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. 

https://www.ncbi.nlm.nih.gov/pubmed/32310187?dopt=Abstract

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

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 M¹, Funke S², Leha A³, Roser AE⁴, Wuestemann AK⁵, Maass F⁶, Bähr M⁷, Grus F⁸, Lingor 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.

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 J¹, Searles Nielsen S², Faust IM³, Racette 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.

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 (28^th 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 

Great Debates

While there are many great debates happening this week in the UK, perhaps the most interesting happened at today’s biannual meeting of the Association of British Neurologists Movement Disorders Special Interest Group, held in the beautiful Oxford Town Hall. The opening session of the meeting was a debate between two giants of the international Parkinson’s world: Professor Donald Grosset from Glasgow, and Professor Ron Postuma from Montreal.

The topic they were debating was “Should research focus on prodromal disease prevention or improving symptomatic therapies?” Professor Grosset set out the reasons for focussing on better treatments in the complex phase of the disease – when the treatments that we have either fail to work or side effects become increasingly troublesome and diffucult to manage. He also pointed out the near-total lack of well-proven treatments for many of the non-motor aspects of Parkinson’s (a point we have laboured in previous blog posts here). He suggested that detection of the prodromal stage was hit-and-miss and that the best case scenario was that trials in this group would costs hundreds of millions of pounds which would be better served investing in treatments for people with definite Parkinson’s.

Ron Postuma countered his argument and opened with the metaphor central to preventive medicine: people are falling over a waterfall and nearly drowning in the pool below. A man is pulling them out one by one and calls to a bystander to help. The bystander walks away, but returns at the top of the waterfall to stop people from falling down in the first place. Although  this metaphor may seem simplistic, it highlights the importance of focussing on the earliest stages. He went on to simplify the drug treatment of established Parkinson’s as “playing with neurotransmitters” – and no matter how successful one might be at doing that, there is an underlying progression of brain death. To deal with that means to effect a change before disease causing cascade of events has become unstoppable – i.e. in the earliest (prodromal) stages. Finally, he highlighted the seismic changes that have occurred in medicine in the last two generations. Penicillin used to be so expensive that patients given penicillin had their urine collected, the excreted penicillin extracted and given back to the patients to make each vial go further. Wards for women with infected wombs after miscarriages who would almost inevitably succumb to their infections closed within weeks. The AIDS wards that were in most hospitals in the 70s and 80s were empty just a few years after HIV medication started being used. New treatments for advanced cancer have changed the landscape for some of these diseases (including nilotonib which is currently being trialed in Parkinson’s), and the last two years has brought these game-changing experiences to neurological diseases with drugs such as Nucinercin – effectively curing an incurable genetic condition that killed children in their first few years. The message, he said, was clear – things we now take for granted were once hard and very expensive, and for Parkinson’s there is change on the horizon.

The rest of the meeting continued with many other fascinating and useful talks from some of the leaders of British neurology, and has offered many insights and ideas that we at Predict-PD can use to help bring us closer to a robust identificaiton of prodromal Prkinson’s and therefore, another step closer to a cure.

RNR

PLAIN ENGLISH: Gout and the risk of Parkinson's disease in older adults

First blog post of the year from me and, after feedback from literally everyone, I will be making a concerted effort to make them easy (easier) to understand. I can't get rid of the science I'm afraid... after all this is a research blog. But I (and we) can make bigger efforts to keep the focus on predicting Parkinson's, the PREDICT-PD study (predictpd.com) and related projects. 

The reason this blog was started was to help researchers, patients and the public understand how we use and weigh emerging research, which in turn informs our approach to our work on Parkinson's.

Take this study as an example... it looked at health insurance claims data from the USA over a 6 year period. The researchers looked at the link between claims for gout and subsequent claims for Parkinson's. They observed that, compared to people that made claims for other illnesses, people that claimed for gout were more likely to claim for Parkinson's in subsequent years. This in turn offers a weak suggestion that gout might be in some way linked with a higher risk of Parkinson's. However... we also know that this is only part of a much bigger story.

The biggest determinant of gout is the amount of a chemical in the blood known as uric acid. Generally speaking, people with higher levels of uric acid are more likely to have gout. It has also been noted on multiple occasions that people with Parkinson's tend to have lower levels of uric acid (both after diagnosis and in the years before)... which in turn has led to strategies to try and boost uric acid levels to treat Parkinson's (without introducing gout). 

So how does that make any sense at all?? High uric acid is associated with an increase in gout, gout is associated with an increase of Parkinson's, but Parkinson's is associated with low uric acid levels...?? We seem to be going in circles. 

