And now spit!

Did you know that human saliva is 99.5% water?


But a recent set of studies have suggested that the remaining 0.5% holds some interesting insights into Parkinson’s disease.

Interesting fact about saliva – while there is a lot of debate as to how much saliva we produce on a daily basis (anywhere between 0.75 to 1.5 litres per day), it is generally accepted that during sleep the amount of saliva produced drops to almost nothing. Why? Big shrug.

Saliva is a solution produced by three main sets of glands in our mouth: the parotid, Sublingual, and Submandibular glands:


The human salivary glands. Source: WebMD 

The solution produced serves several important functions, namely:

  • beginning the process of digestion by breaking down food particles.
  • protecting teeth from bacterial decay.
  • Moisturising food to aid in the initiation of swallowing.

As we mentioned above, 99.5% of saliva is water. The remaining 0.5% is made up of enzymes and antimicrobial agents. There is also a number of cells in each millilitre of saliva (as many as 8 million human and 500 million bacterial cells per millilitre).

By analysing those human cells, scientists can learn a lot about a person. For example, they can conduct genetic analysis and determine if a person has a particular mutation.

So what has this got to do with Parkinson’s disease?

Well, recently several research groups have been looking at saliva with the hope that biomarkers – chemicals that may allow for early detection or better monitoring of Parkinson’s disease – could be found.

And recently, some of that research has seemingly paid big dividends:


Title: Prevalence of Submandibular Gland Synucleinopathy in Parkinson’s Disease, Dementia with Lewy Bodies and other Lewy Body Disorders.
Authors: Beach TG, Adler CH, Serrano G, Sue LI, Walker DG, Dugger BN, Shill HA, Driver-Dunckley E, Caviness JN, Intorcia A, Filon J, Scott S, Garcia A, Hoffman B, Belden CM, Davis KJ, Sabbagh MN.
Journal: J Parkinsons Dis. 2016 [Epub ahead of print]
PMID: 26756744

In this study, published in January of this year, the researchers collected small biopsies of the submandibular gland (one of the three primary producers of saliva) from the bodies of people who died with various conditions (including Parkinson’s disease). They analysed the biopsies for alpha synuclein – the chemical in the brain associated with Parkinson’s disease. We have previously written about alpha synuclein, a chemical in the brain that is associated with Parkinson’s disease (for a primer on alpha synuclein, click here). They found that alpha synuclein was present in the saliva gland of 89% of the subjects who died with Parkinson’s disease, but none of the 110 control samples.

This result led the same research groups to attempt a similar study on live subjects and they published the results of that study in February of this year:


Title: Peripheral Synucleinopathy in Early Parkinson’s Disease: Submandibular Gland Needle Biopsy Findings.
Authors: Adler CH, Dugger BN, Hentz JG, Hinni ML, Lott DG, Driver-Dunckley E, Mehta S, Serrano G, Sue LI, Duffy A, Intorcia A, Filon J, Pullen J, Walker DG, Beach TG.
Journal: Mov Disord. 2016 Feb;31(2):250-6.
PMID: 26799362

The researchers enrolled 25 people with early-stage Parkinson’s disease (less than  5 years since diagnosis) and 10 control subjects. All of these subjects underwent a small biopsy of the submandibular gland. Those biopsies were then analysed for alpha synuclein and the researchers found that 74% of the Parkinsonian biopsies and 22% control biopsies had alpha synuclein present in the submandibular gland.

And remarkably, this report was followed up this last week by a group in Italy, who published some very interesting data:


Title: Abnormal Salivary Total and Oligomeric Alpha-Synuclein in Parkinson’s Disease.
Authors: Vivacqua G, Latorre A, Suppa A, Nardi M, Pietracupa S, Mancinelli R, Fabbrini G, Colosimo C, Gaudio E, Berardelli A.
Journal: PLoS One. 2016 Mar 24;11(3):e0151156.
PMID: 27011009    (this report is OPEN-ACCESS if you would like to read it)

The researchers collected salivary samples – actual spit – from 60 people with Parkinson’s disease and 40 age/sex matched control subjects. They then measured the saliva for different types of alpha synuclein. In this study, the researchers measured both the total amount of alpha synuclein in the saliva and also special forms of alpha synuclein.

Alpha synuclein initially starts out in the brain in a monomeric form – as a single version of alpha synuclein. This form of alpha synuclein is believed to be safe. A more mature form of alpha synuclein, called oligomeric, is believed to be the seed of the aggregations found in the Parkinsonian brain, Lewy bodies.

