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.

New research – Urate and Parkinson’s

January 23, 2016January 23, 2016 ~ Simon ~ 4 Comments

New research this week lends further support to ongoing clinical trials focused on urate in Parkinson’s disease:

urate

Title: Prospective study of plasma urate and risk of Parkinson disease in men and women.
Authors: Gao X, O’Reilly ÉJ, Schwarzschild MA, Ascherio A.
Journal: Neurology. 2016 Jan 13.
PMID: 26764029

The researchers in this study looked at 90,214 participants who are involved in three ongoing US-based longitudinal studies (the Nurses’ Health Study (NHS), the Cancer Prevention Study II Nutrition (CPS-IIN), and the Health Professionals Follow-up Study (HPFS)). They identified 388 people in these cohorts who had developed Parkinson’s disease (202 men and 186 women) since their respective longitudinal studies began, and they matched them to 1,267 randomly selected control subjects.

Blood samples that had been taken from the Parkinson’s and control subjects were analysed, and the level of urate was measured. Normal levels of urate range from 3.5-7.2 milligrams per deciliter (mg/dL). The researchers found that there was no difference between in spectrum of urate levels in the women (with or without Parkinson’s).

In men, however, things were very different. The men with the lowest levels of urate had less than 4.9 mg/dL, while those with the highest levels had 6.3-9.0 mg/dL. Among the men with Parkinson’s disease, 45 had the highest level of urate and 58 had the lowest – if no difference existed, this number should be 50:50, but instead there is more than 30% difference. Men with high levels of urate had a lower chance of developing Parkinson’s disease.

The researchers then combined their results with the results from three previous studies on the same topic and found a very similar result. This led the researchers to conclude that men, but not women, with higher urate concentrations had a lower future risk of developing Parkinson’s, suggesting that urate could be protective against Parkinson’s risk or could slow disease progression during the preclinical stage of disease.

So, what is urate?

During the breaking down of dietary proteins, the liver produces large amounts of a chemical called ‘ammonia’. Ammonia is toxic for the body, so the liver breaks it down further, and one of the products of that process is urate. If the body does not get rid of it, urate can build up and form crystals within the joints. High blood concentrations of urate can lead to gout and is also associated with other medical conditions, such as diabetes and the formation of kidney stones.

Paradoxically, urate is also an ‘antioxidant’ – a chemical that prevents tissue from being damaged by the negative effects of oxygen (yes, we need oxygen but not too much). Other antioxidants include vitamin C, and vitamin E. It is this antioxidant function of urate that researchers believe has a positive effect in Parkinson’s disease.

What are the clinical trials we mentioned?

In September 2015, a Phase III trial of Inosine was initiated. The study will involve 270 people with early-stage Parkinson’s. Inosine is a chemical precursor to urate and Phase III is the ‘acid test’ – a double blind test of treatment efficacy. A Michael J Fox Foundation-funded Phase II study showed that Inosine is safe and tolerable, and it also raised levels of urate in people with early-stage Parkinson’s disease. Now it is time to see if this raising of urate levels has a positive outcome. Enrollment for this trial is currently underway and -given the results of the study published this week – it will be interesting to see if there is a stronger effect in men in this phase III trial.

IMPORTANT EDITOR’S NOTE HERE: Inosine is commercially available as a dietary supplement, but we must stress that patients should act with caution. Inosine has not yet been proven as a therapy for Parkinson’s disease, and, as we indicated above, it can cause serious conditions such as gout and kidney stones. Please do not initiate usage of this chemical without first discussing it with your physician.

New Research -Shared genetic features

January 21, 2016January 22, 2016 ~ Simon ~ Leave a comment

There was an interesting new study published yesterday:

Sanchez-Mut-Title

Title: Human DNA methylomes of neurodegenerative diseases show common epigenomic patterns.
Author: Sanchez-Mut JV, Heyn H, Vidal E, Moran S, Sayols S, Delgado-Morales R, Schultz MD, Ansoleaga B, Garcia-Esparcia P, Pons-Espinal M, de Lagran MM, Dopazo J, Rabano A, Avila J, Dierssen M, Lott I, Ferrer I, Ecker JR, Esteller M.
Journal: Transl Psychiatry. 2016 Jan 19;6:e718. doi: 10.1038/tp.2015.214.
PMID: 26784972 – this article is OPEN ACCESS if you would like to read it.

