Please do not misread the title of this post!
Compounds targeting the Nociceptin receptor (or NOP) could provide the Parkinson’s community with novel treatment options in the not-too-distant future.
In pre-clinical models of Parkinson’s, compounds designed to block NOP have demonstrated neuroprotective properties, while drugs that stimulate NOP appear to be beneficial in reducing L-dopa induced dyskinesias.
In today’s post we look at exactly what NOP is and what it does, we will review some of the Parkinson’s-based research that have been conducted so far, and we will look at what is happening in the clinic with regards to NOP-based treatments.
On the surface of every cell in your body, there are lots of small proteins that are called receptors.
They are numerous and ubiquitous.
And they function act like a ‘light switch’ – allowing for certain biological processes to be initiated or inhibited. All a receptor requires to be activated (or blocked) is a chemical messenger – called a ligand – to come along and bind to it.
An example of a receptor on a cell. Source: Droualb
Each type of receptor has a particular structure, which is specific to certain shaped ligands (the chemical messenger I mentioned above). These ligands are floating around in the extracellular space (the world outside of the cell), having been released (or secreted) by other cells.
And this process represents one of the main methods by which cells communicate with each other.
By binding to a receptor, the ligand can either activate the receptor or alternatively block it. The activator ligands are called agonists, while the blockers are antagonists.
Agonist vs antagonist. Source: Psychonautwiki
Many of the drugs we currently have available in the clinic function in this manner.
For example, with Parkinson’s medications, some people will be taking Pramipexole (‘Mirapex’ and ‘Sifrol’) or Apomorphine (‘Apokyn’) to treat their symptoms. These drugs are Dopamine agonists because they bind to the dopamine receptors, and help with dopamine-mediated functions (dopamine being one of the chemicals that is severely in the Parkinsonian brain). As you can see in the image below the blue dopamine agonists can bypass the dopamine production process (which is reduced in Parkinson’s) and bind directly to the dopamine receptors on the cells that are the intended targets of dopamine.
There are also dopamine antagonists (such as Olanzapine or ‘Zyprexa’) which blocks dopamine receptors. These drugs are not very helpful to Parkinson’s, but dopamine antagonist are commonly prescribed for people with schizophrenia.
Are there other receptors of interest in Parkinson’s?
This week a group of scientists have published an article which indicates differences between mice and human beings, calling into question the use of these mice in Parkinson’s disease research.
The results could explain way mice do not get Parkinson’s disease, and they may also partly explain why humans do.
In today’s post we will outline the new research, discuss the results, and look at whether Levodopa treatment may (or may not) be a problem.
The humble lab mouse. Source: PBS
Much of our understanding of modern biology is derived from the “lower organisms”.
From yeast to snails (there is a post coming shortly on a snail model of Parkinson’s disease – I kid you not) and from flies to mice, a great deal of what we know about basic biology comes from experimentation on these creatures. So much in fact that many of our current ideas about neurodegenerative diseases result from modelling those conditions in these creatures.
Now say what you like about the ethics and morality of this approach, these organisms have been useful until now. And I say ‘until now’ because an interesting research report was released this week which may call into question much of the knowledge we have from the modelling of Parkinson’s disease is these creatures.
You see, here’s the thing: Flies don’t naturally develop Parkinson’s disease.
Nor do mice. Or snails.
Or yeast for that matter.
So we are forcing a very un-natural state upon the biology of these creatures and then studying the response/effect. Which could be giving us strange results that don’t necessarily apply to human beings. And this may explain our long history of failed clinical trials.
We work with the best tools we have, but it those tools are flawed…
What did the new research report find?
This is the study:
Title: Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease
Authors: Burbulla LF, Song P, Mazzulli JR, Zampese E, Wong YC, Jeon S, Santos DP, Blanz J, Obermaier CD, Strojny C, Savas JN, Kiskinis E, Zhuang X, Krüger R, Surmeier DJ, Krainc D
Journal: Science, 07 Sept 2017 – Early online publication
The researchers who conducted this study began by growing dopamine neurons – a type of cell badly affected by Parkinson’s disease – from induced pluripotent stem (IPS) cells.
What are induced pluripotent stem cells?