But what if the explanation is simple... what if Parkinson's disease consumes uric acid and makes it look like low levels of uric acid are causing Parkinson's, when in fact it is the other way around? There have been similar examples in cancer where vitamin E was noted to be low in people that had prostate cancer, leading to the suggestion of supplementing vitamin E to reduce cancer. Instead the cancer rates appeared to increase... so it wasn't that low vitamin E was causing cancer... it was cancer consuming vitamin E and supplementing vitamin E only added more fuel to the fire.

If for some reason Parkinson's consumes uric acid, then gout may actually increase the risk of being diagnosed with Parkinson's and strategies to boost uric acid to treat or protect against Parkinson's may not lead to benefit and have the opposite effect...

Of course, this is speculation and certainly not the final say on the matter. Further research will likely reveal the truth over time...

- Alastair Noyce


BMC Neurol. 2019 Jan 5;19(1):4. doi: 10.1186/s12883-018-1234-x.
Singh JA, Cleveland JD.

BACKGROUND: In the presence of limited available data, our objective was to assess the association of gout with the risk of incident Parkinson's disease (PD) in adults 65 years or older.

METHODS: We used the 5% random sample of Medicare claims data from 2006 to 2012 to examine the association of gout with incident PD. The multivariable Cox regression model adjusted for demographics, comorbidity, and common cardiovascular disease and gout medications. We calculated hazard ratios (HR) and 95% confidence interval (CI). Sensitivity analyses adjusted for comorbidity categorically, or individually and for additional cardiovascular comorbidities.

RESULTS: In a cohort study, 1.72 million Medicare beneficiaries were eligible. The mean age was 75 years (standard deviation [SD], 7.6), 58% were female, 86% were White and 37% had Charlson-Romano comorbidity index score of ≥2. We found that 22,636 people developed incident PD, 1129 with gout and 21,507 without gout. The respective crude incidence rates of incident PD were 3.7 vs. 2.2 per 1000 person-years. We found that gout was associated with 1.14-times higher hazard ratio (95% CI, 1.07, 1.21) of PD in the main analysis; findings were confirmed in sensitivity analyses. We noted that the risk differed slightly by age; ages 65-75, 75-85 and > 85 had hazard ratios of incident PD with gout of 1.27 (95% CI, 1.16, 1.39), 1.07 (95% CI, 0.97, 1.16) and 0.97 (95% CI, 0.79, 1.20), respectively, but no gender or race differences were noted.

CONCLUSIONS: Gout was associated with a higher risk of incident PD in older adults, with the risk being significant in the age group 65-75 years. Future studies need to assess the mechanisms of this increased risk.

The prodromes of Parkinson's

Following on nicely from our last post, we are delighted to publicise our latest peer-reviewed publication.

This will come out in a special edition of the European Journal of Neuroscience, dedicated to the memory of Tom Isaacs. Tom was the founder and leader of the Cure Parkinson's Trust - a truly dynamic leader and a real disruptive presence (in all the right ways) within  Parkinson's research. We are honoured to have our names and our ideas as testimonial to him in this way.

It is clear that Parkinson's is more of an umbrella condition than one single entity. For instance, some people have significant tremor, while others have none. Some progress very slowly, and a decade from diagnosis have barely any more symptoms - others progress more quickly. For many Parkinson's affects mainly movement while others have many non-motor symptoms. It is likely (although not yet proven) that these different subtypes of Parkinson's have a different underlying process causing them.

It therefore stands to reason that the earliest phases are also different. In our article we lay out the evidence that Parkinson's that comes from people with a particular kind of sleep disorder (REM sleep behavioural disorder), smell loss, and genetic forms do all look different. The evidence is not bomb-proof, but in Predict-PD we will be able to shed light on both the sleep disorder, smell loss and try and pick apart differences in the general population.

To see the article, please see the journal website. Please also remember to talk to friends and family to read more about the study and sign up themselves: www.predictpd.com

RNR

Why does Parkinson's cause constipation?

When people think of Parkinson's disease they often think of tremors however often people who actually have Parkinson's are more concerned by the symptoms that are not to do with movement and tremors (non-motor symptoms). The commonest of these symptoms are constipation, tiredness, difficulty sleeping, anxiety and needing to pass urine multiple times at night. These symptoms are not always as immediately obvious to people without Parkinson's but they can be extremely troubling. In this blog I want to talk a bit more about constipation and why people with Parkinson's get constipation.

Constipation is when it is more difficult to go for a poo or when the amount of time between opening your bowels increases. Usually your poo will become a lot harder when this happens and sometimes can result in a bloated feeling and pain in your tummy. So the question is how does Parkinson's, a brain disease, affect your bowels in this way?

