Interesting reading

October 27, 2016October 27, 2016 ~ Simon ~ Leave a comment

There is a very interesting article in this week’s issue of Nature – one of the most eminent scientific journals.

With the 200 year anniversary of Parkinson’s disease coming up next year, the editorial team at Nature are keen to explore what is happening in the field.

There are numerous interesting articles about Parkinson’s disease available on their outlook site, but we thought this one is particularly interesting as it deals with the most controversial topic in Parkinson’s disease research.

Enjoy.

The banner for this brief post was sourced from the HuffingtonPost

Inhaling L-dopa

October 26, 2016October 26, 2016 ~ Simon ~ 7 Comments

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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.

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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).

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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.

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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:

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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.

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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).

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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.
PMID: 18591088

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.

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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.

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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.

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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?

inhaler

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

PAMs for Parkinson’s?

October 17, 2016October 17, 2016 ~ Simon ~ Leave a comment

clinicaltrials

In today’s post we are going to review the results of a phase 1 trial for new kind of drug being oriented at Parkinson’s disease. The results were announced in late September, and they indicate that the drug was well tolerated by subjects taking part in the study.

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Source: Prexton

Here at the Science of Parkinson’s disease we are always on the look out for novel drug therapies. Many of the treatments currently being tested in the clinic are simply different versions of L-dopa or a dopamine agonist.

So when Prexton Therapeutics recently announced the results of their phase 1 clinical trial for their lead drug, PXT002331, we sat up and took notes. PXT002331 (formerly called DT1687) is the first drug of its kind to be tested in Parkinson’s disease.

It is a mGluR4 positive allosteric modulator.

What on earth is mGluR4 positive allosteric modulator?
The metabotropic glutamate receptors (mGluR) are an abundant family of receptors in the brain. Proteins bind to these receptors and activate (or block) an associated function. There are many different types of these receptors and mGluR4 is simply a small subset. The mGluR4s, however, are present in the areas affected by Parkinson’s disease, and this is why this particular family of receptors has been the focus of much research attention.

But what about the positive allosteric modulator part of ‘mGluR4 positive allosteric modulator’

Yes, good question.

This is the key part of this new approach. Allosteric modulators are a new class of orally available small molecule therapeutic agents. Traditionally, most marketed drugs bind directly to the same part of receptors that the body’s own natural occurring proteins attach to. This means that those drugs are competing with those endogenous proteins, thus limiting the potential effect of the drug.

Allosteric modulators get around this problem by binding different parts of the receptor. And instead of simply turning on or off the receptor, allosteric modulators can either turn up the volume of the signal being sent by the receptor or decrease the signals. This means that when the body’s naturally occurring protein binds in the receptor, allosteric modulators can either amplify the effect or reduce it depending on which type of allosteric modulators is being administered.

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How Allosteric modulators work. Source: Addrex Thereapeutics

There are two different types of allosteric modulators: positive and negative. And as the label suggests, positive allosteric modulators (or PAMs) increase the signal from the receptor while negative allosteric modulators (or NAMs) reduce the signal. Thus, mGluR4 PAMS are amplifying the signal of the mGluR4 receptors.

Why do we want an amplification of a particular signal?

That is a hard question to answer.

Here’s the short explanation:

When you are planning to make a movement with your body, the process of actually initiating that movement begins in the cortex, specifically the primary motor cortex:

A cross section of the human brain illustrating the primary motor cortex. Source: Droso4schools

The primary motor cortex receives information from other regions of the brain (such as the prefrontal cortex where you make a lot of your decisions), and it will then send a signal down into the brain and down the spinal cord telling the limbs to move. On the way down through the brain, the signal will pass through a series of check points that will filter the signal and determine the final strength of it.

A schematic of the feedback loop of check points. Source: Parkinson’s Biology

EDITOR’S NOTE: We have borrowed this image from the Parkinson’s biology blog, which we are huge fans of. We highly recommend people visit that site as well as our lovely site. They also provide easy to understand explanations of the biology of Parkinson’s disease.

These checkpoints represent a large feedback loop. The critical step in this process is the processing being conducted in the basal ganglia, which can be broken down into different subregions:

A schematic of the components of the basal ganglia. Source: Parkinson’s Biology

The globus pallidus (GPi) is the last area of the basal ganglia that the signal will pass through on it’s way to the thalamus (the ultimate decider of whether you will move or not), so if there is anything going wrong between these two structures the initiation of movement will be disrupted.