This week a biotech company called Voyager Therapeutics announced the results of their ongoing phase Ib clinical trial. The trial is investigating a gene therapy approach for people with severe Parkinson’s disease.
Gene therapy is a technique that involves inserting new DNA into a cell using a virus. The DNA can help the cell to produce beneficial proteins that go on help to alleviate the motor features of Parkinson’s disease.
In today’s post we will discuss gene therapy, review the new results and consider what they mean for the Parkinson’s community.
On 25th August 2012, the Voyager 1 space craft became the first human-made object to exit our solar system.
After 35 years and 11 billion miles of travel, this explorer has finally left the heliosphere (which encompasses our solar system) and it has crossed into the a region of space called the heliosheath – the boundary area that separates our solar system from interstellar space. Next stop on the journey of Voyager 1 will be the Oort cloud, which it will reach in approximately 300 years and it will take the tiny craft about 30,000 years to pass through it.
Where is Voyager 1? Source: Tampabay
Where is Voyager actually going? Well, eventually it will pass within 1 light year of a star called AC +79 3888 (also known as Gliese 445), which lies 17.6 light-years from Earth. It will achieve this goal on a Tuesday afternoon in 40,000 years time.
Gliese 445 (circled). Source: Wikipedia
Remarkably, the Gliese 445 star itself is actually coming towards us. Rather rapidly as well. It is approaching with a current velocity of 119 km/sec – nearly 7 times as fast as Voyager 1 is travelling towards it (the current speed of the craft is 38,000 mph (61,000 km/h).
Interesting, but what does any of that have to do with Parkinson’s disease?
Well closer to home, another ‘Voyager’ is also ‘going boldly where no man has gone before’ (sort of).
In today’s post we will review recent research regarding one particular family of bacteria, Helicobacter pylori, and what they might be doing in relations to Parkinson’s disease.
In his magnificent book, I contain multitudes, science writer/journalist Ed Yong writes that we – every single one of us – release approximately 37 million bacteria per hour. By talking, breathing, touching, or simply being present in the world, we are losing and also picking up the little passengers everywhere we go.
Reminds me of that Pascal Mercier book “Night Train to Lisbon” – We leave something of ourselves behind when we leave a place,… I’m not sure if this is what he was referring to though.
Yong also points out that: 80% of the bacteria on your right thumb are different to the bacteria on your left thumb.
It’s a fascinating book (and no, I am not receiving any royalties for saying that).
Microbes. Source: NYmag
We have discussed microbes several times on this blog, particularly in the context of the gut and its connection to Parkinson’s disease (Click here, here and here to read some of those posts). Today we are going to re-visit one particular type of microbe that we have also discussed in a previous post: Helicobacter pylori.
Helicobacter pylori. Source: Helico
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
A community in New Brunswick (Canada) was recently shocked to discover that a 2 year old boy in their midst had been diagnosed with Parkinson’s disease (Click here to read more).
Yes, you read that correctly, it’s not a typo: a 2 year old boy.
Juvenile-onset Parkinson’s disease is an extremely rare version of the condition we discuss here at the Science of Parkinson’s. It is loosely defined as being ‘diagnosed with Parkinson’s disease under the age of 20’. The prevalence is unknown, but there is a strong genetic component to form of the condition. In today’s post we will review what is known about Juvenile-onset and look at new research about a gene that has recently been discovered to cause a type of Juvenile-onset Parkinson’s disease.
Dr Henri Huchard. Source: Wikipedia
In 1875, Dr Henri Huchard (1844-1910; a French neurologist and cardiologist) described the first case of a child who, at just 3 years of age, presented all the clinical features of Parkinson’s disease. Since that report, there have been many studies detailing the condition that has become known as ‘juvenile-onset Parkinson’s disease’.
What is juvenile-onset Parkinson’s disease?
Basically, it is a form of Parkinson’s disease that affects children and young people under the age of 20. The defining feature is the age of onset. The average age of onset is approximately 12 years of age (with the majority of cases falling between 7 and 16 years) and males are affected by this condition more than females (at a rate of approximately 5:1).
The actual frequency of juvenile-onset parkinson’s is unknown given how rare it is. When researcher look at people with early onset Parkinson’s disease (that is diagnosis before the age of 40; approximately 5% of the Parkinson’s community), they have found that between 0.5 – 5% of that group of people were diagnosed before 20 years of age. This suggests that within just the Parkinson’s community, the frequency of juvenile-onset parkinson’s is at the most 0.25% (or 2.5 people per 1000 people with Parkinson’s). Thus it is obviously a very rare condition.
