Thursday 2 July 2020

Mild Parkinsonian Signs in a Community Population


One question that many of the PREDICT-PD participants ask me is “I am slower than I used to be, does it mean that I am getting Parkinson’s?”

I am interested in the early motor phases of Parkinson’s disease. They are subtle in appearance and usually start before the classical symptoms of Parkinson’s arise, which are slowness of movement, stiffness and tremor. 

When studying subtle abnormalities it is important to know the full range of normal amongst older people. It can be difficult to establish the boundaries between what is normal and abnormal, especially at very early stages of Parkinson’s and in older people.

What it is known is that mild parkinsonian signs or subtle motor symptoms are quite common in the elderly population (ranging from 15% to 50%). The question of whether their presence occurs as part of normal aging or as the result of neurodegeneration has not been clearly answered. 

Here I share a paper that tries to address the issue mentioned above. 

Abstract.
Background: Mild parkinsonian signs (MPS) are common in the older adult and associated with a wide range of adverse health outcomes. There is limited data on the prevalence of MPS and its significance.

Objective: To determine the prevalence of MPS in the community ambulant population and to evaluate the relationship of MPS with prodromal features of Parkinson’s disease (PD) and cognition.

Methods: This cross-sectional community-based study involved participants aged ≥50 years. Parkinsonian signs were assessed using the modified Unified Parkinson’s Disease Rating Scale (mUPDRS) and cognition using the Montreal Cognitive Assessment (MoCA). Premotor symptoms of PD were screened using a self-reported questionnaire. Linear regression was used to assess the association of MPS with premotor symptoms of PD and cognitive impairment.

Results: Of 392 eligible participants, MPS was present in 105 (26.8%). Mean age of participants with MPS was 68.8 +/- 6.9 years and without MPS was 66.1 +/- 5.9 years (p < 0.001). Multivariate analysis revealed that MoCA scores were significantly lower in the MPS group (b= –0.152, 95% CI = –0.009, –0.138, p < 0.05). A significant correlation between the presence of REM sleep behavior disorder (RBD) and total MPS scores (b= 0.107, 95% CI = 0.053, 1.490, p < 0.05) was also found. Neither vascular risk factors nor other premotor symptoms were significantly associated with MPS.

Conclusion: MPS is common and closely related to cognitive impairment and increasing age. Presence of RBD is predictive of higher MPS scores. This study highlights the necessity of other investigations or sensitive risk markers to identify subjects at future risk of PD.


The main purpose was to know how frequent subtle motor symptoms were in an elderly community without Parkinson´s and evaluate if these features were associated with a loss of cognitive abilities or other features known to be part of the early phase of Parkinson’s including reduced sense of smell, constipation, depression and sleep disturbances. 

To do that, participants were evaluated with motor and memory tasks as well as answering a self-reported questionnaire about the other symptoms mentioned. 

The authors found that one quarter of the group had subtle movement symptoms and this proportion increased with age, with 3 out of 10 people older than 75 having some kind of movement abnormalities. It is important to note that none of these symptoms were strong enough to make the diagnosis of Parkinson’s. They also found that cognitive and motor symptoms were highly associated.

We can extract several conclusions from these results. It is undeniable that once we get older our movement becomes slower and clumsier. The point here is when these motor symptoms occur together with mild memory problems it could mean that some neurodegenerative condition apart from simple aging is occurring.  

In order to these findings be more convincing, we would need to know how many of these people ended up having Parkinson’s or other conditions like Alzheimer’s over time. This was not reported in the study and so further studies are needed.

Cristina Simonet

Friday 17 April 2020

Patients’ views on the ethical challenges of early PD detection

I read this paper this morning and thought it represented an important step forward in our understanding of this delicate issue

Many of us are working on risk factors of Parkinson's and early identification strategies, but what do patients with PD think about finding out they were at risk before the point of diagnosis? Here the authors surveyed >100 patients with PD and found interesting results. 

