Recently I was invited to speak at the 6th Annual East Midlands Parkinson’s Research Support Network meeting at the Link Hotel, in Loughborough. The group is organised and run by the local Parkinson’s community and supported by Parkinson’s UK. It was a fantastic event and I was very grateful to the organisers for the invitation.
They kindly gave me two sessions (20 minutes each) which I divided into two talks: “Where we are now with Parkinson’s research?” and “Where we are going with Parkinson’s research?”. Since giving the talk, I have been asked by several attendees if I could make the slides available.
The slides from the first talk can be found by clicking here.
I have also made a video of the first talk with a commentary that I added afterwards. But be warned: my delivery of this second version of the talk is a bit dry. Apologies. It has none of my usual dynamic charm or energetic charisma. Who knew that talking into a dictaphone could leave one sounding so flat.
Anyways, here is the talk – enjoy!
I hope you find it interesting. When I have time I’ll post the second talk.
As the age of personalised medicine approaches, innovative researchers are rethinking the way we conduct clinical studies. “Rethinking” in radical ways – think: individualised clinical trials!
One obvious question is: Can you really conduct a clinical trial involving just one participant?
In this post, we will look at some of the ideas and evaluate the strengths and weaknesses these approaches.
A Nobel prize medal. Source: Motley
In the annals of Nobel prize history, there are a couple winners that stands out for their shear….um, well,…audacity.
One example in particular, was the award given to physician Dr Werner Forssmann. In 1956, Andre Cournand, Dickinson Richards and Forssmann were awarded the Nobel Prize in Physiology or Medicine “for their discoveries concerning heart catheterisation and pathological changes in the circulatory system”. Forssmann was responsible for the first part (heart catheterisation).
In 1929, at the age of 25, Forssmann performed the first human cardiac catheterisation – that is a procedure that involves inserting a thin, flexible tube directly into the heart via an artery (usually in the arm, leg or neck). It is a very common procedure performed on a daily basis in any hospital today. But in 1929, it was revolutionary. And the audacious aspect of this feat was that Forssmann performed the procedure on himself!
And if you think that is too crazy to be true, please read on.
But be warned: this particular story gets really bonkers.
The protein Alpha Synuclein has long been considered the bad-boy of Parkinson’s disease research. Possibly one of the main villains in the whole scheme of things.
New research suggests that it may be interfering with a neuroprotective pathway, leaving the affected cell more vulnerable to stress/toxins. But that same research has highlighted a novel beneficial feature of an old class of drugs: MAO-B inhibitors.
In today’s post we will outline the new research, discuss the results, and look at whether this new Trk warrants a re-think of MAO-B inhibitors.
The great Harry Houdini. Source: Wikipedia
I’m not sure about you, but I enjoy a good magic trick.
That exhilarating moment when you are left wondering just one thing: How do they do that?
(Seriously, at 4:40 a baguette comes out of thin air – how did he do that?)
Widely believed to have been one of the greatest magicians of all time (Source), Harry Houdini is still to this day revered among those who practise the ‘dark arts’.
Born Erik Weisz in Budapest (in 1874), Houdini arrived in the US in 1878. Fascinated with magic, in 1894, he launched his career as a professional magician and drew attention for his daring feats of escape. He renamed himself “Harry Houdini” – the first name being derived from his childhood nickname, “Ehrie,” and the last name paying homage to the great French magician Jean Eugène Robert-Houdin. In 1899, Houdini’s act caught the eye of Martin Beck, an entertainment manager, and from there the rest is history. Constantly upping the ante, his feats became bolder and more death defying.
And the crowds loved him.
From stage, he moved on to film – ultimately starting his own production company, Houdini Picture Corporation. In addition, he was a passionate debunker of psychics and mediums, his training in magic helping him to expose frauds (which turned him against his former friend Sir Arthur Conan Doyle, who believed deeply in spiritualism).
This is all very interesting, but what does any of it have to do with Parkinson’s?
In a recent post, I discussed research looking at foods that can influence the progression of Parkinson’s (see that post here). I am regularly asked about the topic of food and will endeavour to highlight more research along this line in future post.
In accordance with that statement, today we are going to discuss Cruciferous vegetables, and why we need a clinical trial of broccoli.
I’m not kidding.
There is growing research that a key component of broccoli and other cruciferous vegetables – called Glucoraphanin – could have beneficial effects on Parkinson’s disease. In today’s post, we will discuss what Glucoraphanin is, look at the research that has been conducted and consider why a clinical trial of broccoli would be a good thing for Parkinson’s disease.
Cruciferous vegetables. Source: Diagnosisdiet
Like most kids, when I was young I hated broccoli.
Man, I hated it. With such a passion!