It is interesting to note that Lewy bodies (the clusters of aggregated protein that classically characterise the brains of people with Parkinson’s disease) are very rare in cases of juvenile-onset parkinson’s disease. To our knowledge there has been only one case of Lewy bodies in juvenile-onset parkinson’s disease (Click here to read more on this). This suggests that the juvenile-onset form of Parkinson’s disease may differ from other forms of the condition in its underlying biology.
Do we know what causes juvenile-onset parkinson’s disease?
There is a very strong genetic component to juvenile-onset parkinson’s disease. In fact, the incidence of Parkinsonism in relatives of people with juvenile-onset parkinson’s disease is higher than in the general public AND in the relatives of people with other forms of Parkinson’s disease.
Genetic mutations in three genes are recognised as causing juvenile-onset Parkinson’s disease. The three genes are known to the Parkinson’s world as they are all PARK genes (genetic variations that are associated with Parkinson’s). Those three genes are:
- Parkin (PARK2)
- PTEN-induced putative kinase 1 (PINK1 or PARK6)
- DJ1 (PARK7)
In juvenile-onset Parkinson’s disease, all of these mutations are associated with autosomal recessive – meaning that two copies of the genetic variation must be present in order for the disease to develop.
Parkin mutations account for the majority of juvenile-onset Parkinson’s disease cases. Affected individuals have a slowly progressing condition that is L-dopa responsive. Dystonia (abnormal muscle tone resulting in muscular spasm and abnormal posture) is very common at the onset of the condition, particularly in the lower limbs.
Can the condition be treated with L-dopa?
The answer is: ‘Yes, but…’
L-dopa (or dopamine replacement) treatment is the standard therapy for alleviating the motor features of Parkinson’s disease.
The majority of people with juvenile-onset parkinson’s respond well to L-dopa, but in the Parkin mutation version individuals will typically begin to experience L-dopa-induced motor fluctuations (dyskinesias) early in that treatment regime.
What research is currently being done on this condition?
Given that cases are so very rare and so few, it is difficult to conduct research on this population of individuals. Most of the research that is being conducted is focused on the genetics underlying the condition.
And recent that research lead to the discovery of a new genetic variation that causes juvenile-onset Parkinson’s disease:
Title: Discovery of a frameshift mutation in podocalyxin-like (PODXL) gene, coding for a neural adhesion molecule, as causal for autosomal-recessive juvenile Parkinsonism.
Authors: Sudhaman S, Prasad K, Behari M, Muthane UB, Juyal RC, Thelma BK.
Journal: Journal Med Genet. 2016 Jul;53(7):450-6.
PMID: 26864383 (This article is OPEN ACCESS if you would like to read it)
The researchers who wrote this article were presented with a 10 member Indian family from Aligarh, Uttar Pradesh. Of the 8 children in the family, 3 were affected by Parkinsonian features (tremor, slowness, rigidity and gait problems) that began between 13 and 17 years of age. The researchers conducted DNA sequencing and found that none of the three affected siblings had any of the known Juvenile-onset Parkinson’s disease genetic mutations (specifically, mutations in the genes PARK2, PINK1and DJ1).
They then compared the DNA from the three siblings with the rest of the family and found a genetic variant in a gene called podocalyxin-like (or PODXL). It must be noted that PODXL is a completely novel gene in the world of Parkinson’s disease research, which makes it very interesting. PODXL has never previously been associated with any kind of Parkinson’s disease, though it has been connected with two types of cancer (embryonal carcinoma and periampullary adenocarcinoma).
The researchers then turned to their genetic database of 280 people with Parkinson’s disease have had their genomes sequenced. The researchers wanted to determine if any genetic variants in the PODXL gene were present in other suffers of Parkinson’s disease, but had not been picked up as a major contributing factor. They found three unrelated people with PODXL mutations. All three had classical Parkinson’s features, and were negative for mutations in the Parkin, PINK1 and DJ1 genes.
The researchers concluded that the PODXL gene may be considered as a fourth causal gene for Juvenile-onset Parkinson’s disease, but they indicated that further investigations in other ethnic groups are required.