The researchers were curious to look for common genetic markers between the major neurodegenerative disease. It is often forgotten that the different neurodegenerative conditions, such as Alzheimer’s disease and Parkinson’s disease, share some common pathological features (the characteristic signs of the diseases in the brain).

For example, when you look at the brains of people with Alzheimer’s disease, approximately 50% of them will also have the alpha-synuclein-containing ‘Lewy bodies’ in their brains, which are more commonly associated with Parkinson’s disease. Likewise, Beta-amyloid plaques and neurotangles, which are characteristic features of Alzheimer’s disease are commonly found in Parkinson’s disease brains (click here and click here for more on this topic).

To find these shared genetic markers, the researcher extracted DNA from the prefrontal cortex (Brodmann area 9) of the brains of people with Alzheimer’s disease, dementia with Lewy bodies, Parkinson’s disease and Alzheimer-like neurodegenerative profile associated with Down’s syndrome samples (more than 75 percent of people with Down Syndrome aged 65 and older develop Alzheimer’s disease – click here for more on this).

Importantly, the researchers were looking at DNA methylation, which is a commonly used tool that allows a cell to fix genes in the “off” position. That is to say, the gene can not be activated. Thus the researchers were looking for regions of DNA that have to closed down.

They found that a very defined set of genes are turned off in these neurodegenerative disorders, suggesting that these condition might have similar underlying mechanisms or processes that subsequently develop into different clinical entities. These newly identified regions of DNA methylation will be further investigated with the goal that one day they may be used as biomarkers in diagnosis and also as potential new targets for the regenerative therapies.

Viruses and Parkinson’s – a hit and run story?

January 16, 2016January 22, 2016 ~ Simon ~ 6 Comments

I was recently presenting a talk at a Parkinson’s support group meeting. Afterwards I sat with some of the attendees and we chatted over tea and cookies. At one point the lady sitting beside me tapped me on the arm and said:

“The other day we were discussing some of the commonalities that we [people with Parkinson’s] share. I wonder if they would be of interest to you?”

“Absolutely”‘ I replied, “Let’s hear them”

“Well, firstly, most of us have little or any sense of smell” she said

And I nodded, “this is a common feature amongst people with Parkinson’s disease” (Click here for more on this)

“Ok. Number two, we all have trouble doing ‘number twos'”

I nodded again, and explained that constipation and gastrointestinal problems are also common features of Parkinson’s disease. (Click here for more on this)

“Interesting”, she said, before aiding: “Thirdly, none of us have ever had chickenpox”

I confess I looked at her a long time.

I was speechless.

I had never heard of anything like that.

In science, we are always looking for the presence of possible causal agents – not their absence. I was so intrigued that I took her contact details and told her that I would go away and do some homework on the matter.

I’d like to share my findings here as part of a larger discussion on viruses and Parkinson’s disease.

Given the random and indiscriminate way in which Parkinson’s disease attacks people, scientists have looked for a virus that may be causing the condition.

Throughout our lives, our immune system is constantly under attack from viruses. They are small infectious agent that thrive by replicating themselves inside the living cells of other organisms. Technically speaking they are not alive as they lack most of the machinery which characterizes ‘life’ (most importantly the components that is necessary for reproduction). We currently know of approx. 3000 viruses, but we can only guess at the total number of viruses (it may be in the millions!).

There are several different ways that Parkinson’s disease could theoretically be caused in some way by a virus:

1. There may be a specific virus that we are unaware of that infects the body at some point in one’s life causing the slow progressive disease. This could be consider the ‘lightning bolt’ theory – a single unlucky event with terrible consequences. Such a theory has weight as it would explain why some clusters of Parkinson’s disease is sometimes observed. People often use the example of Michael J Fox and his TV work colleagues in this theory.

leadership-fox-m-img_2

Actor Michael J Fox and three other people who worked on the Canadian TV show ‘Leo & me’ went on to develop Parkinson’s disease. Image source: Michael J Fox Foundation

2. A virus attacking the body coincides with a secondary event (e.g. a bacterial infection) that may result in the slow progressive events that result in Parkinson’s disease. The secondary event may be a genetic mutation or exposure to an environmental toxin. The virus attack in itself may not be enough in itself.

