Older siblings and Parkinson’s disease

April 18, 2016April 19, 2016 ~ Simon ~ 3 Comments

Curious new research results out of Sweden this weekend…

To all of our readers who have older siblings that you grew up fighting with – you should go and give them a hug today, because apparently they have lowered your risk of Parkinson’s disease.

Like I said ‘curious’.

enhanced-873-1401832891-14

Source: Buzzfeed

Older siblings. Nothing but trouble (a bit like younger siblings now that I think about it).

Who needs them.

Well, according to a massive new epidemiological study from the Karolinska Institutet, Stockholm (Sweden), we all do!

Siblings-title

Title: Early-Life Factors and Risk of Parkinson’s Disease: A Register-Based Cohort Study.
Authors: Liu B, Chen H, Fang F, Tillander A, Wirdefeldt K.
Journal: PLoS One. 2016 Apr 15;11(4):e0152841.
PMID: 27082111 (This article is OPEN ACCESS if you would like to read it)

This is a fascinating study, not only in its size and scale, but for the interesting details in the results.

The investigators collected a huge amount of information from multiple nationwide Swedish registers that are cross-linked thanks to the national personal identification number system that is used in Sweden (each Swedish resident is assigned a unique number).

sweden_stockholm

Stockholm, the capital of Sweden. Source: Budgetyourtrip

The information was collected from:

The Swedish Multi-Generation Register (MGR) – which holds information about the biological and adoptive parents for all residents born in 1932 or later, and were alive or lived in Sweden in 1961. This database covers over 95% of Swedish-born residents, plus more than 22% of foreign-born residents in Sweden.
The Swedish Patient Register – established in 1964/1965, this databases collects inpatient discharge records. It became nationwide in 1987, and since 2001, the Patient Register has recorded information on every inpatient visit and vast majority of the outpatient visits for all Swedish residents.
They also linked their data to the Migration Register and Swedish Population and Housing Censuses from 1960, 1970, 1980, and 1990 for information on socio-economic status.

Like I said, ‘a huge amount of information’. They next set up a selection criteria. Within their pool of people for analysis, individuals had to:

be born in Sweden between 1932 and 1970
have information available regarding maternal links in the MGR
be alive and free of Parkinson’s disease on January 1, 2002,
40 years or older on January 1, 2002 or turned 40 years during the study period

3 545 612 people fulfilled this criteria. 8779 cases of Parkinson’s disease were identified within that population of people (a further 2658 people were identified as having Parkinson’s disease, but since they were diagnosed before 2002, they were excluded). When looking at the findings of the analysis of this study:

Unsurprisingly:

the average age of diagnosis was 65.1 years of age
males had a higher risk than females (1.5 times more men than women)
parental occupation as farmers increased risk of Parkinson’s
a family history of the condition results in a higher risk of Parkinson’s disease.
No difference between blue or white collar occupations, or self employed roles
No difference between month/season of birth
No association with early life factors, including flu burden in the year of birth.

Surprisingly:

Compared to those without older siblings, the risk of developing Parkinson’s disease was 7% lower among participants with older siblings (HR = 0.93, 95% CI: 0.89, 0.98). The number of people with no older siblings was 1.68 million, of which 5384 had Parkinson’s disease. But of those with older siblings (1.86 million) only 3395 had Parkinson’s disease. Curiously, however, there was no further associations (eg. the number of older siblings or the interval length between the individual and their older siblings).

The effect (7%) is small, but the number of cases is very large, so we can assume that the finding is real. But how to explain it?!?

Even more surprisingly:

This is not the first time we’ve seen something like this:

Fang-title

Title: Maternal age, exposure to siblings, and risk of amyotrophic lateral sclerosis.
Authors: Fang F, Kamel F, Sandler DP, Sparén P, Ye W.
Journal: Am J Epidemiol. 2008 Jun 1;167(11):1281-6.
PMID: 18367467

In a similar sort of study published in 2008 (also from researchers at the Karolinska Institute in Sweden), it was reported that the risk of amyotrophic lateral sclerosis (ALS, also called Lou Gehrig’s disease; another neurodegenerative condition) increased with the number of younger siblings, and children whose first younger sibling was born after the age of 6 years had the highest risk of ALS. In contrast to the Parkinson’s research above, however, exposure to older siblings was not associated with an increased risk of ALS.