The banner for today’s post was sourced from ClipArtBest
In August of 2015, groups of scientists from North Carolina and Perth (Australia) published a report together in which they noted the high occurrence of Parkinson’s-like features in aging people with Autism.
In this post we will have a look at what links (if any) there may be between Autism and Parkinson’s disease.
Recent estimates suggest that the prevalence of Autistic Spectrum Disorders in US children is approximately 1.5 %. Autism is generally associated with children, and in this way it is almost a mirror opposite of Parkinson’s disease (which is usually associated with the elderly). A fair number of people who were diagnosed with Autism early in their lives are now reaching the age of retirement, but we know very little about what happens in this condition in the aged.
What is Autism?
This is one of those questions that gets people into trouble. There is a great deal of debate over how this condition should be defined/described. We here at SoPD will chose to play it safe and provide the UK National Health System (NHS)‘s description:
Autism spectrum disorder (ASD) is a condition that affects social interaction, communication, interests and behaviour. In children with ASD, the symptoms are present before three years of age, although a diagnosis can sometimes be made after the age of three. It’s estimated that about 1 in every 100 people in the UK has ASD. More boys are diagnosed with the condition than girls.
Wikipedia also has a very thorough page Autism
So what was reported in the study finding a connection between Autism and Parkinson’s disease?
Last year two groups of researchers (from North Carolina, USA and Perth, Australia) noticed an interesting trend in some of the aging Autistic subjects they were observing.
They published their findings in the Journal of Neurodevelopmental disorders:
Title: High rates of parkinsonism in adults with autism.
Authors: Starkstein S, Gellar S, Parlier M, Payne L, Piven J.
Journal: Journal of Neurodev Disord. 2015;7(1):29.
PMID: 26322138 (This report is OPEN ACCESS if you would like to read it)
The article reports the findings of two studies:
Study I (North Carolina) included 19 men with Autism (with an average age of 57 years). When the researchers investigated the cardinal features of Parkinson’s disease, they found that 22 % (N = 4) of the subjects exhibited bradykinesia (or slowness of movement), 16 % (N = 3) had a resting tremor, 32 % (N = 6) displayed rigidity, and 15 % (N = 2) had postural instability issues.
In fact, three of the 19 subjects (16 %) actually met the criteria for a full diagnosis of Parkinson’s disease (one of who was already responding well to L-dopa treatment).
Study II (Perth) was a larger study, involving 32 men and 5 women (with an average age of 51 years). 46 % (N = 17) of the subjects in this study exhibited bradykinesia, 19 % (N = 7) had a resting tremor, 19 % (N = 7) displayed rigidity, and 19 % (N = 7) had postural instability problems. In study II, 12 of the 37 subjects (32 %) met the full diagnostic criteria for Parkinson’s disease.
Given this collective result, the researchers concluded that there may well be an increased frequency of Parkinsonism in the aged people with Autism. They emphasize, however, the need to replicate the study before definitive conclusions can be made.
So how could this be happening?
The short answer is: we don’t have a clue.
The results of this study need to be replicated a few times before we can conclusively say that there is a connection. There are, however, some interesting similarities between Autism and Parkinson’s disease, for example (as the NHS mentioned above) males are more affected than females in both conditions.
There are genetic variations that both Parkinson’s and Autism share. Approximately 10-20% of people with Parkinson’s disease have a genetic variation in one of the PARK genes (we have discussed these before – click here to read that post). The genetics of Autism are less well understood. If you have one child with Autism, the risk for the next child also having the condition is only 2-6% (genetically speaking, it should be a 25-50% level of risk).
There are, however, some genes associated with Autism and one of those genes is the Parkinson’s associated gene, PARK2. it has previously been reported that variants in the PARK2 gene (Parkin) in children with Autism (click here for more on this).
It would be interesting to have a look at the brains of aged people with Autism. This could be done with brain scans (DAT-SCAN), but also at the postmortem stage to see if their brains have alpha synuclein clusters and Lewy bodies – the pathological characteristics of Parkinson’s disease. These studies may well be underway – we’ll keep an eye out for any reports.