More than half would not have wanted to know that they were at risk if there was no medical treatment that could be offered prior to diagnosis... but this number dropped to 15% if there were lifestyle changes that one could make to reduce risk.

10% of patients thought disclosure of being high risk should never happen before diagnosis, but about a quarter (23%) thought that such disclosures should be made. The largest proportion of patients thought that it depended on what an individual wants to know. This personal preference is something that we considered in a paper last year focussed on Early vs Timely diagnosis (link here).

These issues are fundamental to arriving at a point where we have early identification strategies, either lifestyle or medical, and a real preventive approach to neurodegenerative disease. There is an awful lot of work that needs to be done and we require 'buy-in' and commitment from patients, the public, primary care, public health, policymakers and research. Our Time Matters initiative launched last year covers the various requirements to make Preventive Neurology a reality, and studies such as the one outlined here are examples of things that will take us further forward...

- Alastair


Tuesday 28 January 2020

NEW Research - Is Parkinson's Genetic?? - Penetrance of Parkinson's Disease in LRRK2 Carriers Is Modified by a Polygenic Risk Score.

Here is a nice paper by colleagues from the International PD Genomics Consortium (IPDGC)...
https://onlinelibrary.wiley.com/doi/abs/10.1002/mds.27974

One question I frequently get asked is "doctor, please tell me, is it genetic?"... I am instantly caught in conflict between offering swift reassurance because I know what people really mean is "will I pass this on to my children?" OR a providing a rather convoluted explanation along the lines of 'yes in some ways Parkinson's is genetic but because of a whole range of genetic factors affect one's risk of getting Parkinson's just a little bit'.

The truth is that most complex diseases are genetically determined to some extent and Parkinson's is a good example. That doesn't mean that if you have Parkinson's your relatives will definitely also get Parkinson's, but they might be at slightly higher risk. The strength of the genetic factors that they have and the combination of factors adjust the overall risk in individuals. 

This offering from the IPDGC is an example of how different genetic factors combine... 

LRRK2 is the commonest genetic cause of Parkinson's that we know about. Having a mutation in LRRK2 causes Parkinson's in about 30% of carriers in their later years. These mutations have a 50% chance of being passed on to the next generation, who then in turn also have about 30% chance of showing signs of Parkinson's in their later years. What determines the chance of showing signs of Parkinson's? Well at least in part it is likely due to the other genetic risk factors that you have. 

In this paper, the authors show that having other genetic risk factors for Parkinson's (combined in a score) affects how likely carriers of LRRK2 mutations are to show signs of Parkinson's and that on average they tend to show them earlier in life. 

Why is this important? LRRK2 drugs are being tested to see how they might protect people carrying mutations of LRRK2 against getting Parkinson's. It is likely that the combination of other genetic factors that people have will help select groups for trials and might also affect the response to treatment. This kind of research gets a little bit closer to realistic precision medicine for Parkinson's 

Alastair Noyce






Thursday 23 January 2020

NEW Research - Motor complications in Parkinson's disease: 13‐year follow‐up of the CamPaIGN cohort

Back on the blog for the first time in a long time...

This marks another NY resolution to speak and flag more about the research that I/we think is interesting or important in the early identification or prediction of PD. In addition, we like to mention good quality clinical and genetic studies that tell us more about PD in general (not just prediction and early identification). 

First off, the latest from the CAMPAIGN study. CAMPAIGN is one of the most rigorous and thorough long term studies of PD. The team have managed to follow up the people that they recruited with PD for a long, long time in order to help us learn more about the features that emerge over time.

In the present study, they show that eventually motor complications may be inevitable and that current drugs become less effective/predictable over time. Importantly they provide further support for the notion that levodopa replacement itself is not a cause of motor fluctuations and that thoughts about saving levodopa for the future (i.e. not starting after diagnosis) are probably outdated ideas.

