perfect examples of this human approach, with no equipment other than a tendon hammer necessary to make the diagnosis.

taken from https://www.tate.org.uk/art/artworks/fildes-the-doctor-n01522 with thanks

However, today's world has moved on leaps and bounds, and medicine and neurology are desperately trying to keep pace. In the 130 years since this scene was painted, our world has changed almost unrecognisably (although a Google image search of 'doctor' would make anyone believe that it is still delivered primarily by middle aged white men - which thankfully is less true now than ever).

It is old hat to say that technology continues at a blistering pace. Miniaturisation  has made yesterday's science fiction into the everyday. 'The Fantastic Voyage' described a vessel that was shrunk and inserted into a person's body to save them - well thrombectomy for stroke, stunting for heart attacks, and a video camera so small you can swallow it to get diagnostic pictures throughout the gut are all in routine clinical practice in the NHS today.

The Fantastic Voyage (1966) - picture from https://www.britannica.com/topic/Fantastic-Voyage

High street technology has revolutionised our lives. There is more processing power in my 4 year old iPhone than Armstrong, Aldrin and Collins had on Apollo 11. There is now an enormous market in wearable technology that will give you a beat-by-beat analysis of your heart rate, count your steps in a day, your calorie output, measure your power in watts on a bike, feet climbed on the stairs and just about any other metric you can imagine.

Just a small number of the dizzying array of activity tracking watches available on the high street (picture from  Groupon.co.uk)

All this brings me onto a review I have read, "Optimizing clinical assessments in Parkinson's disease through the use of wearable sensors and data driven modelling"

The article offers a review on some of the hardware software and statistical approaches to understanding the data. At its heart is the understanding that a neurologist sees their patient for perhaps 3 or 4 15-20 appointments in a year. That clearly leaves 8,759 hours per year where the neurologist has no ability to observe their patient move. Wearable technology brings us a (relatively) non-intrusive window into the 'real lives' of our patients. With the vast amounts of data that this can bring, we need very sophisticated algorithms to understand it, and we need to understand the computer science and mathematical constructs that underlie those algorithms.

Going further than mere observation is prediction - the holy grail in healthcare, and our clearly stated aim in PREDICT-PD. This article concludes by cautioning us about the variation in quality and output of this technology, but offering us the hope that these devices and underlying data analysis will improve clinical decision making, provide more personalised care, and better understand and highlight the differences in the manifestations of what we currently call 'Parkinson's disease', leading to better trials, treatments and one day - cure.

RNR