And a similar sort of result has also been observed in cases of Schizophrenia:

Westergaard-title

Title: Exposure to prenatal and childhood infections and the risk of schizophrenia: suggestions from a study of sibship characteristics and influenza prevalence.
Authors: Westergaard T, Mortensen PB, Pedersen CB, Wohlfahrt J, Melbye M.
Journal: Arch Gen Psychiatry. 1999 Nov;56(11):993-8.
PMID: 10565498

This research came from a different Scandinavian capital (Copenhagen), and involved only 1.74 million people, but it suggested that larger sibships were associated with an increased risk of developing schizophrenia. This result was independent of birth order or interval length between siblings.

Why these effects exist is a question yet to be answered. In each of these studies, the authors propose elaborate possibilities (eg. developmental theories involving the immune system, etc), but there is no evidence (yet) to support them. Given that the effects are small (just a 7% reduction in risk in the case of Parkinson’s), it would be interesting to investigate differences between subjects within the Parkinson’s population, to determine if there is a subset of individuals more affected than others by this sibling phenomenon. By comparing which commonalities they may share (genetic, environmental or otherwise) we could identify patterns of risk factors for specific individuals.

So while the Parkinson’s connection is an interesting finding, obviously more research is required to better understand what is going on.

Curious result though, right?

Disco-needs-ya – the science of dyskinesias

March 1, 2016March 8, 2016 ~ Simon ~ 13 Comments

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.

Dykinesias

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.

Dyskinesia

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:

Dyskinesia_title

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.

Neurosurgery

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!

New Research – on how movement is controlled

February 9, 2016 ~ Simon ~ 4 Comments

A couple of very interesting studies were published a week ago that help us to better understand how we move. They are particularly important with respects to Parkinson’s disease.

The parts of the brain involved in movement

Movement is largely controlled by the activity in a specific collection of brain regions, collectively known as the ‘Basal ganglia‘.

B9780702040627000115_f11-01-9780702040627

The location of the basal ganglia structures (blue) in the human brain. Source: iKnowledge

The basal ganglia receives signals from the overlying cortex, processes that information before sending the signal on down the spinal cord to the muscles that are going to perform the movement.

There is also another important participant in the regulation of movement: the thalamus.

Brain_chrischan_thalamus

A brainscan illustrating the location of the thalamus in the human brain. Source: Wikipedia

The thalamus is a structure deep inside the brain that acts like the central control unit of the brain. Everything coming into the brain from the spinal cord, passes through the thalamus. And everything leaving the brain, passes through the thalamus. It is aware of most everything that is going on and it plays an important role in the regulation of movement.

The direct/indirect pathways

The processing of movement in the basal ganglia involves a direct pathway and an indirect pathway. In simple terms, the direct pathway encourages movement, while the indirect pathway does the opposite (inhibits it). The two pathways work together like a carefully choreographed symphony.

The motor features of Parkinson’s disease (slowness of movement and resting tremor) are associated with a breakdown in the processing of those two pathways, which results in a stronger signal coming from the indirect pathway – thus inhibiting/slowing movement.

Pathways

Excitatory signals (green) and inhibitory signals (red) in the basal ganglia, in both a normal brain and one with Parkinson’s disease. Source: Animal Physiology 3rd Edition

Both the direct and indirect pathways finish in the thalamus, but their effects on the thalamus are very different. The direct pathway leaves the thalamus excited and active, while the indirect pathway causes the thalamus to be inhibited.

The thalamus will receive signals from the two pathways and then decide – based on those signals – whether to send an excitatory or inhibitory message to the cortex, telling it what to do (‘get excited and movement’ or ‘don’t get excited and don’t move’, respectively).