Ultimately, whilst the available treatment options are good for most patients, the results here support our ongoing desire to find drugs that delay progression rather than just manage the symptoms...

The link to the study is here and it is open access (👌). The abstract is copied below.
https://onlinelibrary.wiley.com/doi/full/10.1002/mds.27882

Alastair Noyce



Tuesday 6 August 2019

Salbutamol and PD risk

Recently at one of our movement disorders meeting we began to discuss whether people with PD should be prescribed salbutamol. Salbutamol is a drug that has been used to treat asthma and COPD (a smoking related breathing disorder) for a long time. There has been lots of interest in Salbutamol because in epidemiological studies it appears to be protective against developing PD.

Salbutamol works by activating a receptor called the beta-adrenergic receptor which in turn causes the airways to expand; making it easier to breath. There are also medications that do the opposite of this, block the beta-adrenergic receptor. Examples of these medications are bisoprolol, atenolol, propanolol and metoprolol. Interestingly these medications regularly come up as risk factors for PD in similar studies. So based on this data; medications which block the beta-adrenergic receptor increase the risk of PD and medications which activate the beta-adrenergic receptor protect people against PD. This has the potential to be a critical finding as it would mean clinicians may have a simple medication which could prevent Parkinson's disease.

Unfortunately the link between the beta receptor and PD may not be as clear as these studies imply. There are a number of other possible explanations and confounders. As I mentioned earlier is used to treat Asthma and COPD, COPD is a lung disease that is almost exclusively found in smokers. Smoking is known to be associated with a decreased risk of PD. Therefore people who are prescribed salbutamol are much more likely to smoke and subsequently more likely to develop PD. So that could potentially explain why the beta agonists appear to protect people from PD but then why do beta-blockers seem to increase the risk of PD? One of the earliest symptoms of PD is a tremor and patients are often misdiagnosed initially as having an essential tremor. The treatment for essential tremor involves a beta-blocker called propanolol or metoprolol. So it is possible that people with early Parkinson's disease are mistakenly being prescribed beta-blockers so in studies they appear to increase the risk of PD.

A recently published case-control study from Denmark has explored some of these associations. First of all they found again that people with PD are much less likely to take beta-agonists. But they found two key things that indicate that this relationship is driven by smoking rather than beta-agonists. First of all the same reduced odds ratio for PD was found for all medications used to treat COPD in smokers such as anti-cholinergics and inhaled steroids. All of these medications are much more likely to be prescribed in smokers indicating  that beta-agonists are not having a special effect on PD. Also the same reduction in odds ratio for PD was found for people who had been prescribed beta-agonists regardless of the duration of beta-agonist use. The same reduced odds ratio was seen even for people who had been prescribed beta-agonists within the past year which is very unlikely to be having a disease modifying effect on PD as the neurodegeneration typically occurs over years.

With regard to beta-blockers they found that short term beta-blocker prescriptions had a much stronger association with PD than long term beta-blocker prescriptions. This suggests that the association is much more likely to be driven by early PD symptoms being mistaken for essential tremor rather than beta blockers actually causing PD. Also, interestingly, they only found the association for beta-blockers used for treating tremor (such as propanolol and metoprolol) but they did not find an association with other beta blockers such as bisoprolol which can not be used to treat tremor.

This is a really fascinating study which provides important information about the link between beta-adrenergic medication and PD. The data indicates that all of the PD protective effects of beta-agonists are actually mediated by smoking and the risk of beta-blockers is accounted for by attempts to treat the early symptoms of PD.


Neurology. 2019 Jul 9;93(2):e135-e142. doi: 10.1212/WNL.0000000000007694. Epub 2019 May 24.
Use of ÎČ2-adrenoreceptor agonist and antagonist drugs and risk of Parkinson disease.
Hopfner F1Wod M1Höglinger GU1Blaabjerg M1Rösler TW1KuhlenbÀumer G1Christensen K1Deuschl G1PottegÄrd A2.