The two theories outlined above are just theories. We do not know if Parkinson’s disease is caused by a viral infection.

There is, however, some lines of evidence supporting the idea:

Influenza and Parkinson’s disease

Between January 1918 and December 1920 there were two outbreaks of an influenza virus during an event that became known as the 1918 flu pandemic. Approximately 500 million people across the globe were infected, and this resulted in 50 to 100 million deaths (basically 3-5% of the world’s population). Given that is occurred during World War 1, censors limited the media coverage of the pandemic in many countries in order to maintain morale. The Spanish media were not censored, however, and this is why the 1918 pandemic is often referred to as the ‘Spanish flu’.

Influenza is the virus that causes ‘the flu’. Most commonly in a mild form (runny nose, sore throat, coughing, and fatigue), the symptom will arise two days after exposure and last for about a week. There are three types of influenza viruses, called Type A, Type B, and Type C. Type A are the most virulent in humans. The influenza virus behind both of the outbreaks in the 1918 pandemic was a Type A. It was called H1N1.

NOTE: The “H” (hemagglutinin) and the “N” (neuraminidases) are both proteins that are found on the outer surface of the virus. Different viruses have different hemagglutinin and neuraminidase proteins, hence the numbering.

At the same time that H1N1 was causing havoc, a Romanian born neurologist named Constantin von Economo reported a number of unusual symptoms which were referred to as encephalitis lethargica (EL). This disease left many of the victims in a statue-like condition, both motionless and speechless. You may be familiar with the Oliver Sacks book ‘Awakenings’ which was turned into a film starring Robin Williams and Robert De Niro – the patients in that book were victims of EL.

robin_williams_con_robert_de_niro_en_1990

Robin Williams and Robert De Niro in Awakenings

Historically, it was believed that EL was caused by the influenza virus from the 1918 Spanish influenza pandemic. This was largely due to a temporal association and the finding of influenza antigens in some of the suffers of EL. More recent evidence rejects this hypothesis (e.g. an absence of viral RNA recovered from the brains of postencephalitic PD patients – click here for more on this). We genuinely don’t know what caused EL.

But there has recently been some evidence suggesting a link between Parkinson’s disease and influenza:

Jang-title

Title: Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration.
Author: Jang H, Boltz D, Sturm-Ramirez K, Shepherd KR, Jiao Y, Webster R, Smeyne RJ.
Journal: Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):14063-8.
PMID: 19667183

The researchers in this study found that when they injected the highly infectious H5N1 influenza virus into mice, the virus progressed from the periphery into the brain, where it induced Parkinson’s disease-like symptoms. The virus also caused a significant increase in the aggregation of the protein Alpha Synuclein. Importantly, they witnessed the loss of dopamine neurons in the midbrain of the mice 60 days after resolution of the infection.

This study supports the theory we discussed above (theory 1.) of a virus possibly causing Parkinson’s disease. These same researchers have also looked at other influenza viruses and found additional results:

Sadasivan-title

Title: Induction of microglia activation after infection with the non-neurotropic A/CA/04/2009 H1N1 influenza virus.
Author: Sadasivan S, Zanin M, O’Brien K, Schultz-Cherry S, Smeyne RJ.
Journal: PLoS One. 2015 Apr 10;10(4):e0124047.
PMID: 25861024

In this second study, however, the different type of influenza (H1N1) did not infect the brain, but did cause the immune system to flare up. This is an interesting example of the second theory we discussed above (theory 2.), the double hit theory of Parkinson’s disease, in which the virus doesn’t necessarily cause Parkinson’s disease but plays a supportive role to some other toxic agent in attacking the body.