The answer lies in looking at the large intestine. This is a large pipe near the end of the path from your mouth to your bum (the GI tract). By the time your dinner reaches the large colon it has mainly been digested and had all of the useful vitamins, protein and carbohydrates removed from it. This means that when your dinner reaches the large colon it is made up of waste products (poo) and lots of water; in fact it is so watery at this point that it is completely liquid. The role of the large colon is to turn this liquid into a solid poo and to get the water out of it so that you can stay hydrated. So what changes in Parkinson's disease?

In Parkinson's disease if you measure the amount of time it takes a piece of food to move from the beginning of the large intestine to exiting out of your bum it would take double the amount of time that it would take a healthy person. In other words: poo moves through the large intestine at half the speed if you have Parkinson's. Because the large intestine is so good at draining water from your poo, the poo becomes much drier and harder as the large intestine has double the amount of time to remove as much water as possible. This explains why people with Parkinson's have drier harder poos and subsequently have more constipation.

The large intestine pushes food along it by tensing the muscles around it in a rhythmic way that propels the poo downstream. Like the rest of the body, in Parkinson's, these movements become much slower. The reason for this is not as clear but is probably due to the layer of nerve cells around the gut wall called the enteric nervous system. Studies where they have looked at samples of the gut wall have found build ups of Lewy Bodies (the characteristic thing found in the brain in Parkinson's) also in the gut wall. It is possible that this build up is what also causes the slowness in the gut.

It is important to remember that there are many other things that cause constipation other than Parkinson's. There are many medications that can be tried to help improve constipation but some of the simple things that can help are increasing the amount of water you drink or increasing the amount of fibre that you eat, but discuss with your doctor if this is a problem for you.

Curr Treat Options Neurol. 2018 Oct 25;20(12):54. doi: 10.1007/s11940-018-0539-9.

Gastrointestinal Dysfunction in Parkinson's Disease.

Pfeiffer RF

Author information

Abstract

PURPOSE OF REVIEW:

During the past 25 years, there has been an explosion of information regarding the occurrence of gastrointestinal dysfunction in Parkinson's disease. In this review, the clinical features of gastrointestinal dysfunction in Parkinson's disease will be described and information regarding the potential role of the enteric nervous system and the gut microbiome in the genesis of Parkinson's disease will be addressed.

RECENT FINDINGS:

Recognition is growing regarding the role that gastroparesis and small intestinal dysfunction may play in Parkinson's disease, especially with regard to erratic responses to anti-Parkinson medication. The presence of enteric nervous system involvement in Parkinson's disease is now well established, but whether the enteric nervous system is the starting point for Parkinson's disease pathology remains a source of debate. The potential role of the gut microbiome also is beginning to emerge. Gastrointestinal dysfunction is a prominent nonmotor feature of Parkinson's disease and dysfunction can be found along the entire length of the gastrointestinal tract. The enteric nervous system is clearly involved in Parkinson's disease. Whether it is the initial source of pathology is still a source of controversy. There also is growing recognition of the role that the gut microbiome may play in Parkinson's disease, but much more research is needed to fully assess this aspect of the disorder.

PLAIN ENGLISH: Does removal of the appendix impact the risk of Parkinson's Disease?

Multiple large news organisations yesterday were reporting the results of a study showing that people who have had appendectomies (surgical removal of the appendix) have a lower chance of developing Parkinson's disease. Its a neat paper which links large amounts of data from medical databases and histology results (looking at tissue under the microscope) on a much smaller number of patients.

First they looked at the Swedish National Patient Registry, a database of 1,698,000 people followed up for 52 years, and identified anyone who had a history of an appendectomy (551,647 people). They then matched these patients to two 'control' patients who had not had appendectomies but were similar in age, sex and geographical to the original patients. They interestingly found that the chance of having Parkinson's disease was 19.3% lower in the participants with appendectomies than the 'control' participants who had not had appendectomies. They also found that the participants who had appendectomies and developed Parkinson's on average developed Parkinson's 1.6 years later than the Parkinson's patients who still had their appendix. Interestingly this effect was not observed in participants who had known genetic mutations causing their Parkinson's suggesting that if the appendix has any effect on the development of Parkinson's it is only in patients whose Parkinson's has an 'environmental' trigger or cause.

This part of the study was not novel or new and previous similar studies have been done and found no association between appendectomy and PD. In a Canadian study they actually found a higher rate of PD in patients who had appendectomies in the past 5 years. So despite the results of this study being very interesting they are not backed up by previous studies.