Curiously, in this study the researchers found that the total amount of alpha synuclein in the salivary of people with Parkinson’s disease was lower than that of the control subjects. But – and it’s a big ‘but’ – the amount of alpha synuclein oligomers was higher in the people with Parkinson’s disease than normal healthy controls.

The researchers proposed that the decreased concentration of total alpha-synuclein may reflect the formation of lewy bodies in the brain, and that this test might help the early diagnosis of Parkinson’s disease.


Here at the Science of Parkinson’s we are approaching this research cautiously. Previous attempts at measuring saliva in Parkinson’s disease have not had such significant results when comparing people with Parkinson’s disease and controls (click here for more about that study). The need for better biomarkers of Parkinson’s disease provides the reasons for this research, but the variability between the results different groups are getting leaves one wondering about the viability of the approach. It would indeed make for a very easy, non-invasive testing platform for Parkinson’s disease (‘Please spit into this tube for me’), but more research is needed before it can be applied on the large scale.

We’ll keep watching and hoping.

Another connection between skin and Parkinson’s disease

This is very interesting.

We have previously written blog posts dealing with the connection between melanoma and Parkinson’s disease. And now, there is new research providing a new link between another skin condition and Parkinson’s disease.


What is Rosacea?

Rosacea is a chronic skin condition, classically characterized by a redness of the face. This is the result of dilation of blood vessels in the facial skin, and is usually accompanied by pustules and swelling. Rosacea is indiscriminate in which age group it afflicts and there are four subtypes: three specifically affecting the skin and another affecting the eyes (ocular rosacea).


An example of Rosacea.Source: Medscape

Rosacea is diagnosed in women almost three times more than men. It is also more common in people between the ages of 30 and 50, and appears to have a preference for Caucasians of northwestern European descent (hence it’s nickname: the “curse of the Celts”).

What has this skin condition got to do with Parkinson’s disease?

Well, back in 2001 this study was published:


Title: Skin function and skin disorders in Parkinson’s disease.
Authors: Fischer M, Gemende I, Marsch WC, Fischer PA.
Journal: J Neural Transm. 2001;108(2):205-13.
PMID: 11314773

In this study, the researchers were investigating seborrheic dermatitis (similar to rosacea, this is an inflammation condition that presents itself as flaky, itchy, and red skin) and hyperhidrosis (abnormal increase in sweating) in Parkinson’s disease. They measured these afflictions in  70 people with Parkinson’s disease and 22 matched control subjects. Almost 20% of the people with Parkinson’s disease had seborrheic dermatitis and half of the Parkinson’s population had hyperhidrosis. The researchers also found that half of the Parkinson’s group also had abnormal sebum levels – sebum being a waxy substance produced by the skin (interestingly, we have previously mentioned sebum in a post about a lady who can smell Parkinson’s disease).

This was an interesting result, but it was never really followed up…until this last week, when another study was published:


Title: Exploring the Association Between Rosacea and Parkinson Disease: A Danish Nationwide Cohort Study.
Authors: Egeberg A, Hansen PR, Gislason GH, Thyssen JP.
Journal: JAMA Neurol. 2016 Mar 21. [Epub ahead of print]
PMID: 26999031

The size of this new study is amazing: the researchers looked at data from an national database which includes all Danish citizens 18 years or older from January 1, 1997 to December 31, 2011. That is a reference population of 5.4 million individuals!

Of these, 22 387 individuals (43.8% women) received a diagnosis of Parkinson disease between 1997 -2011, and 68 053 individuals (67.2% women) had a history of the skin condition rosacea.

The general population rate of Parkinson disease was 3.5 cases per 10 000 person. But in the population that had a history of rosacea the rate of Parkinson’s disease was 7.6 cases per 10 000 people – almost twice as high as the general population. Interestingly, when they looked at the subtypes of rosacea, the researchers found that there was a more than 2-fold increase in the risk of Parkinson disease in patients who had a history of ocular rosacea.

Even more interesting: treatment with tetracycline – an antibiotic – appears to have reduced the risk of Parkinson’s disease. The researchers also noted that people with severe rosacea have the same risk of developing Parkinson’s disease as do those who have more moderate rosacea.

This is an interesting study, further indicating a connection between the skin and Parkinson’s disease. Whether the relationship indicates anything causal or simply occurring in parallel is yet to be determined. But given similar previous association, we obviously need to take a closer look at skin.

Does the age of onset make a difference?