There are alternative explanations for the connection between Autism and Parkinson’s disease suggested by this study. For example, 36 of the 56 subjects involved in the two studies were on medication for their Autism (the medication is called neuroleptics). Those medications did not appear to explain the rates of parkinsonism in either study (after excluding subjects currently on neuroleptic medications, the frequency of parkinsonism was still 20 %). Most of the subjects in both studies have been prescribed neuroleptics at some point in their lives. Thus it is possible that long-term use of neuroleptics may have had the effect of increasing the risk for parkinsonism later in life. This is pure speculation, however, and yet to be tested. Any future studies would need to investigate this as a possibility.
EDITOR’S NOTE: If you have a child or loved one on the Autism spectrum, it is important to understand that the study summarised here are novel results that are yet to be replicated. And if it turns out that adults with Autism do have a higher risk of developing Parkinson’s disease it does not necessarily mean that they will – simply that they are at greater risk than normal. It is best to consult a medical practitioner if you have further concerns.
The banner at the today’s post was sourced from Sailing Autistic Seas.
This is Tom Isaacs. He is the charismatic founder of the Cure Parkinson’s trust.
Tom Isaacs. Source: GrannyButtons
He’s a dude.
The man walked the entire coastline of the UK to raise money/awareness for Parkinson’s disease! Trust me, he’s a dude.
The title of today’s post is a salute to Tom’s efforts to offer a humourous label to what is a very serious and debilitating aspect of Parkinson’s disease.
In this post, we will discuss the science of dyskinesias
For the last 50 years, Levodopa (L-dopa) has been the “gold standard” treatment for Parkinson’s disease. By replacing the lost dopamine, L-dopa allows for the locomotion parts of the brain to become less inhibited and for people with Parkinson’s disease to feel more in control of their movements.
This miraculous treatment, however, comes at a terrible cost.
After long-term use of the drug, abnormal and involuntary movements can begin to appear. These movements are called dyskinesias.
An example of a person with dyskinesia. Source: JAMA Neurology
What are Dyskinesias?
Dyskinesias (from Greek: dys/dus – difficulty, abnormal; and kinēsis – motion, movement) are simply a category of movement disorders that are characterized by involuntary muscle movements. They are certainly not specific to just Parkinson’s disease.
In Parkinson’s disease, they are associated with long-term use of L-dopa.
An example of dyskinesia can be seen in this video of Tom Isaacs and David Sangster discussing life with Parkinson’s disease (Tom was diagnosed at age 26 years of age and has lived with Parkinson’s for 20 years – he has dyskinesias. David was diagnosed in 2011 at age 29; since diagnosis he foundered www.1in20Parkinsons.org.uk. He’s also a dude!).
How do dyskinesias develop in Parkinson’s disease?
Before beginning a course of L-dopa, the locomotion parts of the brain in people with Parkinson’s disease is pretty inhibited. This results in the slowness and difficulty in initiating movement. They want to move, but they can’t. They are akinetic.
L-dopa tablets provide the brain with the precursor to the chemical dopamine. Dopamine producing cells are lost in Parkinson’s disease, so replacing the missing dopamine is one way to treat the motor features of the condition. Simply giving people pills of dopamine is a non-starter: dopamine is unstable, breaks down too quickly, and (strangely) has a very hard time getting into the brain. L-dopa, on the other hand, is very robust and has no problem getting into the brain.
Once inside the brain, L-dopa is quickly converted – via an enzymatic reaction – into dopamine allowing the locomotion parts of the brain to function close to normal. In understanding this process, it is important to appreciate that when a tablet is taken and L-dopa enters the brain, there is a sudden rush of dopamine. A spike in it’s supply, and for the next few hours this gradually wears off as the dopamine is used up. This tablet approach to L-dopa treatment gives a wave like shape to the L-dopa levels in the brain over the course of the day (see the figure below).
After prolonged use of L-dopa (7-10 years on average), the majority of people with Parkinson’s disease will experience a shorter response to each dose of L-dopa. They will also find that they have more time during which they will be unable to move (exhibiting akinesia). This is simply the result of the disease progression – L-dopa treats the motor features of the disease but hides the fact that the disease is still progressing.
This shortening of response is often associated with subtle abnormal involuntary movements that appear when the levels of l-DOPA are highest (usually soon after taking a tablet). It is as if there is too much dopamine for the system to handle.