In a follow up study to their 2009 report on H5N1, these same researchers found that the Parkinson’s disease-like symptoms that they observed were actually only temporary:

Jang-title2

Title: Inflammatory effects of highly pathogenic H5N1 influenza virus infection in the CNS of mice.
Authors: Jang H, Boltz D, McClaren J, Pani AK, Smeyne M, Korff A, Webster R, Smeyne RJ.
Journal: Journal for Neuroscience, 2012 Feb 1;32(5):1545-59.
PMID: 22302798

This third study may give further support to the double hit theory (theory 2.), but also indicates how complicated a viral component to Parkinson’s disease can be.

And influenza is not the only virus to be associated with Parkinson’s disease.

Hepatitis C and Parkinson’s disease

Hepatitis C is a contagious liver disease, which is caused by the hepatitis C virus (HCV). The virus has been found in the brains of infected people, and it has also been shown to kill dopamine neurons in cell culture. Only in the last few months, however, has a more direct association with Parkinson’s disease been proposed:

HepC-Title

Title: Hepatitis C virus infection as a risk factor for Parkinson disease: A nationwide cohort study.
Authors: Tsai HH, Liou HH, Muo CH, Lee CZ, Yen RF, Kao CH.
Journal: Neurology, 2015 Dec 23. Published early online.
PMID: 26701382

The researchers in this study wanted to investigate whether hepatitis C could be a risk factor for Parkinson’s disease. They did this by analyzing data from 2000-2010 drawn from the Taiwan National Health Insurance Research Database.

The database included 49,967 people with either hepatitis B, hepatitis C or both, in addition to 199,868 people without hepatitis. During the 12 year period, 270 participants who had a history of hepatitis developed Parkinson’s disease (120 still had hepatitis C). This compared with 1,060 participants who were free of hepatitis, but went on to develop Parkinson’s disease.

When the researchers controlled for potentially confounding factors (such as age, sex, etc), the researchers found participants with hepatitis C had a 30% greater risk of developing Parkinson’s disease than the controls.

Summary

It is tempting to consider a viral theory for Parkinson’s disease, especially as the condition seems to strike indiscriminately from out of the blue. Maybe a virus works in cahoots with another factor (unable to do the job alone). The evidence of this, however, has not been apparent to allow for a definitive conclusion.

Finally, regarding my homework…

Never having Chickenpox could mean two different things – never being exposed to it OR being exposed to it and not getting infected (missing a particular protein required for infection). The first would suggest that exposure to the virus would given some kind of resistance to Parkinson’s disease. The latter would suggest that a protein which makes you vulnerable to Chickenpox gives you resistance to Parkinson’s disease.

As to the scientific literature, there have been two studies published regarding Chickenpox and Parkinson’s disease. The first:

Title: Parkinson’s disease: a test of the multifactorial etiologic hypothesis.
Authors: Semchuk KM, Love EJ, Lee RG.
Journal: Neurology, 1993 Jun;43(6):1173-80.
PMID: 8170564

In this study, the researchers collected life-time information (family history, occupational and medical records, etc) from 130 people with Parkinson’s disease. When the looked at all of the variables, they noted that a family history of Parkinson’s had the strongest association with Parkinson’s disease. This was followed by head trauma and occupational herbicide use. The subjects with Parkinson’s disease did not differ from control subjects with regards to:

exposure to smoking or ionizing radiation
family history of essential tremor
work-related contact with aluminum, carbon monoxide, cyanide, manganese, mercury, or mineral oils
history of arteriosclerosis, chicken pox, encephalitis, hypertension, hypotension, measles, mumps, rubella, or Spanish flu.

They proposed that the results supported the idea of a multifaceted cause of Parkinson’s disease, “probably involving genetic, environmental, trauma, and possibly other factors”.

And the second published study was:

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 significantly associated to mumps, scarlet fever, influenza, whooping cough and herpes simplex infections. But they found no association between Parkinson’s disease and Tuberculosis, measles or chickenpox.

So it would appear that chickenpox is not associated with Parkinson’s disease. And at a subsequent Parkinson’s support group meeting I asked the audience for a raise of hands as to who has had chickenpox and there was a sea of hands.