Where does dopamine come into the picture?

In Parkinson’s disease, the cells in the brain that produce the chemical dopamine are lost. These cells reside in a structure called the substantia nigra (or SNc in the figure above). What effect does this cell loss have on the direct and indirect pathways? Under normal circumstances the dopamine neurons excite the direct pathway and inhibit the indirect pathway.

In Parkinson’s disease the loss of dopamine neurons results in increased activity in the indirect pathway. As a result, the thalamus is kept inhibited. With the thalamus subdued, the overlying motor cortex has trouble getting excited, and thus the motor system is unable to work properly.

So what was published last week?

Two papers.

Both from the same lab (Well done!)

One in the prestigious scientific journal, Cell and the other in her sister journal, Neuron:

Roseberry-title

Title: Cell-Type-Specific Control of Brainstem Locomotor Circuits by Basal Ganglia.
Authors: Roseberry TK, Lee AM, Lalive AL, Wilbrecht L, Bonci A, Kreitzer AC.
Journal: Cell, 2016 Jan 28;164(3):526-537.
PMID: 26824660

The researchers in this study discovered signal sent from the basal ganglia that selectively activates a group of neurons an area of the brainstem called the ‘mesencephalic locomotor region’. Some of the neurons in this area release a chemical called glutamate. Glutamate is a neurotransmitter that excites the cells it comes into contact with. The researchers who conducted this study found that these glutamate-releasing cells in the mesencephalic locomotor region are responsible for initiating movement.

The researchers used a new technique called ‘optogenetics’ that allows light to activate or inhibit specific cells in the brain. By using this technique on the cells in the direct (dMSN in the figure above) or indirect pathways (iMSN) of the basal ganglia, the researchers were able to control the glutamate-releasing neurons in the mesencephalic locomotor region of mice -initiating or inhibiting their movement, respectively.

The researchers then took the study one step further and used the optogenetics approach directly on the glutamate-releasing neurons in the mesencephalic locomotor region, and they were able to control the initiation of movement in the mice irrespective of the signal being generated by the direct or indirect pathways. That is to say, when the glutamate-releasing neurons in the mesencephalic locomotor region were activated, the mouse would move even when the basal ganglia was sending an inhibitory signal.

So what does it all mean?

While some of the findings of the study were already known, the researchers here have elegantly linked the workings of the basal ganglia and the mesencephalic locomotor region, helping us to better understand the neurological functioning of movement. Deep brain stimulation of the mesencephalic locomotor region has already been attempted and it has demonstrated mixed results in people with Parkinson’s disease (it does appear to help with regards to reducing falls – click here and here for more on this).

It will be interesting to follow the research resulting from this current study.

Parker-title
Title: Pathway-specific remodeling of thalamostriatal synapses in Parkinsonian mice
Authors: Parker PRL, Lalive AL, Kreitzer AC.
Journal: Neuron, 2016
PMID: 26833136

In the second study, the researchers (the same folks who gave us the first paper!) found that the basal ganglia is biased towards the direct pathway. The signal coming from the neurons involved in the direct pathway are stronger than those in the indirect pathway. When dopamine is removed however (as in the case of Parkinson’s disease), the system swings in the opposite direction and becomes biased toward the indirect pathway – the neurons in the direct pathway begin to produce a weaker signal than their counters in the indirect pathway which increase the strength of their signal.

Given that both pathways influence the activity of the thalamus, the researchers next turned their attention to that structure. Again using the ‘optogenics‘ (light-activation) technique, the investigators reduced the inhibitory signal coming from the thalamus and were able to reversibly correct the motor impairs observed in the mice with Parkinson’s-like features.

What does this mean for Parkinson’s disease?
This study turns our attention away from what is happening in the basal ganglia and focuses it on the thalamus, which has not receive the same amount of attention with regards to Parkinson’s disease.