In a normal brain, the chemical dopamine is being produced in an area called the substantia nigra pars compacta (say that three times really fast). That dopamine is released in the striatum and other areas of the basal ganglia, and it has a mediating effect on the signal passing through these structures.

A schematic of the source of dopamine. Source: Parkinson’s Biology

In Parkinson’s disease, however, the dopamine producing cells of the pars compacta are loss – 60% by the time a person starts to have the clinical motor features appearing. The loss of this dopamine leaves the whole system ‘unmediated’. The feedback loop becomes extremely inhibited, resulting in problems initiating movement.

Deep brain stimulation can un-inhibit the globus pallidus, by mediating the signal passing through that structure. But this requires surgery and the implanting of probes deep inside the brain.

A schematic of deep brain stimulation of the globus pallidus. Source: Parkinson’s Biology (great website!)

A better way of reducing the inhibition in this feedback loop is the replacement of dopamine (which we do via the taking of treatments like L-dopa). This has been the standard approach for more than 50 years.

A new method of reducing the inhibition in the feedback loop would be to chemically targeting the globus pallidus, and this is what scientists are trying to do with the mGluR4 PAMS. By amplifying the signal of mGluR4s in the globus pallidus, the scientists believe that they can reduce the level of inhibition in the feedback loop.

The hope is that this approach is a less Parkinson’s disease-affected treatment. That is to say, the globus pallidus is structurally less affected by Parkinson’s disease than the substantia nigra pars compacta, and thus any treatment of the globus pallidus should be more stable over time (as the disease progresses).

That said, it is acknowledged that mGluR4 PAMS are NOT a potential cure for Parkinson’s disease, but rather a better way of treating the condition.

What research has been done on mGluR4 PAMS and Parkinson’s disease?

In August of 2003, some researchers at the pharmaceutical company Merck published a study which indicated that activation of mGluR4 could decrease the excessive levels of inhibition in the globus pallidus.

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Title: Group III metabotropic glutamate receptor-mediated modulation of the striatopallidal synapse.
Authors: Valenti O, Marino MJ, Wittmann M, Lis E, DiLella AG, Kinney GG, Conn PJ.
Journal: Journal of Neuroscience. 2003 Aug 6;23(18):7218-26.
PMID: 12904482 (This article is OPEN ACCESS if you would like to read it)

The researchers found that an mGluR4 agonist (a protein that binds to the receptor directly, encouraging the associated action) reduced inhibitory signal being produced in the globus pallidus (through a presynaptic mechanism of action). They next demonstrated that the effect did not happen in mice which do not have mGluR4s, illustrating the specificity of the effect. They finished the study by injecting the mGluR4 agonist into a rodent model of Parkinson’s disease and found beneficial effects – that were equivalent to L-dopa.

Based on this research, the scientists at Merck next turned their attention to modulating the mGluR4s in the globus pallidus using allosteric modulators:

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Title: Allosteric modulation of group III metabotropic glutamate receptor 4: a potential approach to Parkinson’s disease treatment.
Authors: Marino MJ, Williams DL Jr, O’Brien JA, Valenti O, McDonald TP, Clements MK, Wang R, DiLella AG, Hess JF, Kinney GG, Conn PJ.
Journal: Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13668-73.
PMID: 14593202 (This article is OPEN ACCESS if you would like to read it)

In this article, the same researchers introduce a positive allosteric modulator called ‘PHCCC’ which has a preference for binding to mGluR4. They found that when they put PHCCC – in combination with the mGluR4 agonist used in the previous study – onto cells in petri dishes, they got an amplification of the reduction in inhibition in the cells. Administered alone, PHCCC also produced a marked reversal of the motor deficit observed in a rodent model of Parkinson’s disease.

