On Tuesday 21st December, 1824, James Parkinson passed away in his home – two days after suffering a stroke.
It was the end of an amazing and extremely productive life.
In this post about James Parkinson – the final in the series of four observing the 200th anniversary of his first observation of Parkinson’s disease – we look at what happened following his death, and reflect on his overall legacy.
St Leonard’s church in Hoxton, London – James’ church
At the end of the third post on the life of James Parkinson (Click here to read that post), the Battle of Waterloo had just occurred and James was publishing the last of his writings.
One of the last major events in the life of James Parkinson occurred in 1823, when James was awarded the Royal College of Surgeons’ first Gold Medal.
Understand that this was a big deal.
The college had established the award way back in 1802 for “distinguished labours, researches and discoveries”. But it took them a full 21 years to find anyone that they thought worthy enough to be the first recipient.
And that first recipient: one James Parkinson
This event, however, represents very nicely how the legacy of James has changed over time. While the world currently associates James Parkinson with a neurological condition that he first described in 1817, the Royal College of Surgeons awarded him their first gold medal not for any of his medical publications, but rather for his “splendid Work on Organic Remains”.
As I have written before, James was a bit of a rockstar to the geological/palaeontology community. His writings on what he called his “favourite science”, had earned him an international reputation and one has to wonder how he would feel now if he knew that his reputation lies elsewhere.
As JP aficionado Dr Cherry Lewis once wrote: history is fickle.
For more than 50 years, L-dopa (a critical ingredient used by the brain to produce the chemical dopamine) has been one of the primary therapies used in the treatment of Parkinson’s disease. Over those years, there have been several different versions of L-dopa, providing advantages over previous forms. Last week, the results of clinical trials involving a new inhalable version of L-dopa were published.
In this post we will review the results of those studies.
Inhalers. Source: Verywell
The motor features (a resting tremor in one of the limbs, slowness of movement, and rigidity in the limbs) of Parkinson’s disease begin to appear when most of the dopamine producing neurons in the brain have been lost (specifically, >60% of the midbrain dopamine neurons). Thus for the last 50 years the primary means of treating Parkinson’s disease has been via dopamine replacement therapies.
Why don’t we just inject people with dopamine?
The chemical dopamine has a very difficult time crossing the blood-brain barrier, which is a thick membrane surrounding the brain. This barrier protects the brain from unwanted undesirables (think toxic chemicals), but it also blocks the transfer of some chemicals that exert a positive impact (such as dopamine).
When dopamine is blocked from entering the brain, other enzymes can convert it into another chemical called ‘norepinephrine’ (or epinephrine) and this conversion can cause serious side effects in blood pressure and glucose metabolism.
In addition, any dopamine that does find its way into the brain is very quickly broken down by enzymes. Thus, the amount of time that dopamine has to act is reduced, resulting in a very limited outcome. And these reasons are why doctors turned to L-dopa instead of dopamine in the treatment of Parkinson’s disease.
What is L-dopa?
Basically, Levodopa (L-dopa) is a chemical intermediary in the production of dopamine. That is to say, you need L-dopa to make dopamine. L-dopa is very stable inside the body and crosses the blood-brain-barrier very easily.
In the UK, a commonly used version is known as ‘Sinemet®‘(produced by Merck).
The chemical structure of L-dopa. Source: Wikipedia
The best way to understand what L-dopa is probably be to explain the history of this remarkable chemical.
The history of L-dopa
Until the 1950s there were few treatment options for Parkinson’s disease, but a young scientist in Sweden was about to change that.
This is Arvid Carlsson.
Prof Arvid Carlsson. Source: Alchetron
He’s a dude.
In 1957, he discovered that when he injected the brains of rabbits with a neurotoxin (reserpine) it killed the dopamine neurons (and the animals exhibited reduced movement). He also discovered that by injecting the dopamine precursor –L-dopa – into those same animals, he was able to rescue their motor ability. Importantly, he found that the serotonin precursor (called 5-hydroxytryptophan) was not capable of reversing the reduction in motor ability, indicating that the effect was specific to L-dopa.
Here is the 1957 report:
Title: 3,4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists.
Authors: Carlsson A, Lindqvist M, Magnusson T.
Journal: Nature. 1957 Nov 30;180(4596):1200. No abstract available.
PMID: 13483658 (the article on the Nature website – access required)
This was a fantastic discovery. A Nobel prize winning discovery in fact.
But what to do with it?
At the time, we did not know that dopamine was depleted in Parkinson’s disease. And people with Parkinson’s continued to suffer.
It was not until 1960 that the critical discovery of Parkinson’s disease was made by another young European scientist. Carlsson’s research (and that of others) inspired the Austrian researcher, Oleh Hornykiewicz to look at dopamine levels in people with Parkinson’s disease.
And what he found changed everything.
Prof Oleh Hornykiewicz. Source: Kurienwissenschaftundkunst
In his study, Hornykiewicz found very high levels of dopamine in the basal ganglia of normal postmortem adult brains, but a marked and consistent reduction (approx. 10-fold) in six postmortem cases of Parkinsonisms. The basal ganglia is one of the main regions of the brain that dopamine neurons communicate with (releasing dopamine there).
Title: Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system
Authors: Ehringer H, Hornykiewicz O.
Journal: Parkinsonism Relat Disord. 1998 Aug;4(2):53-7. No abstract available.
Importantly, Hornykiewicz did not stop there.