The novel part of this study is the histological analysis where the researchers analysed the 48 peoples appendixes under the microscope. These participants did not have PD. The appendixes were analysed under the microscope for clumps of protein which have stuck together that we call 'aggregates of α-syneuclein'. These are the key feature of PD that can be found in PD patients brains at autopsy. In other words the misfolded protein that causes PD when it is seen in the brain can be seen in young, healthy peoples appendix. These misfolded proteins were detected in both young and old people.

There are some problems with this study; first is that in large databases it is very difficult to know the accuracy of the Parkinson's diagnosis and previous studies investigating the reliability of this found only a 70.8% chance that it is reliable. They also only examined the appendix under the microscope and did not check any other tissues to compare.

This study does provide some food for thought; at the end of the paper the authors hypothesise that the appendix is the source of the misfolded protein that then spreads through the gut and up the vagus nerve to the brain thereby causing Parkinson's disease. This gut to brain model of the development of Parkinson's disease is often discussed and is a popular research topic at the moment. However the results of this study should still be taken with a pinch of salt because there are a number of large scale similar studies that precede this study that do not come to the same conclusion, that doesn't stop it being interesting though!

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. 

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

Treatable causes of memory problems in Parkinson's?

Following on from Alastair's post about links between metabolic syndrome and risk of Parkinson's disease, I've been reading this study which looks at a concept related to the metabolic syndrome - vascular risk. Here the authors are interested in how risk factors such as high blood pressure, diabetes and body mass affect people in the early stages of Parkinson's and particularly how they relate to the subtle problems with thinking and memory.

They studied 140 people with early-stage Parkinsons and around 60 healthy people of the same age, who were assessed for vascular risk factors and performance on tests of thinking and memory and followed up for 4 years. These patients and healthy subjects all had MRI scans to look for subtle signs of damage to the brain due to problems with blood vessels.

They looked at links between factors such as diabetes and blood pressure, scores on cognitive tests and the number of areas of abnormalities on MRI. Their first important finding was no difference between areas of abnormality on MRI scan between Parkinson's patients and healthy participants. However, in Parkinson's disease but not healthy people, MRI abnormalities were associated with poor performance on memory tests. Furthermore, the risk score was associated with a deterioration in an overall test of mental processes over time.

There are some issues with this study - in traditional statistics, we set a standard of certainty, which allows for a small amount of error. The more experiments you do, the more chance you will make an error and find a positive result by chance. This study looks at many associations, increasing the risk that some results may not be true.

However, it's particularly important to study these associations due to the fact that factors such as blood pressure and diabetes are treatable with current medications. If these factors play any significant role in memory problems in Parkinson's, we will need to look for them and aggressively treat them from early in the disease. We need to build up an evidence basis for this, looking in more detail for example at the level of blood pressure over which treatment will improve outcomes. In the meantime, it's a good reminder for physicians and patients of the multiple additional potential benefits of managing blood pressure, diabetes and weight.

- anna

https://www.ncbi.nlm.nih.gov/pubmed/30169897?log$=activity

Eur J Neurol. 2018 Aug 31. doi: 10.1111/ene.13797. [Epub ahead of print]

Modifiable Vascular Risk Factors, White Matter Disease, and Cognition in Early Parkinson's Disease

Chahine LM, Dos Santos C, Fullard M, Scordia S, Weintraub D, Erus G, Rosenthal L, Davatzikos C, McMillan CT.

Dementia in Parkinson's Disease (PD) is common and disabling. Identification of modifiable risk factors for it is essential. Vascular risk factors may be associated with cognitive decline in early PD. Biomarkers that serve as surrogates of the long-term effect of vascular risk factors on PD are needed. To that end, we aimed to quantitate white matter hyperintensities in early PD, measure associations with vascular risk factors, and examine relationships between white matter hyperintensities and longitudinal cognition.
Participants in the Parkinson Progression Markers Initiative study (141 PD patients, 63 healthy controls) with adequate baseline structural brain MRIs were included. Hypertension and diabetes history, and body mass index, were combined to create a vascular risk score. White matter hyperintensities were quantitated via automated methods. Cognition was assessed annually with a comprehensive test battery.
Vascular risk score was associated with white matter hyperintensities for total brain (β=0.210;p=0.021), total white matter (β=0.214;p=0.013), frontal (β=0.220;p=0.002) and temporal (β=0.212;p=0.002) regions. Annual rate of change in global cognition was greater in those with higher vascular risk score (β=-0.040;p=0.008) and greater white matter hyperintensities (β=-0.029;p=0.049). Higher temporal white matter hyperintensity burden was associated with great decline over time in verbal memory (β=-0.034;p=0.031).
In early PD, modifiable vascular risk factors are associated with white matter hyperintensities on brain MRI. Temporal white matter hyperintensity burden predicts decline in verbal memory. White matter hyperintensities may serve as a surrogate marker for the effect of vascular risk factors on cognitive abilities in PD. This article is protected by copyright. All rights reserved.