Usually they were boiled or steamed to the point at which they have little or no nutritional value, and they largely became mush upon contact with my fork.
The stuff of my childhood nightmares. Source: Modernpaleo
As I have matured (my wife might debate that statement), my opinion has changed and I have come to appreciate broccoli. Our relationship has definitely improved.
In fact, I have developed a deep appreciation for all cruciferous vegetables.
And yeah, I know what you are going to ask:
What are cruciferous vegetables?
Cruciferous vegetables are vegetables of the Brassicaceae family (also called Cruciferae). They are a family of flowering plants commonly known as the mustards, the crucifers, or simply the cabbage family. They include cauliflower, cabbage, garden cress, bok choy, broccoli, brussels sprouts and similar green leaf vegetables.
Cruciferous vegetables. Source: Thetherapyshare
So what have Cruciferous vegetables got to do with Parkinson’s?
Well, it’s not the vegetables as such that are important. Rather, it is a particular chemical that this family of plants share – called Glucoraphanin – that is key.
What is Glucoraphanin?
The motor features of Parkinson’s disease can be managed with treatments that replace the chemical dopamine in the brain.
While there are many medically approved dopamine replacement drugs available for people affected by Parkinson’s disease, there also are more natural sources.
In today’s post we will look at the science and discuss the research supporting one of the most potent natural source for dopamine replacement treatment: Mucuna pruriens
When asked by colleagues and friends what is my ‘plan B’ (that is, if the career in academia does not play out – which is highly probable I might add – Click here to read more about the disastrous state of biomedical research careers), I answer that I have often considered throwing it all in and setting up a not-for-profit, non-governmental organisation to grow plantations of a tropical legume in strategic places around the world, which would provide the third-world with a cheap source of levodopa – the main treatment in the fight against Parkinson’s disease.
Plan B: A legume plantation. Source: Tropicalforages
The response to my answer is generally one of silent wonder – that is: me silently wondering if they think I’m crazy, and them silently wondering what on earth I’m talking about.
As romantic as the concept sounds, there is an element of truth to my Plan B idea.
I have read many news stories and journal articles about the lack of treatment options for those people with Parkinson’s disease living in the developing world.
Hospital facilities in the rural Africa. Source: ParkinsonsLife
Some of the research articles on this topic provide a terribly stark image of the contrast between people suffering from Parkinson’s disease in the developing world versus the modernised world. A fantastic example of this research is the work being done by the dedicated researchers at the Parkinson Institute in Milan (Italy), who have been conducting the “Parkinson’s disease in Africa collaboration project”.
The researchers at the Parkinson Institute in Milan. Source: Parkinson Institute
The project is an assessment of the socio-demographic, epidemiological, clinical features and genetic causes of Parkinson’s disease in people attending the neurology out-patients clinic of the Korle Bu Teaching and Comboni hospitals. Their work has resulted in several really interesting research reports, such as this one:
Title: The modern pre-levodopa era of Parkinson’s disease: insights into motor complications from sub-Saharan Africa.
Authors: Cilia R, Akpalu A, Sarfo FS, Cham M, Amboni M, Cereda E, Fabbri M, Adjei P, Akassi J, Bonetti A, Pezzoli G.
Journal: Brain. 2014 Oct;137(Pt 10):2731-42.
PMID: 25034897 (This article is OPEN ACCESS if you would like to read it)
In this study, the researchers collected data in Ghana between December 2008 and November 2012, and each subject was followed-up for at least 6 months after the initiation of Levodopa therapy. In total, 91 Ghanaians were diagnosed with Parkinson’s disease (58 males, average age at onset 60 ± 11 years), and they were compared to 2282 Italian people with Parkinson’s disease who were recruited during the same period. In long-term follow up, 32 Ghanaians with Parkinson’s disease were assessed (with an average follow period of 2.6 years).
There are some interesting details in the results of the study, such as:
- Although Levodopa therapy was generally delayed – due to availability and affordability – in Ghana (average disease duration before Levodopa treatment was 4.2 years in Ghana versus just 2.4 years in Italy), the actual disease duration – as determined by the occurrence of motor fluctuations and the onset of dyskinesias – was similar in the two populations.
- The motor fluctuations were similar in the two populations, with a slightly lower risk of dyskinesias in Ghanaians.
- Levodopa daily doses were higher in Italians, but this difference was no longer significant after adjusting for body weight.
- Ghanaian Parkinson’s sufferers who developed dyskinesias were younger at onset than those who did not.
Reading these sorts of research reports, I am often left baffled by the modern business world’s approach to medicine. I am also left wondering how an individual’s experience of Parkinson’s disease in some of these developing nations would be improved if a cheap alternative to the dopamine replacement therapies was available.