In November 1960, Hornykiewicz approached Walther Birkmayer, a doctor at a home for the aged in Vienna, and together they began some clinical trials of L-dopa in July 1961. Birkmayer injected 50 to 150 mg intravenously in saline into 20 volunteers with Parkinsonism. In their report, Birkmayer and Hornykiewicz wrote this regarding the results:
“The effect of a single intravenous injection of l-dopa was, in short, a complete abolition or substantial relief of akinesia. Bedridden patients who were unable to sit up, patients who could not stand up when seated, and patients who when standing could not start walking performed after l-dopa all of these activities with ease. They walked around with normal associated movements, and they could even run and jump. The voiceless, aphonic speech, blurred by palilalia and unclear articulation, became forceful and clear as in a normal person. For short periods of time the people were able to perform motor activities, which could not be prompted to any comparable degree by any other known drug”
Despite their initial excitement, Birkmayer and Hornykiewicz found that the response to L-dopa was very limited in its duration. In addition, subsequent trials by others were not able to achieve similar results, with many failing to see any benefit at all.
And that was when George stepped into the picture.
Dr George Cotzias…and yes, he is holding a brain. Source: New Scientist
Dr George Cotzias was a physician working in New York who became very interested in the use of L-dopa for Parkinson’s disease. And he discovered that by starting with very small doses of L-dopa, given orally every two hours and gradually increasing the dose gradually he was able to stabilize patients on large enough doses to cause a dramatic changes in their symptoms. His studies led ultimately to the Food and Drug Administration (FDA) approving the use of L-dopa for use in PD in 1970. Cotzias and his colleagues were also the first to describe L-dopa–induced dyskinesias.
How does L-dopa work?
When you take an L-dopa tablet, the chemical will enter your blood. Via your bloodstream, it arrives in the brain where it will be absorbed by cells. Inside the cells, another chemical (called DOPA decarboxylase) then changes it into dopamine. And that dopamine is released, and that helps to alleviate the motor features of Parkinson’s disease.
The production of dopamine, using L-dopa. Source: Watcut
Outside the brain, there is a lot of DOPA decarboxylase in other organs of the body, and if this is not blocked then the effect of L-dopa is reduced in the brain, as less L-dopa reaches the brain. To this end, people with Parkinson’s disease are also given Carbidopa (Lodosyn) which inhibits DOPA decarboxylase outside of the brain (Carbidopa does not cross the blood-brain-barrier).
How does the L-dopa inhaler work?
The company behind this new product, Acorda Therapeutics, spent many years developing a powdered version of levodopa that could be delivered to the lungs. Early on in this developmental process the scientists realised a problem: while normal asthma inhalers only need to release micrograms of their medicine to the lungs, a L-dopa inhaler would need to deliver 1,000 times more than that to have any effect. The huge amounts were needed to ensure that enough L-dopa would get from the lungs into the brain to be effective. Thus, the ARCUS inhaler delivers 25 to 50 milligrams in two breaths.
The inhaler contains capsules of L-dopa, which are designed to break open so that the powder can escape. By sucking on the inhaler (see image below), the open capsule starts spinning, releasing the levodopa into the air and subsequently into the lungs.
The ARCUS inhalation technology. Source: ParkinsonsLife
Pretty straightforward, right? Nice idea, cool design, easy to use.
But does it work?
What were the results of the clinical trials?
Title: Preclinical and clinical assessment of inhaled levodopa for OFF episodes in Parkinson’s disease.
Authors: Lipp MM, Batycky R, Moore J, Leinonen M, Freed MI.
Journal: Sci Transl Med. 2016 Oct 12;8(360):360ra136.
PMID: 27733560 (This article is OPEN ACCESS if you would like to read it)
In their research report, the scientists provided data from three studies: preclinical, phase one clinical, and phase two clinical. In the preclinical work, they measured the levels of L-dopa in dogs who had inhaled levodopa powder. When they looked at blood samples, they found that levodopa levels peaked in all of the animals 2.5 min after administration. This represented a very quick route to the blood system, as dogs that were given levodopa plus carbidopa orally did not exhibit peak blood levodopa levels until 30 min after administration.
In the phase one (safety) clinical trial, 18 healthy persons were enrolled, and again comparisons were made between inhaled CVT-301 and orally administered carbidopa/levodopa. This study demonstrated that CVT-301 was safe and had a similar rapidity of action as in the preclinical dog study.
Next, the researchers conducted a phase two (efficacy) clinical study. This involve 24 people with Parkinson’s disease inhaling CVT-301 as a single 50mg dose during an OFF episode (periods of no prescribed medication). 77% of the CVT-301 treated subjects showed an increase in plasma levodopa within 10 min. By comparison, only 27% of a group of subjects taking oral doses of carbidopa/levodopa at a 25-mg/100-mg dose achieved the same levels within that time. Improvements in timed finger tapping and overall motor function (as measured by the Unified Parkinson’s Disease Rating Scale) were observed between 5 and 15 minutes after administration.
The most common adverse event was cough, but all of the coughing events were considered mild to moderate, generally occurring at the time of inhalation. In most cases, they were resolved rapidly and became less frequent after initial dosing.
So what does it all mean?
Inhalation of L-dopa may represent a novel means of treating people with Parkinson’s disease, especially those who struggle with swallowing pills. The most obvious benefit is the speed with which the subjects see results.
The amount of L-dopa being used is very high, however, and we will be interested to see the results of more long term studies before passing judgement on the inhaler approach. We’ll keep you informed as more information comes to hand.
The banner for today’s post is sourced from the BBC
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.