Back to the drawing board I guess.

The Placebo effect and Parkinson’s disease

January 3, 2016 ~ Simon ~ 10 Comments

According to our friends at Wikipedia:

A placebo (/pləˈsiboʊ/ plə-see-boh; Latin placēbō, “I shall please” from placeō, “I please”) is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient. Sometimes patients given a placebo treatment will have a perceived or actual improvement in a medical condition, a phenomenon commonly called the placebo effect or placebo response.

In our previous post we wrote about cell transplantation and we cited the two double-blind clinical studies that found little positive effect resulting from the procedure.

In both of those studies, half the participants were given a sham surgery – that is, they were put into the surgery room, anesthetized, an incision was made in their scalps, but nothing was injected into their brains. They (and their assessing investigators) were not told if they were in the transplant group or the sham/control group and they were left in this ‘blind’ state for 12-18 months.

Time is a funny thing.

After a couple of weeks of wondering which group they were in and self assessing their abilities since the surgery, some of the individuals in those studies may have started to think that you are in one group or the other. This is a very human thing to do.

The effect is VERY strong. And it can mess with a clinical study in terrible ways.

In one of the double-blind clinical studies discussed in the last post (Freed et at, 2001), one of the patients had described herself as ‘not being physically active for several years’ before her surgery. Shortly after her surgery, she found that she was able to hike and ice skate again. A miraculous change in situations.

Twelve months after the surgery, however, she found out that she’d had been in the sham/control surgery group. Nothing had been injected into her brain. She had received NO treatment.

Her response was solely due to the placebo effect.

The Placebo effect in Parkinson’s disease

Early last year there was an interesting study conducted that looked at the placebo effect and Parkinson’s disease.

Title: Placebo effect of medication cost in Parkinson disease: a randomized double-blind study.
Author: Espay AJ, Norris MM, Eliassen JC, Dwivedi A, Smith MS, Banks C, Allendorfer JB, Lang AE, Fleck DE, Linke MJ, Szaflarski JP.
Journal: Neurology. 2015 Feb 24;84(8):794-802.
PMID: 25632091

The investigators conducted a double-blind study involving 12 patients with moderate-severe Parkinson disease (average age of the subjects was 62.4 ± 7.9 years; and their average time since diagnosis was 11 ± 6 years). The study involved two visits to the clinic – the first visit involved a clinical assessment while the subjects were both ‘off’ and ‘on’ their standard medication. The assessment also involved a brain scan (fMRI). This was done to determine the magnitude of the dopaminergic benefit of their standard medication.
During the second visit, the subjects were told that they would be given two formulations – a “cheap” and “expensive” – of a “novel injectable dopamine agonist”. Both of these solutions were simply the same saline (medical salt water) solution. Four hours after being give the first injection, the subjects were given the other solution. In this manner, the subjects were exposed to both the ‘cheap’ and ‘expensive’ solutions. During visit 2, the subjects were clinically assessed and brain scanned 3 times, once before the first solution was injected, once after the first solution, and once after the second solution was given.

Below is a flowchart illustrating the structure study:

Source: Neurology

The results were interesting:

Both of the placebos improved motor function when compared with the baseline (no medication state)
The expensive placebo had more effect than the cheap placebo (remember: they were the same solution!)
The benefits were greater when patients were randomized first to expensive placebo followed by the cheap.
There was a significant difference in the level of improvement between the cheap and expensive placebos (UPDRS-III), with the expensive placebo giving better benefits
Brain imaging demonstrated that activation was greater when the cheap placebo was given first.

The authors concluded that the “expensive placebo significantly improved motor function and decreased brain activation in a direction and magnitude comparable to, albeit less than, levodopa. Perceptions of cost are capable of altering the placebo response in clinical studies“.

The authors also wrote a summary of the debriefing that followed the study, where the subjects were informed about the true nature of the study. They told the subjects that rather than being injected with a novel dopamine agonist, they were simply given a saline solution – the same solution for both ‘cheap’ and ‘expensive’. They reported that “responses ranged from disbelief to amazement regarding changes experienced“. It must have been rather bewildering to have been told that the positive benefits you experienced were ‘all in your head’ and not based on any pharmacological effect.