News from the Land of Milk and Honey

I had the good fortune to attend a conference on Precision Medicine and Ageing today. This brought some of the leading scientists from the UK and Israel together, as part of the British Council’s Britain Israel Science and Innovation Network. The day included speakers talking about the latest breakthroughs in genomics, neuroscience, cellular biology and many other fields of scientific endeavour and how they relate to the biology of ageing (in health as well as disease) and how these breakthroughs are bringing us closer to the ‘promised land’ of Personalised, or Precision medicine.

The talk that I found the most interesting came from Dr Maya Leventer-Roberts, from the Clalit Research Institute. This is not a university department, but the in-house research arm of the largest of Israels four health providers. They have an unparallelled treasure-trove of health data. She explained that all Israeli citizens belong to one of these four organisations who provide all aspects of care: GP, pharmacy, testing laboratories, hospitals – you name it. What’s more, very few people change providers, so they have a well-coded database of people’s wellness, illness and health behaviour at all stages of life.

I have since found a paper from last year which uses some of their data to examine a relatively neglected aspect of Parkinson’s – depression. Unfortunatley a huge proportion of people with Parkinson’s struggle with depression. We also know that late onset depression is a risk factor for Parkinson’s. 

In this study, they looked at mortality rates in Parkinson’s and the association with how adherent people were with antidepressents. They analysed the data of 10,000 people with a diagnosis of Parkinson’s as well as at least one prescription of an antidepressant. They then categorised people into how frequently they tookthe antidepressants by comparing their prescriptions from the doctor with the number of purchases of antidepressants from the pharmacies. Finally they looked at death by any cause over the 4 year study period.

They found that the people who had Parkinson’s and depression who took their antidepressants the least were 43% more likely to die within the 4 year period, compared to those who took it the most regularly. The increased mortality was exacerbated by having an increasing number of other medical problems.

I must stress the old adage: association does not equal causation. This kind of retrospective observational study cannot provethat one thing causes another. However, it is an important reminder that depression is an important aspect of Parkinson’s, and that poorly managed depression is associated with increased mortality. It also reminds me that older people, with Parkinson’s, depression and perhaps four or five other medical conditions may be on 15-20 or more tablets a day. What can I do as a clinician to help them remember what each is for, and why each is important to take? What can we do as a society to help people with depression with both drug and non-drug treatment options? How can we better prepare ourselves, individually and societally, for ageing and the only true inevitability of life?

RNR

Shoval G, Stubbs B, Balicer RD, Feldman B, Hoshen M, Zalsman G, et al. 

Low adherence to antidepressants is associated with increased mortality in Parkinson disease patients. 

Parkinsonism Relat Disord. 2017 Oct;43:92–6.

INTRODUCTION:The purpose of this study was to evaluate the relationship between adherence to antidepressants (AD) and all-cause mortality in a population-based cohort of patients with Parkinson's Disease (PD).

METHODS:From a database of more than 4 million people, 8553 patients with PD who purchased an AD at least once between the years 2008-2011 were retrospectively followed for all-cause mortality over 4-years. Adherence was measured as a ratio between dispensed and prescribed durations and was modeled as: non-adherence (<20%, n = 1566), poor (20%-50%, n = 1184), moderate (50%-80%, n = 1584), and good (>80%, n = 4219) adherence. Multivariable survival analyses adjusted for demographic and clinical variables including physical comorbidities known to influence mortality were conducted, however there was no adjustment for other psychiatric disorders and medications.

RESULTS:Unadjusted mortality rates were 20.4%, 25.1%, 23.4% and 25.6% in those classified as non-adherent, poor, moderate and good adherence respectively (χ2 = 18.45, p < 0.0001). The non-adherent and poor adherence groups had significantly increased adjusted mortality hazard ratios (HR) of 1.43 (CI: 1.26-1.62) and 1.26 (CI: 1.1-1.44) respectively compared to the good adherence group. Using the same model, the adjusted HR for death among males was 1.49 [95% CI: 1.36-1.62] compared to females. People with PD and Charslon's Comorbidity Index score of 3-4 (HR 1.3, P < 0.001) and 5+ (HR 1.78, P < 0.001) were more likely to die than those with 0-2 comorbidities.

CONCLUSIONS:Our findings suggest that poor adherence to AD is associated with increased all-cause mortality in people with PD. Given the high prevalence of depression and AD effectiveness, efforts to promote adherence should be prioritized in clinical practice.