With these results, the scientists could begin building the justification for taking mGluR4 PAMs to the clinic. They were interested, however, in what impact mGluR4 PAMs could have on the involuntary motor problems associated with long-term L-dopa use, called dyskinesias (we have previously written about these – click here to read that post). So they decided to investigate whether mGluR4 PAMs may have an impact on dyskinesias:

Title: Pharmacological stimulation of metabotropic glutamate receptor type 4 in a rat model of Parkinson’s disease and L-DOPA-induced dyskinesia: Comparison between a positive allosteric modulator and an orthosteric agonist.
Authors: Iderberg H, Maslava N, Thompson AD, Bubser M, Niswender CM, Hopkins CR, Lindsley CW, Conn PJ, Jones CK, Cenci MA.
Journal: Neuropharmacology. 2015 Aug;95:121-9.
PMID: 25749357 (This article is OPEN ACCESS if you would like to read it)

In this study, the investigators compared a mGluR4 PAM with a mGluR4 agonist (similar to that used in the previous studies) in rodent models of L-dopa induced dyskinesias. They found that the neither of the two drugs modified the development of dyskinetic behaviours, nor could they modify the behaviours when given together with L-dopa. In fact, when a low dose of L-dopa was given to the animals (resulting in only mild dyskinesias), the researchers found that by adding mGluR4 PAM the dyskinetic behaviours became more exaggerated. The investigators concluded that stimulation of mGluR4 does not have anti-dyskinetic activity. This is an important characteristic to determine before taking a drug to the clinic for Parkinson’s disease.

So what were the results of the phase 1 clinical trial?

In July of 2012, Merck spun off the research into a new company called Prexton Therapeutics. The company almost immediately started setting up a phase 1 safety clinical trial for its lead compound, the mGluR4 PAM: PXT002331. A total of 64 healthy volunteers were enrolled to evaluate the safety and tolerability of several different doses of orally taken PXT002331. The study was completed on time and demonstrated that PXT002331 is safe and well tolerated (at doses well above those that produce robust effects in Parkinson’s disease animal models).

Very positive news.

The planning of a phase 2 clinical trial in people with Parkinson’s disease is now underway. It will take place in the first half of 2017, and this study will provide the first indications as to whether this new treatment approach will be effective in human at treating the features of Parkinson’s disease. We will keep you posted on the success of that study when the results become available.

Are other biotech companies using this approach?

Yes, PAM-based therapies for Parkinson’s disease are very much in vogue at the moment.

Just this month, the biotech company Asceneuron received a grant from The Michael J. Fox Foundation for Parkinson’s Research for the development of positive allosteric modulators of the M1 muscarinic acetylcholine receptor (M1 PAMs). So we can hopefully expect more from this approach to therapies.

Interesting times. And hopefully positive results to come.

EDITOR’S NOTE: It is important to remember that any clinical trial research discussed on this blog is of an educational nature. Nothing written here can or should be mistaken as medical advice. All of these drugs are still experimental and require extensive testing before being offered to the general population. Please speak with a certified clinician before attempting any change to your current medical treatment regime.

The image used in the banner of today’s post was sourced from MedTechBoston

The curious case of Bulgarian Gypsies and the incidence of Parkinson’s disease

October 11, 2016October 11, 2016 ~ Simon ~ Leave a comment

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In 2000, a research paper investigating the incidence of Parkinson’s disease in Bulgaria was published in the journal Neuroepidemiology.

The results were rather startling.

In their study, the researchers included a subpopulation of over 6,000 gypsies. In a population of that size they had expected to find 10-30 cases of Parkinson’s disease (based on the incidence in other populations of people).

What they actually found didn’t make any sense.

In this post we will look at the incidence of Parkinson’s disease around the world and why the Bulgarian gypsies are unique in the data.

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Bulgarian gypsies. Source: Youtube

Trying to determine how frequently a particular phenomenon occurs within a given population sounds like a pretty straightforward task, right?

In practise, however, it proves to be very difficult. In some cases, almost impossible. In the western/developed world – where the medical records databases exist – the task of determining certain medical characteristics within a population of interest is slightly easier, but most experts will agree that most measures of incidence still include a pinch of error and a smidgen of guesstimating.

Beyond the developed world, determining incidence in a population is a ‘door-knocking’ job. Researchers literally have to go from house to house and asking for a survey to be filled in, or conduct doorstep evaluations of the inhabitants. A much harder task and cultural characteristics begin to play a role in the outcomes (such as lower incidence of a particular disease in communities that don’t like to ‘lose face’).