This is Dr Henri Huchard (1844-1910; a French neurologist and cardiologist):


Source: Wikipedia

In 1875, he described the case was of a child who, at just 3 years of age, presented with all the clinical features of Parkinson’s disease. Since that report, there have been many studies detailing the condition that has come to be known as ‘juvenile Parkinsonism‘. Currently the youngest person diagnosed with Parkinson’s disease is a young lady from Oklahoma. She was diagnosed at 10-years of age, but had shown symptoms since the age of 2.

We are going to explore juvenile Parkinson’s disease in future post, but today’s post will review some new research that looks at the differences in Parkinson’s disease features of people diagnosed at different ages.

For most members of the general public, Parkinson’s disease is considered a condition of the elderly. And this is a fair line of thinking given what they probably observe out there in the big wide world.


A few years ago though, Parkinson’s UK commissioned and published a report of the statistics/demographics of Parkinson’s disease in the UK (Click here for a copy of that report). In that report, they present this table:


It illustrates the estimated number of people in each age bracket that have Parkinson’s disease. As you can see, the bulk of the people affected are over the age of 60. But this does not mean that Parkinson’s disease is simply a condition of the aged. It is believed that worldwide at least 5% of diagnoses are to people below the age of 50 – this is considered early onset Parkinson’s disease.

There are many people – actor Michael J Fox among them – who have been diagnosed below the age of 40.


Actor Michael J Fox was diagnosed with Parkinson’s disease at age 30.
Source: MJFox foundation

Given this wide spectrum of age of onset, it is curious that more research has not been conducted comparing the differences in features of the condition between the different age groups. This situation, however was remedied recently:


Title: Age at onset and Parkinson disease phenotype.
Authors: Pagano G, Ferrara N, Brooks DJ, Pavese N.
Journal: Neurology. 2016 Feb 10.
PMID: 26865518

The investigators in this study took 422 people who had recently been diagnosed with Parkinson’s disease (none of them were on any anti-Parkinson’s medication, eg. L-dopa). The subjects were divided into 4 groups according to their age at diagnosis:

  1. younger than 50 years (58 subjects)
  2. 50-59 years (117 subjects)
  3. 60-69 years (168 subjects)
  4. older than 70 years (79 subjects)

The researchers then investigated differences in:

  • side of onset (left or right; dominant or non-dominant side of the body)
  • type of symptoms (rigidity or tremor, etc)
  • localization of symptoms occurrence (eg. arms, legs, etc)
  • severity of motor features (rigidity, tremor,…)
  • severity of nonmotor features (memory, attention,…)
  • severity nigrostriatal function (brain imaging of the dopamine system)
  • CSF biomarkers (Chemicals in the cerebrospinal fluid which surrounds the brain)

Curiously in all of the four groups, a quarter of the people had a family history of Parkinson’s disease. Familial history could suggest a genetic connection, and the genetic aspect of Parkinson’s disease has generally been associated with the early onset group. But this does not appear to be the case in this  study – there was no bias towards the younger onset group.

Asymmetry of motor features onset (eg. tremor, etc) was apparent in 97.8% of the total population, with 55% of those subjects having symptoms on their dominant side. It is interesting to note here, however, that the young onset group were the only group in which the non-dominant side was more affected than the dominant. Similarly, almost all of the symmetrical onset individuals (exhibiting no asymmetry in their motor features) were in the oldest group.

In all four groups, the arm was the more likely site of motor features (this was the case in approx. 85% in all groups). When considering other sites of onset, the head was more frequent in the older groups than the younger group, while the leg was more common in the younger group than the older group.

The older the age at onset the more severe the motor (eg. resting tremor, and postural instability scores) and nonmotor features (including autonomic, olfactory, and cognitive functions). This was accompanied by a greater dopaminergic dysfunction on the brain scan, and a reduction of alpha synuclein floating around in the cerebrospinal fluid.

Rigidity was more common in the young-onset group.

There were no differences between the groups in terms of issues associated with activities of daily living, measures of depression and anxiety, impulsive control, or sleep problems.

What does it all mean?

Why these difference exist and what they might tell us about the condition is yet to be determined. The results are interesting when one considers that the subjects had similar disease duration (they had all just been diagnosed; within 6 months of diagnosis). This suggests that the observed differences may be specific to the different age groups. A direct contribution of the aging process, however, has to be considered when assessing the older group.

This kind of analysis is necessary as it is the only way small details about the disease can be determined. We thought this was an interesting study

Herpes Simplex virus and Alpha-Synuclein

The theory of universal gravitation is not cast-iron. No theory is, and there is always room for improvement – Isaac Asimov

Previously we have discussed the possibility that a virus could be one of the causative agents in Parkinson’s disease (Click here for that post).