Gradually, the response time (during which normal movement is possible) will grow shorter and to combat this the dose of L-dopa is increased. But with increased levels of L-dopa, there is an increase in the involuntary movements, or dyskinesias.
This figure illustrates the course of Parkinson’s disease for some people on L-dopa. The waving line indicates the level of L-dopa in the blood (as a result of taking L-dopa medication). The white space is the area where normal movement is possible, while the grey area illustrates periods of akinesia (inability to move). Without L-dopa, people with Parkinson’s disease would be stuck in this area, and as the L-dopa pill wears off (during the downward part of the waving line) they fall back into the akinesia area, thus requiring another pill. As the disease progresses, the akinetic (grey) area increases, requiring higher levels of L-dopa to be administered in order to escape it. The tan coloured area in the top right corner demonstrates the introduction of dyskinesias.
Are there different types of dyskinesias?
Yes there are. Dyskinesias have been broken down into many different subtypes, but the two main types of dyskinesia are:
Chorea – these are involuntary, irregular, purposeless, and unsustained movements. To an observer, Chorea will look like a very disorganised/uncoordinated attempt at dancing (hence the name, from the Greek word ‘χορεία’ which means ‘dance’). While the overall activity of the body can appear continuous, the individual movements are brief, infrequent and isolated. Chorea can cause problems with maintaining a sustained muscle contraction, which may result in affected people dropping things or even falling over.
Dystonia – these are sustained muscle contractions. They often occur at rest and can be either focal or generalized. Focal dystonias are involuntary contractions in a single body part, for example the upper facial area. Generalized dystonia, as the name suggests, are contraction affecting multiple body regions at the same time, typically the trunk, one or both legs, and another body part. The intensity of muscular movements in sufferers can fluctuate, and symptoms usually worsen during periods of fatigue or stress.
When were Dyskinesias first discovered?
Ironically but unsurprisingly, L-dopa induced dyskinesias were first reported by the same scientists who first reported the drug’s amazing effects in Parkinson’s disease:
Title: Modification of Parkinsonism – chronic treatment with L-dopa.
Authors: Cotzias GC, Papavasiliou PS, Gellene R.
Journal: New England Journal of Medicine. 1969 Feb 13;280(7):337-45.
George Cotzias was one of the first physicians to give L-dopa to people with Parkinson’s disease.
Dr George Cotzias. Source: NewScientist
Cotzias and colleagues administered L-dopa to 28 people with Parkinson’s disease (17 males and 11 females) and observed modest to moderate response in 8 of them, a marked response in 10, and dramatic responses in the other 10 people. During their two year observation period, they also reported seeing involuntary movements (dyskinesias) in half of the subjects in the study (14/28). They ranged from rare and fleeting (eg. grimacing or gnawing and wave-like motions of the head) to severe (eg. full body/limb movements). They noted that the dyskinesias were most severe in the people with the longest duration of the disease.
It should be noted that the speed with which some of the patients (that Cotzias was treating) developed their dyskinesias – less than 2 years – was a reflection on the late stage of the condition at which the treatment was begun. When the administration of L-dopa is started at an earlier stage, the window of effective treatment is generally longer (5-10 years, depending on individual cases).
So what causes the dyskinesias?
This question is the source of much debate.
Volumes of text have been bashed out and sides have been taken. We are going to have to tread very carefully here for fear of upsetting folks is the world of Parkinson’s research.
There is some agreement, however, that the factors associated with the development of L-dopa-induced dyskinesias include:
- the duration of the disease
- the severity of the disease
- the dose of L-dopa (cue the debating)
- young age onset
There are also some genetic forms of Parkinson’s disease that can have an impact on the chances of developing dyskinesias.
Duration/severity of the disease – Experimental studies in animal models of Parkinson’s disease indicate that, if L-dopa is given to the animals, involuntary movements will only develop when the loss of dopamine in the brain exceeds 80–85% of normal. Clinical observations, however, indicate that the severe loss of dopamine in the brain is not sufficient for patients to develop dyskinesias.
This has lead to theories regarding intact part of the brain, suggesting that there are changes in the neurons that the dopamine is acting on. And indeed postmortem analysis of brains from people with & without dyskinesias suggests that there are differences in the neurons that dopamine act on (Click here and here for more on this).