Thursday 27 June 2019

You are what you eat



You are what you eat!

It is a rare day that reading a scientific report of basic research makes the hairs on my neck stand up, but today is one such day. 
An article published in the prestigious journal Neuroncarries the rather dry title “Transneuronal propagation of pathologic α-synuclein from the gut to the brain models Parkinson’s disease”. In their research the authors at Johns Hopkins in Baltimore injected an abnormal protein (α-synuclein preformed fibrils) into the walls of the stomach and intestines of some mice. They left some to develop, but did an operation (that used to be common in humans) to cut the nerve that supplies the stomach in others.




Within one month, the protein was found within the brainstem. At three months this has progressed and the protein is found in the substantia nigra (the ‘seat’ of Parkinson’s) and at seven months this has progressed further in the brain. What’s more, although not seen at 1 or 3 months, by 7 months there was loss of dopamine neurones in the brain and this progressed by 10 months. These changes were not seen in the mice who had the operation.

Not only did they do multiple different kinds of microscopic and imaging experiments to directly detect the spread and progression of this protein, they also looked at the movements and behaviour of the mice. Sure enough, the mice who had the intact nerve (and therefore the spread of the protein to the brain), did worse on movement tests (they were slower and less balanced). They also did significantly worse on memory and decision making tests for mice.

Why is this so (potentially) revolutionary? There are several reasons. 
Firstly, there has been a hypothesis for over 15 years that Parkinson’s starts in the gut and spreads to the brain, and these experiments very strongly support that. This backs up observational data from Scandinavia that showed that humans that had had the nerve-cutting operation (vagotomy) for stomach ulcers were less likely to go on to develop Parkinson’s.
Secondly, not only did these mice show pathological changes on imaging and under the microscope, they behaved like mice with Parkinson’s in many methods of testing. This is all the more novel given that these mice didn’t have any genetic changes that made Parkinson’s more likely – they were ‘ordinary’ mice. Until now animal models of Parkinson’s have been very crude and totally unlike the human form of the pathology (either pure genetic strains or given a toxic compound that causes an ‘instant’ Parkinsons-like picture).
Thirdly, (and leading on from the previous point) with an animal model that is so much more similar to the human form of the disease, it is much more likely that we can identify and try new treatments using this model, that is much more related to human Parkinson’s and therefore much more likely to work for the majority of patients. These treatments need not merely treat the symptoms but genuinely slow, stop or even reverse the condition.
Fourthly (I won’t say finally, because there is so much to unpack from this study), this sheds new light on how Parkinson’s starts, gets to the brain and progresses. The suggestion is that there may be something in the environment that makes its way into individuals and then goes on to cause Parkinson’s. Imagine if we can identify and potentially eliminate that! 

So, for many reasons, this is a truly exciting study, and one that has the potential to revolutionise the field and bring us closer to a cure. One small step for mice, one giant leap for mankind.

The study can be found here.

RNR


Monday 15 April 2019

More PD genes to discover?

Epidemiological studies involving islands have a long and proud history; they always provide fascinating reading and food for thought. In the Faroe islands there were no reported cases of Multiple Sclerosis until 1943 when british troops occupied the islands. After this there was an epidemic of 21 cases. This pattern led to researchers hypothesising that british troops introduced asymptomatic infection to the islands which could be linked to the development of MS. The island of Crete has also been noted to have a rate of sporadic Creutzfeldt-jakob disease that is 5 times the expected numbers for a population of that size. More relevant to Parkinson's is the island of Guam where a peculiar condition that has signs of Parkinson's and a variant of motor neurone disease (called amyotrophic lateral sclerosis) is endemic and not found anywhere else in the world. 

Again in the Faroe islands researchers have noticed that there are twice the number of people living with Parkinson's that you would normally expect for a population of that size. Analysis of the patterns of Parkinson's in families in the Faroe islands indicated that there was probably a genetic cause for this increased number of people with Parkinson's, rather than an environmental cause. But it is not caused by any of the genes we currently know are associated with Parkinson's.