There is a lot already known about changes in the thalamus in Parkinson’s disease (click here for more on this), and deep brain stimulation of structures in neighbouring regions is a regular therapy for Parkinson’s disease (targeting the subthalamic nuclei). But this new paper further breaks down the circuitry of movement for us and offers novel directions for future therapeutic approaches for Parkinson’s disease.

We can be sure that a lot of Parkinson’s disease research is now going to focus on the thalamus.

The vulnerability of dopamine cells in the brain

January 25, 2016 ~ Simon ~ Leave a comment

The classical clinical motor features of Parkinson’s disease (slowness of movement, rigidity and a resting tremor in one of the limbs) are associated with the loss 60% of the dopamine neurons in the midbrain.

What does this mean?

The midbrain is a structure at the top of the spinal cord – just as you enter the brain proper – and dopamine is a chemical that is produced in the brain. The dopamine neurons in the midbrain form connections with different areas of the brain, and are involved in many basic neurological functions, such as movement, motivation and addiction.

CD-Pathology-Parkinson'sDisease Chptr19-Fig 19-3 Parkinson DiseaseGrossMidbrain copy

Sections of the human midbrain from a healthy individual (left) and a person who had Parkinson’s disease (right). The dopamine cells in the control subject can be seen on both sides of the brain with the eye because they produce a chemical (neuromelanin) that makes them black. These cells are noticeably absent in the Parkinsonian brain. Source: Springer

Not all midbrain dopamine neurons are affected in the same way in Parkinson’s disease though.

There are three basic groupings of dopamine neurons in the midbrain region:

The substantia nigra pars compacta (or SNC)
The ventral tegmental area (or VTA)
The retrorubral fields (this is a very small group compared with the VTA and SNC)

Subdivisions

As the image above illustrates the SNC is divided into two regions – a dorsal layer and a ventral layer.

It has been acknowledged for a long time that the dopamine neurons in the SNC are more vulnerable in Parkinson’s disease than dopamine neurons in the VTA. We have no idea why this specific vulnerability exists. A great deal of attention has been focused on the SNC as a result.

The vulnerability of the SNC dopamine neurons when compared to the VTA, however, is not as clear as many researchers would believe.

In an interesting study published last year, some researchers from the University of Iowa, reviewed previous studies of postmortem analysis of the brains of people with Parkinson’s disease, in particular, focusing on the studies that had counted the number of dopamine neurons in the VTA and the SNC. The results were very interesting:

VTA-title

Title: The Vulnerable Ventral Tegmental Area in Parkinson’s Disease.
Authors: Alberico SL, Cassell MD, Narayanan NS.
Journal: Basal Ganglia. 2015 Aug 1;5(2-3):51-55.
PMID: 26251824

In essence, the study was very simple: the researchers compared the percentage of VTA and SNC dopamine neurons lost in Parkinson’s disease as determined by eight previous studies. They then conducted their own postmortem analysis and compared the results.

In their review of the previous studies, the researchers found that while the SNC was more vulnerable in Parkinson’s disease (approximately 70% of the dopamine neurons are lost), the VTA region still lost 50% of it’s dopamine neurons (see table below).

VTA-table

Curiously, the researcher’s own postmortem analysis found that the VTA was actually more vulnerable than the SNC. Their analysis, however, was based on only 3 brains. In addition, questions can be raised as to how the previous studies defined the borders of the SNC and VTA. Difference exist in those delineations of borders, which may impact on the number of dopamine neurons counted in each region.

The important message, however, is that the VTA is also badly affected in Parkinson’s disease. And given that the VTA is a region involved in mood and motivation, acknowledging its involvement in the disease will help to focus more research attention on to those areas of functioning in Parkinson’s.

The difference between men and women

November 28, 2015November 28, 2015 ~ Simon ~ 3 Comments

At the bottom of our previous post, we mentioned that Japan is the only country where women have a higher incidence of Parkinson’s disease than men.