The dose of L-dopa – in a large clinical study, the researchers found that an average daily L-dopa dose of 338 mg was not associated with dyskinesias, while an average daily dose of 387 mg was (Click here and here to read more on this).
Young age onset – Given the length of time that people with early-onset Parkinson’s disease will be on L-dopa, there is a strong association between early-onset and dyskinesias.
EDITORIAL NOTE: We are now about to discuss what can be done to alleviate dyskinesias. Before doing so, we here at the Science of Parkinson’s disease would just like to repeat our standard warning that the contents provided on this website is of an informative nature, and no actions should be taken based on what you have read without first consulting your doctor. Please seek medical advice before changing or experimenting with your treatment regime.
And what can be done to alleviate dyskinesias?
There are several methods of reducing dyskinesias:
Reducing L-dopa dose
Obviously, one can lower the dose of L-dopa. This almost always results in a reduction of dyskinesias. BUT, this almost always results in a worsening of Parkinson’s disease motor features, so it can’t really be considered a solution.
Dopamine receptor agonists
Rather than giving the brain L-dopa or dopamine, chemicals that behave exactly like dopamine can be administered. Dopamine receptor agonists are drugs that act on the receptors of dopamine that are present on the cells that dopamine acts on. These drugs have a longer half‐life than levodopa, meaning that they hang around in the brain for longer (eg. they are not broken down or used up as quickly as L-dopa).
In a large double‐blind study that compared the safety and efficacy of a dopamine receptor agonist – ‘Ropinirole’ – with that of levodopa over a period of five years, researchers found that the incidence of dyskinesia (regardless of levodopa supplementation) was 20% in the ropinirole group and 45% in the levodopa-only group (Click here for more on that study, and click here for a similar study with the dopamine agonist pramipexole).
One cautionary note – Dopamine agonists have been associated with the development of compulsive and impulsive behaviours (Click here for more on this).
Drugs acting on NMDA receptors
N-methyl-D-aspartate receptors (NMDA receptors) are receptors of the chemical glutamate. They are widely found in the brain, but during dyskinesias they appear to become more abundant. As a result, researchers have used drugs that block NMDA receptors (called NMDA receptor antagonists) as potential treatment for dyskinesias. And they appear to help in many cases.
In a double‐blind, placebo‐controlled study of 18 people with Parkinson’s disease, researchers found that the NMDA receptor antagonist ‘Amantidine’ reduced the duration of L-dopa-induced dyskinesias by 60% (Click here for more on this).
Drugs acting on serotonergic systems
Recently there has been a lot of attention focused on the role in dyskinesias of another chemical in the brain: serotonin. There is significant loss of serotonergic cells and fibres in the brain of people with Parkinson’s disease, though not to the same scale as dopamine.
A recent clinical study investigating the use of drugs that prolong the serotonin floating around in the brain (called selective serotonin reuptake inhibitors or SSRIs), found that they did not protect people with Parkinson’s disease from dyskinesias, but may delay their onset (Click here for more on this). There are also clinical trials investigating the use of serotonin receptor agonists in Parkinson’s disease with dyskinesias, based on positive results from preclinical studies (Click here for more on this).
More recently researchers have been investigating the role of serotonin cells in the production of dopamine from L-dopa. Serotonin cells are known to absorb L-dopa and to convert it into dopamine, but they do not have any means of storing it and they release it in an uncontrolled fashion. Recent studies in rodent models of L-dopa-induced dyskinesias have reported reductions in dyskinetic behaviour as a result of lesioning the serotonin cells or blocking specific serotonin receptors. The clinical relevance of these finding is yet to be tested, however.
The use of ‘pacemaker’ surgeries (such as deep brain stimulation targeting regions such as the globus pallidum or subthalamic nucleus) have been shown to be effective in treating advanced Parkinson’s disease. The resulting motor improvements are also associated with a reduction in dyskinesias.
A blinded pilot study comparing the safety and efficacy of deep brain stimulation in people with advanced Parkinson’s disease reported a 60-90% reduction in dyskinesias, depending on the region of the brain that was targeted (Click here for more on this).