The researchers had the bright idea to follow up people who had migrated from the Faroe islands to Denmark. They found that despite living in Denmark the Faroese migrants still had a much higher chance of developing Parkinson's, even when they had lived in Denmark for more than 10 years! This indicates that either; the underlying environmental factor that is driving this relationship takes place at a much younger age. Alternatively, and much more likely, is that genetics is the cause of this increased prevalence of Parkinson's disease. But the genes causing this are yet to be discovered...





Mov Disord. 2019 Apr 9. doi: 10.1002/mds.27692.
What does migration between the faroe islands and denmark tell us about the etiology of Parkinson's disease?
Petersen MS1,2Lophaven SN3Lynge E4Weihe P1,2.

Friday 22 March 2019

Smelling Parkinson's

In the news this week you might have seen a perplexing story about a lady who can smell Parkinson's! Her husband was diagnosed with Parkinson's and she noticed a strange smell. She only connected the dots when she attended a Parkinson's UK support group and was suddenly surrounded by the smell.

This is not the first report of people being able to smell diseases. Patients with Type 1 diabetes whose sugars have gone very high and blood acidic start to smell like pear drops. There are many reports of nurses who can smell specific types of bacteria.

This phenomena is not limited to humans either! One of my colleagues at medical school presented on the fascinating topic of animals that can smell diseases which included rats which can smell tuberculosis and dogs which can smell cancer. (Also a non-smell related one but equally interesting is that pidgeons can be trained to identify breast cancer on mammograms and pathology slides)

Joy Milne was given 12 t shirts to smell, 6 had been worn by Parkinson's patients and 6 were from people without Parkinson's. She correctly identified the 6 people with Parkinson's and also thought that one of the healthy controls had the smell as well, this person was subsequently diagnosed with Parkinson's so she had 100% accuracy at smelling Parkinson's.

From a scientific point of view, there must be a particular chemical that she is smelling and she has been working with a team in Manchester to try to identify the chemical that she is smelling. Fortunately they have found two chemicals that could be the source of this smell. This is a really important finding because it can lead to a potential quick test to diagnose Parkinson's. This test could even be used to diagnose Parkinson's earlier.




Discovery of volatile biomarkers of Parkinson’s disease from sebum
Drupad K Trivedi, Eleanor Sinclair, Yun Xu, Depanjan Sarkar, Camilla Liscio, Phine Banks, Joy Milne, Monty Silverdale, Tilo Kunath, Royston Goodacre, Perdita Barran
Parkinson’s disease (PD) is a progressive, neurodegenerative disease that presents with significant motor symptoms, for which there is no diagnostic test. We have serendipitously identified a hyperosmic individual, a ‘Super Smeller’ that can detect PD by odor alone, and our early pilot studies have indicated that the odor was present in the sebum from the skin of PD subjects. Here, we have employed an unbiased approach to investigate the volatile metabolites of sebum samples obtained noninvasively from the upper back of 64 participants in total (21 controls and 43 PD subjects). Our results, validated by an independent cohort, identified a distinct volatiles-associated signature of PD, including altered levels of perillic aldehyde and eicosane, the smell of which was then described as being highly similar to the scent of PD by our ‘Super Smeller’

Monday 18 March 2019

Crying out for a new biomarker

The hunt for a biomarker for Parkinson's has led researchers to investigate a lot of different bodily fluids and techniques! A biomarker is a test that can diagnose Parkinson's, at the moment the only way to diagnose Parkinson's is by using your eyes and your ears. Previously people have tested blood, CSF (the fluid around your brain), skin, saliva, MRI scans, skin samples and even samples of colon. But this pilot study is about a potential location for a biomarker that I had not yet heard of: Tears.