We also suggested that we have no idea why this difference exists. Well, a study presented at the Cardiovascular, Renal and Metabolic Diseases conference in Annapolis City (Maryland) last week may now be able to explain why this is.

The prevalence of Alzheimer’s disease is significantly higher in women compared to men. One recent estimate suggested that almost two-thirds of individuals diagnosed with Alzheimer’s disease are women (More information here). One possible reason for this is that Alzheimer’s disease is a condition of the elderly and women live longer.

So why is it then is the exact opposite true in Parkinson’s disease???

Source: The Telegraph Newspaper

Men are approximately twice as likely to develop Parkinson’s disease as females (More information here)

In addition, women are on average diagnosed 2 years later than men (More information here)

This gender difference has long puzzled the Parkinson’s research community. But now a group from the University of North Texas Health Science Center think that they may have the answer.

The researchers – lead by Shaletha Holmes from Dr Rebecca Cunningham’s lab – observed that when they stressed dopamine neurons, adding the male hormone testosterone made the damage worse. Interestingly, they found that testosterone was doing this by acting on a protein called cyclooxygenase 2 (or COX2). When they blocked the actions of COX2 while stressing dopamine neurons, they found that they also blocked the damaging effect of testosterone. The researchers concluded that testosterone may exacerbate the damage (and death) in dopamine neurons that occurs in Parkinson’s disease, thus possibly explaining the sex differences described above.

Now, there are several interesting aspects to this finding:

Firstly, the use of Ibuprofen, the nonsteroidal anti-inflammatory drug used for relieving pain, has long been associated with reducing the risk of Parkinson’s disease (More information here).

Ibuprofen is a COX2 inhibitor.

But more importantly, several years ago it was shown that Japanese men have lower levels of testosterone than their Western equivalents. Here is the study:

Title: Evidence for geographical and racial variation in serum sex steroid levels in older men.
Authors: Orwoll ES, Nielson CM, Labrie F, Barrett-Connor E, Cauley JA, Cummings SR, Ensrud K, Karlsson M, Lau E, Leung PC, Lunggren O, Mellström D, Patrick AL, Stefanick ML, Nakamura K, Yoshimura N, Zmuda J, Vandenput L, Ohlsson C; Osteoporotic Fractures in Men (MrOS) Research Group.
Journal: Journal of Clinical Endocrinol. Metab. 2010 Oct;95(10):E151-60.
PMID: 20668046

The study suggested that total testosterone levels (while similar in men from Sweden, Tobago and the US) were 16 per cent higher in men from Hong Kong and Japan. BUT – and here’s the catch – Japanese men also had higher levels of a testosterone-binding hormone (Sex hormone-binding globulin or SHBG), so there is less of the testosterone floating around free to act. As a result, Japanese men had the lowest levels of active testosterone in the study.

Intriguingly, the researchers found that Japanese men who emigrated to the US had similar testosterone levels to men of European descent, suggesting that environmental influences may be having an effect of testosterone levels. Diet perhaps?

If testosterone is found to play a role in the gender difference found in Parkinson’s disease, the lower levels of free testosterone observed in Japanese men may explain why women in Japan have a higher risk of Parkinson’s disease than men.

EDITOR’S NOTE: WHILE WE HAVE NO DOUBTS REGARDING THE RESEARCH OF DR CUNNINGHAM AND HER GROUP, WE ARE TAKING A LEAP IN THIS POST BY APPLYING THE TESTOSTERONE RESULTS TO THE GENDER DIFFERENCE IN JAPAN. THIS IS PURE SPECULATION ON OUR PART. WE HAVE SIMPLY SAT DOWN AND TRIED TO NUT OUT POSSIBLE REASONS AS TO WHY THERE IS A REVERSED GENDER DIFFERENCE FOR PARKINSON’S DISEASE IN JAPAN. OUR THEORY IS YET TO BE TESTED, AND MAY BE COMPLETELY BONKERS. WE PRESENT IT HERE PURELY FOR DISCUSSION SAKE AND WELCOME YOUR THOUGHTS.