Are any cheap alternatives available?
In addition to looking at current Parkinson’s disease research on this website, I like to look at where technological advances are taking us with regards to future therapies.
In July of this year, I wrote about a new class of engineered viruses that could potentially allow us to treat conditions like Parkinson’s disease using a non-invasive, gene therapy approach (Click here to read that post). At the time I considered this technology way off at some point in the distant future. Blue sky research. “Let’s wait and see” – sort of thing.
So imagine my surprise when an Italian research group last weekend published a new research report in which they used this futurist technology to correct a mouse model of Parkinson’s disease. Suddenly the distant future is feeling not so ‘distant’.
In today’s post we will review and discuss the results, and look at what happens next.
Technological progress – looking inside the brain. Source: Digitial Trends
I have said several times in the past that the pace of Parkinson’s disease research at the moment is overwhelming.
So much is happening so quickly that it is quite simply difficult to keep up. Not just here on the blog, but also with regards to the ever increasing number of research articles in the “need to read” pile on my desk. It’s mad. It’s crazy. Just as I manage to digest something new from one area of research, two or three other publications pop up in different areas.
But it is the shear speed with which things are moving now in the field of Parkinson’s research that is really mind boggling!
Take for example the case of Squalamine.
In February of this year, researchers published an article outlining how a drug derived from the spiny dogfish could completely suppress the toxic effect of the Parkinson’s associated protein Alpha Synuclein (Click here to read that post).
The humble dogfish. Source: Discovery
And then in May (JUST 3 MONTHS LATER!!!), a biotech company called Enterin Inc. announced that they had just enrolled their first patient in the RASMET study: a Phase 1/2a randomised, controlled, multi-center clinical study evaluating a synthetic version of squalamine (called MSI-1436) in people with Parkinson’s disease. The study will enrol 50 patients over a 9-to-12-month period (Click here for the press release).
Wow! That is fast.
Yeah, I thought so too, but then this last weekend a group in Italy published new research that completely changed my ideas on the meaning of the word ‘fast’. Regular readers will recall that in July I discussed amazing new technology that may one day allow us to inject a virus into a person’s arm and then that virus will make it’s way up to the brain and only infect the cells that we want to have a treatment delivered to. This represents non-invasive (as no surgery is required), gene therapy (correcting a medical condition with the delivery of DNA rather than medication). This new study used the same virus we discussed in July.
In my previous post, we briefly reviewed the results of the phase II double-blind, randomised clinical trial of Exenatide in Parkinson’s disease. The study indicates a statistically significant effect on motor symptom scores after being treated with the drug.
Over the last few days, there have been many discussions about the results, what they mean for the Parkinson’s community, and where things go from here, which have led to further questions.
In this post I would like to address several matters that have arisen which I did not discuss in the previous post, but that I believe are important.
I found out about the Exenatide announcement – via whispers online – on the afternoon of the release. And it was in a mad rush when I got home that night that I wrote up the post explaining what Exenatide is. I published the post the following evening however because I could not access the research report from home (seriously guys, biggest finding in a long time and it’s not OPEN ACCESS?!?!?) and I had to wait until I got to work the next day to actually view the publication.
I was not really happy with the rushed effort though and decided to follow up that post. In addition, there has been A LOT of discussion about the results over the weekend and I thought it might be good to bring aspects of those different discussion together here. The individual topics are listed below, in no particular order of importance:
1. Size of the effect
There are two considerations here.
Firstly, there have been many comments about the actual size of the effect in the results of the study itself. When people have taken a deeper look at the findings, they have come back with questions regarding those findings.
And second, there have also been some comments about the size of the effect that this result has already had on the Parkinson’s community, which has been considerable (and possibly disproportionate to the actual result).
The size of the effect in the results
The results of the study suggested that Exenatide had a positive effect on the motor-related symptoms of Parkinson’s over the course of the 60 week trial. This is what the published report says, it is also what all of the media headlines have said, and it sounds really great right?
The main point folks keep raising, however, is that the actual size of the positive effect is limited to just the motor features of Parkinson’s disease. If one ignores the Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores and focuses on the secondary measures, there isn’t much to talk about. In fact, there were no statistically significant differences in any of the secondary outcome measures. These included:
For many people diagnosed with Parkinson’s disease, one of the scariest prospects of the condition that they face is the possibility of developing dyskinesias.
Dyskinesias are involuntary movements that can develop after long term use of the primary treatment of Parkinson’s disease: Levodopa
In todays post I discuss one experimental strategy for dealing with this debilitating aspect of Parkinson’s disease.