Well, recently an interesting research report was published that offers evidence to support that idea and proposes an interesting new idea:


Title: Humoral cross reactivity between α-synuclein and herpes simplex-1 epitope in Parkinson’s disease, a triggering role in the disease?
Authors: Caggiu E, Paulus K, Arru G, Piredda R, Sechi GP, Sechi LA.
Journal: J Neuroimmunol. 2016 Feb 15;291:110-4.
PMID: 26857504

In this study, the researchers began with a simple hypothesis:

Pathogens that resemble normal proteins in the body may cause the immune system to attack cells that have those normal proteins.

A pathogen is a biological entity that can cause damage or disease in our bodies. Our immune system’s response is to generate antibodies – small proteins that label the pathogen as foreign (or ‘not self’). The removal cells in the immune system then know which stuff in the body to attack and which to leave alone.

But what happens if parts of a particular pathogen look very similar to a normal protein in the body? Causing an immune response through a process of ‘molecular mimicry’. This is the question that the scientists behind today’s study were asking.

To test their hypothesis, the scientists looked at the herpes simplex virus 1 and compared it with the Parkinson’s disease-related protein, alpha synuclein. They found that there were two regions on the herpes simplex virus 1 that exhibited the same appearance as regions on the alpha synuclein protein.

Importantly, when they analysed the blood of people with Parkinson’s disease and some age-matched control, they found a statistically significant difference in the levels of antibodies generated against of those one regions of the Herpes simplex virus 1 (that regions was Ul4222–36) in people with Parkinson’s disease. Those antibodies were also reactive to a site on the alpha synuclein protein (that region was 100–114).

The researchers suggested that the results may implicate the involvement of Herpes simplex virus 1 in stimulating immune cells against the alpha synuclein resulting in neurons that have a lot of alpha synuclein in the brain being attacked (especially those that have alpha synuclein containing Lewy bodies).

What is Herpes simplex virus 1?


Herpes simplex virus. Source: Wikipedia

Herpes simplex virus 1 and 2 are members of the herpesvirus (Herpesviridae) family of viruses that infect humans. The two viruses should not be confused – Herpes simplex virus 1 produces cold sores, while herpes simplex virus 2 is associated with genital herpes.

Both herpes simplex virus 1 & 2 are not only able to infect neurons in the brain, but they can able to become dormant and hide in neurons, away from the immune system. They can remain in that state until suddenly/spontaneously becoming reactivated for reasons unknown.

Is there any association between Parkinson’s disease and Herpes simplex virus 1?

There is one paper published in 1993, that found an association between previous exposure to Herpes and developing Parkinson’s disease:

Title: Infections as a risk factor for Parkinson’s disease: a case-control study.
Authors: Vlajinac H, Dzoljic E, Maksimovic J, Marinkovic J, Sipetic S, Kostic V.
Journal: Int J Neurosci. 2013 May;123(5):329-32. doi: 10.3109/00207454.2012.760560. Epub 2013 Feb 4.
PMID: 23270425

In this study, the researchers found that Parkinson’s Disease was also significantly associated to mumps, scarlet fever, influenza, and whooping cough as well as herpes simplex 1 infections. They found no association between Parkinson’s disease and Tuberculosis, measles or chickenpox though.

This result raises the tantalizing possibility that other viruses may be stimulating the immune system by ‘molecular mimicry’. Obviously this still needs to be tested. Plus that study was based only 110 people with Parkinson’s (compared with 220 controls) in one particular geographical location (Belgrade, Serbia).

Other than making the immune system attack cells, could the antibodies to the virus be having other effects?

In the discussion of their paper, the authors of the Herpes simplex virus 1 study point out that alpha synuclein can be divided in three parts:

  1. the N-terminal region (which contains several of the point mutations related to early onset Parkinson’s disease)
  2. the central region (which appears to promote aggregation)
  3. the C-terminal portion (which tends to decrease protein aggregation)

The segment of alpha synuclein (100–114) that cross reacts with antibodies for Herpes simplex virus 1 (Ul4222–36) is part of the C-terminal region. Given that antibodies are binding to and removing to that non-aggregating section of alpha synuclein, are the remaining segments of α-synuclein left in place to foster aggregation (and perhaps forming Lewy bodies)?

Interesting research report that leaves us with new questions to explore.

Disco-needs-ya – the science of dyskinesias

This is Tom Isaacs. He is the charismatic founder of the Cure Parkinson’s trust.

tom isaacs

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 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.
PMID: 4178641

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?

Oh boy.

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.
PMID: 26920358

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.

Stay tuned!