Additional problems with measuring incidence

Other problems with measuring incidence within a population include:

Unimpeded access to the population (eg. some people live in isolated locations/communities)
Accurate measures/criteria of the disease (eg. remember we don’t have an accurate diagnostic test for Parkinson’s disease)
No response bias (posted surveys receive a limited response, and many affected individuals within a community will live with a condition without alerting their doctor)
The size of the effect (if only one or two people are affected by a characteristic, the task of determining incidence becomes much harder – consider the very low incidence of juvenile onset Parkinson’s disease – Click here for more on this)

With all of that said, many efforts have been made in trying to determine the incidence of Parkinson’s disease. Some consensus has become apparent, but there are some interesting differences.

The incidence of Parkinson’s disease

The incidence of Parkinson’s disease varies around the world and there are some interesting differences.

Most studies agree, however, that the incidence of Parkinson’s disease is approximately 0.3% of the general population in industrialized countries. That is, 1 person in every 2-300. As we are all aware, Parkinson’s disease is more common in the elderly, and as such the incidence rises to about 1% (or 1 in 100) in those over 60 years of age. The incidence rate continues to rise with age to 4% of the population over 80 years of age (almost 1 in every 20 people over 80 year of age).

In 2009, Parkinson’s UK published their report on the incidence of Parkinson’s disease within the UK and their numbers are very similar to those summarised above (Click here for a PDF file of that report).

Disease burden – another way of measuring a disease

Many epidemiologists (the people who measure all of this incidence stuff) now incorporate a different kind of population-disease measurement into their analysis: ‘Disease burden’.

Below is a map of ‘hotspot’ countries (in red) around the world that have the disease burden due to Parkinson’s disease according to the World Health Organisation (WHO) (click here for their raw data – Microsoft Excel file).

A world map of Parkinson’s disease burden (red = high incidence). Source: Wikipedia

The map illustrates the disability-adjusted life year (DALY) rates from Parkinson disease by country (per 100,000 inhabitants).

Yeah I know. It sound complicated, but it isn’t really.

The DALY is simply a measure of the overall disease burden that a population experiences, and it is expressed as the number of years lost due to ill-health, disability or early death. Put another way, the DALY for any given country is calculated by taking the total number of the years of life lost due to dying early and adding it to the number of years lost due to disability. So for the map above, the Maldives (dark red dot in the Indian Ocean) exhibits the highest burden with the country loses 557 years per 100,000 inhabitants.

And importantly these measures are ‘age adjusted’, so that countries with a higher proportion of elderly people (such as Japan) do not appear to have a higher burden due to Parkinson’s disease than a country with a younger population. The WHO numbers are provided by the government health services in each country.

The highest incidence of Parkinson’s disease

Ok, so if we leave the global/macro world of Parkinson’s disease incidence and focus on particular nations/communities of people, what does the research literature tell us about the incidence of Parkinson’s disease?

Well, one of the highest incidence occurs in the Amish community of the US midwest.

The Amish communities of the American midwest. Source: DartMed

The Amish community started in Switzerland in the 17th century. In the 18th and 19th centuries, many adherents
immigrated to the USA in an attempt to flee religious persecution. They now live in communities rather culturally isolated from society – maintaining a traditional way of life, ignoring the modern conveniences, and
marrying strictly within their religion (maintaining strict endogamy). They are not completely isolated, however, as they are work/conduct business with mainstream society. From a scientific standpoint, the Amish are a wonderful cases study. They have diligently kept meticulous family records dating far back in history. In addition, they forbid consumption of alcohol or use of tobacco.

Many years ago, researchers began to notice a high incidence of Parkinson’s features within the community. Several population studies have been conducted on the Amish, including this one:

Title: A population-based study of parkinsonism in an Amish community.
Authors: Racette BA, Good LM, Kissel AM, Criswell SR, Perlmutter JS.
Journal: Neuroepidemiology. 2009;33(3):225-30.
PMID: 19641327 (This article is OPEN ACCESS if you would like to read it)

The researcher in this study tried to recruit all of the individuals over the age of 60 (total 262 people) in an Old-Order Amish community of 4,369 people. Of the 213 subjects who agreed to participate, 15 had Parkinson’s disease while a further 73 individuals had a UPDRS (Unified Parkinson’s Disease Rating Scale) motor score of >9 (indicating early stages of Parkinson’s). The researchers calculated the prevalence of Parkinson’s disease in this population of people at 5,703/100,000 or 5% of the population over 60 years of age. This was far higher than the 1% of the 60+ years population in the rest of the world.