Its well known already that people with Parkinson's have reduced amounts of tears and a lower blink rate. And the researchers point out the the nerves that control the tear gland (lacrimal gland) connect to the brainstem. The brainstem is where a lot of the changes in early Parkinson's take place.

In this study they took 36 people with Parkinson's and 18 healthy people without Parkinson's and collected their tears by using some filter paper to absorb them. They then extracted the proteins from the collected tears.

They found that the Parkinson's participants had a smaller volume of tears but the protein concentration in the tears was about the same as healthy controls. They also identified 21 proteins that people with Parkinson's had significantly higher amounts of and 19 that were significantly reduced in Parkinson's too.

This is only a very small pilot study so we need some further studies in larger groups of patients before we draw any conclusions. But tears are a very attractive biomarker simply because they are so accessible. So this is definitely one to keep in mind and watch out for any further studies about.





Parkinsonism Relat Disord. 2019 Mar 6. pii: S1353-8020(19)30094-X. doi:
Proteomic analysis of tear fluid reveals disease-specific patterns in patients with Parkinson's disease - A pilot study.
Boerger M1Funke S2Leha A3Roser AE4Wuestemann AK5Maass F6BĂ€hr M7Grus F8Lingor P9.
Abstract
BACKGROUND:
The diagnosis of Parkinson's disease (PD) is still challenging and biomarkers could contribute to an improved diagnostic accuracy. Tear fluid (TF) is an easily accessible body fluid reflecting pathophysiological changes in systemic and ocular diseases and is already used as a biomarker source for several ophthalmological disorders. Here, we analyzed the TF of patients with PD and controls (CTR) to describe disease-related changes in TF and identify putative biomarkers for the diagnosis of PD.
METHODS:
Unstimulated TF samples of a pilot cohort with 36 PD patients and 18 CTR were collected via Schirmer tear test strips and then analyzed via a Bottom-up liquid chromatography electrospray ionization tandem mass spectrometry (BULCMS) workflow, followed by functional analysis encompassing protein-protein interaction as well as cellular component and pathway analysis.
RESULTS:
BULCMS analysis lead to the identification of 571 tear proteins (false discovery rate, FDR < 1%), whereby 31 proteins were exclusively detected in the PD group and 7 only in the CTR group. Whereas 21 proteins were significantly increased in the PD versus CTR groups, 19 proteins were significantly decreased. Core networks of proteins involved in immune response, lipid metabolism and oxidative stress were distinctly altered in PD patients.
CONCLUSIONS:
To our best knowledge, this is the first description of TF proteome in PD patients. Tear protein level alterations suggest the contribution of different disease-related mechanisms in ocular pathology in PD and propose candidate proteins to be validated as potential biomarkers in larger cohorts.

Wednesday 6 March 2019

PLAIN ENGLISH: Organ transplants and risk of Parkinson's


This is another interesting study borne out of large USA health insurance databases (Medicare database). The team from Washington noticed, whilst using the same data to see if they could identify people at high risk of Parkinson’s, that people with Parkinson’s were less likely to have received an organ transplant than someone without Parkinson’s. This implies that people who have had organ transplants have a reduced risk of Parkinson’s. They decided to investigate this further because it could important implications in developing a medication to prevent Parkinson’s.

They identified 94,155 people with Parkinson’s and then they randomly selected 118,295 people without Parkinson’s in a similar age group. Overall 278 people with Parkinson’s had also had a tissue transplant and 302 of the people without Parkinson’s had a tissue transplant. They found that the odds of having Parkinson’s after a tissue transplant were reduced.

It’s unclear what is causing this effect but one of the possibilities is the medication that transplant patients are on. People who have received transplants are usually started on medication that lowers the body’s immune system to prevent the body rejecting the transplant. It is possible that these medications could be protecting the brain in some way from Parkinson’s. Unfortunately we cannot be sure at the moment and more research is needed to understand the science underlying this!