Surgical lesions targeting the thalamus, globus pallidum or subthalamic nucleus have also been used in the treatment of advanced Parkinson’s disease, with reductions in dyskinesias also being observed. It is effective in both young as well as elderly subjects, with benefit persisting for up to 5 years. These surgical lesion procedures, however, are irreversible.
Recent advances in our understanding
We always like to bring you new research here at the Science of Parkinson’s disease and recently there have been some interesting results published. For example, this one:
Title: Serotonin-to-dopamine transporter ratios in Parkinson disease: Relevance for dyskinesias.
Authors: Roussakis AA, Politis M, Towey D, Piccini P.
Journal: Neurology. 2016 Published Feb 26.
The researchers in this study conducted brain imaging on people with Parkinson’s disease who did have dyskinesias (17 people) and did not have dyskinesias (11 people). Specifically they were looking to see the difference in the density of dopamine and serotonin fibres in particular areas of the brain affected by dyskinesias. They found that people with Parkinson’s disease AND dyskinesias had a higher ratio of serotonin fibres to dopamine fibres than people with Parkinson’s disease but no dyskinesias. This result adds further support to the role that serotonin cells are playing in the development of L-dopa-induced dyskinesias.
Phew, long post.
If you have got this far and you are still reading – thanks! We hope it was informative.
In (shorter) future posts, we will be assessing new research dealing the mechanisms of and novel ways to treat dyskinesias. This post was meant to be an introduction that we will refer back to from time to time.
Something different for you today – a history lesson…with some science.
The history of Parkinson’s disease dates back well before Dr James Parkinson made his observations about 6 patients 199 years ago (oh, big anniversary coming up! Who knew)
But it may surprise you to know that the history of Parkinson’s disease dates back before even Jesus turned up.
You actually have to go back a long back in order to get to the beginning…
If you were demonstrating the early features of Parkinson’s disease in the year 500 BCE, there was really only one place in the world that you wanted to be:
India. Source: blogs.umb.edu
Not only did India have a extremely sophisticated system of diagnosis for what we call Parkinson’s disease, but they also have a VERY effective treatment!
Don’t believe me? Read on.
Around 5000 BCE, the wise and farsighted members of the Indian medical establishment began pooling their collective knowledge – firstly in an oral form, but then eventually in a written format. That written material became the text known as the Ayurveda (/aɪ.ərˈveɪdə/; Sanskrit for “the science of life” or “Life-knowledge”).
It can not be understated how sophisticated the Ayurveda was for its time. This was a period bridging the ‘new stone age’ and the ‘Bronze age’. People’s understanding of medical afflictions was basically limited to what the Gods and evil spirits were doing to them.
The earliest account of Parkinson’s disease features in the Ayurveda was compiled by Susruta (the 600 BC author of “Susruta Samhita”). He described slowness (cestasanga in Sanskrit) and akinesia (cestahani) in certain individuals, and also (curiously) reported that certain poisons could cause rigidity and tremor.
To demonstrate to you just how sophisticated the Ayurveda was, consider this: when faced with a person exhibiting tremor a practitioner using the Ayurveda could chose between six different types of tremor:
- Vepathu (a generalised tremor)
- Prevepana (excessive shaking)
- Kampa vata (tremors due to vata)
- Sirakampa (head tremor)
- Spandin (quivering)
- Kampana (tremors)
Number 3 (Kampa vata) on that list is what we now refer to as Parkinson’s disease. Kampa basically means ‘tremor’, while Vata is more difficult to define – it is essentially the property/force that governs all movement in the mind and body (blood flow, breathing, etc – even the movement of thoughts).
Since the 3rd century BCE, practitioner of the Ayurveda have been using the seeds of Mucuna pruriens in treating conditions of tremor.
Mucuna Prurien seeds. Source: Kisalaya
Authors: Damodaran M, Ramaswamy R.
Journal: Biochem J. 1937 Dec;31(12):2149-52. No abstract available.
PMID: 16746556 (this article is OPEN ACCESS and available to read if you would like)
Authors: Katzenschlager R, Evans A, Manson A, Patsalos PN, Ratnaraj N, Watt H, Timmermann L, Van der Giessen R, Lees AJ.
Journal: J Neurol Neurosurg Psychiatry. 2004 Dec;75(12):1672-7.
PMID: 15548480 (this report is OPEN ACCESS if you would like to read it)