There are over 200,000 Amish in North America, and they have played a prominent historical role in Parkinson’s disease research – the first Parkinson’s-related genetic mutations were identified in genetically isolated Amish populations (Click here for more on this). The genetics of Parkinson’s disease in the Amish is not clear, however, as a recent large population analysis demonstrated:

Title: Parkinson disease loci in the mid-western Amish.
Authors: Davis MF, Cummings AC, D’Aoust LN, Jiang L, Velez Edwards DR, Laux R, Reinhart-Mercer L, Fuzzell D, Scott WK, Pericak-Vance MA, Lee SL, Haines JL.
Journal: Hum Genet. 2013 Nov;132(11):1213-21.
PMID: 23793441 (This article is OPEN ACCESS if you would like to read it)

The scientists behind this study collected DNA samples from 798 individuals (31 with diagnosed Parkinson’s disease) who are part of a 4,998 individuals living in the Amish communities of Indiana and Ohio. Although there were a couple of areas of DNA that may confer susceptibility towards Parkinson’s disease, the researchers did not find any major/significant regions (or loci) suggesting that even within the Amish the genetics of Parkinson’s disease may be more extensive than previously appreciated.

Is there a gender bias in the incidence of Parkinson’s disease?

Yes there is.

On average women have a later onset of Parkinson’s disease than men. In addition, around the world, men are more likely to be affected by Parkinson’s disease than women by a ratio of approximately 2:1.

Curiously, there is one country that bucks this trend: Japan

Source: Emaze

There are now several studies that find the incidence of Parkinson’s disease in Japan is higher in females than males (Click here for more on this), and we have previously looked at this curious difference in a previous post (Click here to read that post)

Is there any evidence that the incidence of Parkinson’s disease is increasing?

Interesting question, and yes there is:

Title: Time Trends in the Incidence of Parkinson Disease
Authors: Savica R, Grossardt BR, Bower JH, Ahlskog JE, Rocca WA.
Journal: JAMA Neurol. 2016 Aug 1;73(8):981-9.
PMID: 27323276

This very recent study analysed the incidence of Parkinson’s disease by using medical records from the Rochester Epidemiology Project to identify incidence cases of Parkinson’s disease and other types of parkinsonism in Olmsted County (Minnesota) between 1976 to 2005. And the researchers made an interesting discovery: between 1976 and 2005, the incidence of Parkinson’s disease has increased, particularly in men 70 years and older. The researchers speculate as to whether this increase is associated with a dramatic decrease in the rates of smoking or other environmental/life styles changes.

We should add that there is some research that refutes this finding and we are waiting to see what follow up analysis shows us – we will report that when it is available.

So what about the Bulgarian gypsies?

Oh yeah, almost forgot.

Title: Prevalence of Parkinson’s disease in Bulgarian Gypsies.
Authors: Milanov I, Kmetski TS, Lyons KE, Koller WC.
Journal: Neuroepidemiology. 2000 Jul-Aug;19(4):206-9.
PMID: 10859500

So between January and November of 1997, the Bulgarian scientists sent out their questionnaire, and they conducted door-to-door visits, eventually collecting a pool of over 6,000 people of gypsy descent. They were trying to determine the incidence of Parkinson’s disease within this community, but what they discovered was not what they expected:

Just one case of Parkinson’s disease.

A 61 year old man.

Given the incidence in most other communities, in a population of 6,000 people one might expect to see maybe 20 cases. Not just one!

The researchers concluded that the prevalence of Parkinson’s disease in the Gypsies was found to be 16/100,000 (based on that 1 case out of 6163 people), compared to 137/100,000 for Caucasians (based on 119 cases from 87,025 people). This means that Bulgarian gypsies have the lowest incidence of Parkinson’s disease in the world.

What? How?

Our answer: ????

We really do not know. No one does.

The authors of the research paper suggest that gypsies are believed to originate from North India, and given that the inhabitants of Asia have a lower rate of Parkinson’s disease than their western counterparts, this may partly explain the low frequency in the Bulgarian gypsies. This is only applicable, however, if similar low rates of Parkinson’s disease are found in other gypsy populations. To our knowledge, these studies have not been done (please feel free to correct us on this matter).

The banner for today’s post was sourced from BalkanMusicNight