Parkinsonism Relat Disord. 2019 Feb 14. pii: S1353-8020(19)30059-8. doi: 10.1016/j.parkreldis.2019.02.013. [Epub ahead of print]

Transplant and risk of Parkinson disease.
Fan J1Searles Nielsen S2Faust IM3Racette BA4.
Author information
Abstract
INTRODUCTION:
The pathophysiology of Parkinson's disease (PD) remains unclear, but growing evidence supports a role of neuroinflammation. The purpose of this study was to investigate the association between tissue transplantation and PD risk, given the importance of immunosuppressants in post-transplant management.
METHODS:
We performed a case-control study among Medicare beneficiaries age 66-90 using claims from 2004 to 2009. We used International Classification of Diseases, Ninth Edition (ICD-9) and Current Procedural Terminology (CPT) codes to identify PD (89,790 incident cases, 118,095 population-based controls) and history of tissue transplant (kidney, heart, liver, lung, and bone marrow). We investigated risk of PD in relation to tissue transplant in logistic regression models, adjusting for age, sex, race, smoking, and overall use of medical care.
RESULTS:
Beneficiaries who had received a tissue transplant at least five years prior to PD diagnosis or reference had a lower risk of PD (odds ratio [OR] 0.63, 95% confidence interval [CI] 0.53, 0.75) than those without tissue transplant. This inverse association was observed for kidney (OR 0.63, 95% CI 0.47, 0.84), heart (OR 0.58, 95% CI 0.40, 0.83), lung (OR 0.41, 95% CI 0.21, 0.77), and bone marrow (OR 0.57, 95% 0.38, 0.85) transplants. Associations were attenuated, but remained, following adjustment for indications for the respective type of transplant. Liver transplant was not associated with PD risk.
CONCLUSIONS:
Patients undergoing tissue transplant may have a lower risk of developing PD than the general population. Further studies are needed to determine if this association is causal and if immunosuppressants mediate this association.

Friday 1 March 2019

The Parkinson’s Drug Trial: A Miracle Cure?


I’m sure many of you have seen the programme about a landmark Parkinson’s study, that was aired on the BBC last night (28th February 2019). It is a very well-produced fly-on-the-wall documentary that follows the investigators, inventors and some participants that have pioneered a truly ‘disruptive’ trial. If you haven’t seen it, stop reading and watch now (UK readers only).

The inimitable Tom Isaacs, who was one of the first patients into the study, and who's charity the Cure Parkinson's Trust funded this study.


What made it so unique – after all, there are thousands of drug studies that take place across the UK every day. Usually a study is designed to test one thing – most often a drug. In this study, they didn’t just test if the new drug worked. They had to invent new hardware – that needed to be tested. They had to invent a new kind of brain surgery – that needed to be tested. They had to persuade fairly risk-averse regulatory bodies and ethics panels that doing all three, together, at once was fair, safe and acceptable. Regardless of the outcomes of the study, I can only marvel at the courage and dedication shown by every person involved, from the chief investigator and the whole study team, to each and every participant and their families. Medicine usually progresses by small evolution, this study was a major revolution.


So what did the study show? ***Spoiler alert*** (The second part of the documentary is due to be aired next week. Here I will review the peer-reviewed scientific data that was published in two papers this year)

The one sentence summary from the first paper might, on the surface, appear to indicate defeat, “At the 40-week point, however, we have not shown clinical benefit despite this putamen-wide tissue engagement.” However, despite the headline ‘failure’, there is so much to celebrate.
Firstly, the managed to recruit (in fact, for 42 study ‘spots’, they had over 200 people volunteer). This is no small challenge, especially when there is the very real risk of making people worse off, and asking people with Parkinson’s to travel to Bristol every month for nearly a year.
Secondly, they proved that the hardware and surgery worked, and worked safely. 
Image from BBC.com
Thirdly, and very importantly, they showed that after 40 weeks, there was no change in the dopamine-scan in those who’d had placebo; but in the GDNF group there was a marked change that took the appearances back to those expected at the early stage of Parkinson’s. Bear in mind that on average, the participants had had symptoms of Parkinson’s for over 10 years, and in some for well over 15 years!