Dyskinesia. Source: JAMA Neurology
There is a normal course of events with Parkinson’s disease (and yes, I am grossly generalising here).
First comes the shock of the diagnosis.
This is generally followed by the roller coaster of various emotions (including disbelief, sadness, anger, denial).
Then comes the period during which one will try to familiarise oneself with the condition (reading books, searching online, joining Facebook groups), and this usually leads to awareness of some of the realities of the condition.
One of those realities (especially for people with early onset Parkinson’s disease) are dyskinesias.
What are dyskinesias?
Dyskinesias (from Greek: dys – abnormal; and kinēsis – motion, movement) are simply a category of movement disorders that are characterised by involuntary muscle movements. And they are certainly not specific to Parkinson’s disease.
As I have suggested in the summary at the top, they are associated in Parkinson’s disease with long-term use of Levodopa (also known as Sinemet or Madopar).
Sinemet is Levodopa. Source: Drugs
Two months ago a research report was published in the scientific journal ‘Nature’ and it caused a bit of a fuss in the embryonic stem cell world.
Embryonic stem (ES) cells are currently being pushed towards the clinic as a possible source of cells for regenerative medicine. But this new report suggested that quite a few of the embryonic stem cells being tested may be carrying genetic variations that could be bad. Bad as in cancer bad.
In this post, I will review the study and discuss what it means for cell transplantation therapy for Parkinson’s disease.
For folks in the stem cell field, the absolute go-to source for all things stem cell related is Prof Paul Knoepfler‘s blog “The Niche“. From the latest scientific research to exciting new stem cell biotech ventures (and even all of the regulatory changes being proposed in congress), Paul’s blog is a daily must read for anyone serious about stem cell research. He has his finger on the pulse and takes the whole field very, very seriously.
For a long time now, Paul has been on a personal crusade. Like many others in the field (including yours truly), he has been expressing concern about the unsavoury practices of the growing direct-to-consumer, stem cell clinic industry. You may have seen him mentioned in the media regarding this topic (such as this article).
The real concern is that while much of the field is still experimental, many stem cell clinics are making grossly unsubstantiated claims to draw in customers. From exaggerated levels of successful outcomes (100% satisfaction rate?) all the way through to talking about clinical trials that simply do not exist. The industry is badly (read: barely) regulated which is ultimately putting patients at risk (one example: three patients were left blind after undergoing an unproven stem cell treatment – click here to read more on this).
While the stem cell research field fully understands and appreciates the desperate desire of the communities affected by various degenerative conditions, there has to be regulations and strict control standards that all practitioners must abide by. And first amongst any proposed standards should be that the therapy has been proven to be effective for a particular condition in independently audited double blind, placebo controlled trials. Until such proof is provided, the sellers of such products are simply preying on the desperation of the people seeking these types of procedures.
The image above presents a ‘before treatment’ (left) and ‘after treatment’ (right) brain scan image from a recent research report of a clinical study that looked at the use of Acetylcysteine (also known as N-acetylcysteine or simply NAC) in Parkinson’s disease.
DaTscan brain imaging technique allows us to look at the level of dopamine processing in an individual’s brain. Red areas representing a lot; blue areas – not so much. The image above represents a rather remarkable result and it certainly grabbed our attention here at the SoPD HQ (I have never seen anything like it!).
In today’s post, we will review the science behind this NAC and discuss what is happening with ongoing clinical trials.
Source: The Register
Let me ask you a personal question:
Have you ever overdosed on Paracetamol?
Regardless of your answer to that question, one of the main treatments for Paracetamol overdose is administration of a drug called ‘Acetylcysteine’.
Why are you telling me this?
Because acetylcysteine is currently being assessed as a potential treatment for Parkinson’s disease.
Oh I see. Tell me more. What is acetylcysteine?
Acetylcysteine. Source: Wikimedia
Acetylcysteine (N-acetylcysteine or NAC – commercially named Mucomyst) is a prodrug – that is a compound that undergoes a transformation when ingested by the body and then begins exhibiting pharmacological effects. Acetylcysteine serves as a prodrug to a protein called L-cysteine, and – just as L-dopa is an intermediate in the production of dopamine – L-cysteine is an intermediate in the production of another protein called glutathione.
Take home message: Acetylcysteine allows for increased production of Glutathione.
What is glutathione?
Glutathione. Source: Wikipedia
Glutathione (pronounced “gloota-thigh-own”) is a tripeptide (a string of three amino acids connected by peptide bonds) containing the amino acids glycine, glutamic acid, and cysteine. It is produced naturally in nearly all cells. In the brain, glutathione is concentrated in the helper cells (called astrocytes) and also in the branches of neurons, but not in the actual cell body of the neuron.
It functions as a potent antioxidant.