Fourthly, at the end of 40 weeks, no patients in the placebo group had movement scores that improved by 10 or more points. However, 9 out of the 17 participants given GDNF improved by between 10 and 16 points. This was not only statistically significant (albeit as a post hoc analysis), but most definitely clinically significant.
So what else can be said? Well, firstly, there was a very strong placebo effect. At one point in the film, the mother of one of the participants says, “To have a huge operation like that, and then have to have a placebo. Is that human? Not really, is it!” The BBC have produced a very good summary on the placebo (and nocebo) effects. The fact that the placebo group did improve so much, means that there is much less of a difference between the two groups. This doesn’t necessarily mean that the GDNF didn’t work, it means that the effect is ‘lost’ in the statistical analysis. 
Furthermore, the numbers in the study were very small, with only 41 patients in total, (21 GDNF, 20 placebo.) This further reduces the chance of finding statistical differences.

A - model showing the novel equipment that was designed and made specifically for this study. B - the port that participants lived with, with which they were 'hooked up' to treatment. C - brain scan showing that the drug delivery worked exactly where it needed to. D - patient sat being infused with treatment via the 'head port'. E - A (not-so) ordinary infusion suite. (image from linked Brain paper)

After the original 40 week study, both groups continued to get another 40 weeks treatment, this time with everyone getting the GDNF. At the end of this phase, there was still no overall group differences from the very beginning to the very end between those who had 80 weeks vs 40 weeks of GDNF treatment, in terms of the movement scores off all treatment. However, those who’d had GDNF all along had fewer increases in their regular medication (to a tune of nearly 5 tablets-worth per day (59mg vs 289mg)). There was also ongoing improvement in the ability to do daily activities in those having GDNF for 80 weeks, and a continued improvement in the proportion of the day when the medication was working well.
There are several other factors that need to be borne in mind. The study cost £3m. Divided over each of the participants amounts to over £73,000 per person. Although this seems like a lot, the actual treatment cost, should this every come to clinical practice would likely be much lower, as it includes all the extra costs associated with running a complex clinical trial. Furthermore, if GDNF is ultimately shown to slow the progression of the condition, if it means that someone maintains their independence and can either carry on working (and paying tax), or stay in their own home independently, rather than take early retirement or move to a nursing home, this really is small change – and when you factor in Quality of Life benefits, must surely be a price worth paying.
Finally (and thank you for bearing with me to this point), all these patients had a diagnosis of Parkinson’s disease for around 8 years. This means that they had the pathology for approaching 20 years. Many were profoundly affected by their symptoms. To use a metaphor I’ve used previously on this blog, it is easier to blow out a match than fight a forest fire. The brain of someone with advanced Parkinson’s is vastly more effected than at the early, or even pre-symptomatic stages. Any restorative attempts are far more likely to work if you can catch it early and intervene early. This is the overwhelming conclusion from treating infections and the whole concept of cancer treatment. 
Hopefully, you and your friends will help us reach that goal with Parkinson’s. You can do your bit by helping us to identify the very earliest phase of Parkinson’s: www.predictpd.com. Taking part involves 25 minutes in front of your own computer at home, and certainly doesn’t pose any of the risks that this study did!
As a final note, I would like to say that this programme reminded me how much of a privilege it is to look after people with Parkinson’s in the clinics of the Royal Free and Luton & Dunstable Hospital; how much of a privilege it is to be at the forefront of Parkinson’s research, funded by Parkinson’s UK, and how much this motivates me while training for the London Landmarks half-marathon and Virgin Money London Marathon.
RNR 

Mild Parkinsonian Signs in a Community Population

One question that many of the PREDICT-PD participants ask me is “I am slower than I used to be, does it mean that I am getting Parkinson’...