While extremely unethical, we here at the SoPD can’t help but wonder about long this placebo effect could last. Would the difference between the cheap and expensive solutions still exist in 12 months time if the subjects were left blinded and continued to take them?

So how might this work?
We know that the placebo effect in Parkinson’s disease is controlled by the release of dopamine – one of the chemicals in the brain that is affected by Parkinson’s disease. Importantly, we know that it the endogenous dopamine that is causing the effect – that is the dopamine our brains are producing naturally as opposed to the L-dopa treatment.

The dopamine that helps to control our motor movements is also involved with positive anticipation, motivation, and response to novelty. Thus when the placebo solution was given to subjects in this study, they believed that they were receiving an active drug and demonstrated an “expectation of reward” response. And the more expensive solution simply heightened the expectation and positive anticipation, therefore increasing the amount of dopamine produced/released.

Given that dopamine is involved with both the features of Parkinson’s disease AND with the mechanisms of anticipation/expectation, you can begin to understand why the placebo effect is such an enormous problem for clinicians undertaking clinical trials.

It would be nice, however, to have a better understanding of the placebo effect and try to harness its positive benefits while also treating Parkinson’s with diseasing slowing/halting therapies.

Cell transplantation – Replacing what has been lost

January 2, 2016 ~ Simon ~ 12 Comments

Parkinson’s disease is a neurodegenerative condition. That means that cells in the brain (neurons) are dying. By the time the motor features of Parkinson’s disease (rigidity, slowness of movement, and a resting tremor or shaking of a limb) become apparent to an individual, they will have lost 60-70% of the dopamine neurons in a region of the brain called the midbrain.

Above are slices of human brain, taken from the midbrain of a healthy control subject (left) and an individual who died with Parkinson’s disease. 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

While there is a lot of research investigating how to stop or slow down the disease, at present, the only realistic way to deal with what has already been lost is to replace it. This could be done with cell transplantation.

Cell transplantation has had a long and colourful history of trial and error with regards to Parkinson’s disease. Importantly, given that there is currently no clinically approved cell transplantation procedure for Parkinson’s disease, the approach must be considered experimental, at best. This has not, however, stop numerous unscrupulous practitioners from advertising their services and preying on desperate individuals. They offer expensive operations, that have little if any peer-reviewed scientific evidence backing them.

Let us repeat: there is currently NO clinically approved cell transplantation procedure for Parkinson’s disease.

The history of cell transplantation in Parkinson’s disease

There has been an enormous amount of cell transplant work conducted in rodent models of Parkinson’s disease – in which the dopamine system is lesioned unilaterally. Many different types of cells have been used, but by far the most successful have been immature dopamine neurons (collected from embryos). The success of that work resulted in numerous clinical trials in the 1990s. Those trials began with a group in Lund (Sweden) who, in 1991, transplanted fetal midbrain tissue into six patients: four with advanced idiopathic Parkinson’s disease and two from the ‘Frozen addicts’ cohort (see the book “The case of the frozen addicts” for an explanation of these two individuals). Similar programmes had been initiated in England, Spain, Mexico, Cuba, France, and Belgium. These were all considered to be relatively successful, except for the fact that they were all open-label/not blinded studies, meaning that everyone involved in the study knew who was getting transplanted.

In the USA, these developments took place amid a major debates about the ban on federal funding for fetal tissue research that had been introduced by the Reagan administration in 1988. The Clinton administration lifted this ban in January, 1993, and this reversal opened the way for the National Institutes of Health (NIH) to provide funding for the two placebo-controlled studies. Those two trials were:

Trial no. 1: The Colorado/Columbia Trial:

A double blind trial in which 40 subjects (with advanced PD) received transplants of fetal midbrain tissue and 34 additional subjects (with advanced PD) had a sham surgery and were considered controls. Critically, neither the subjects nor the practitioners knew who was in which group. No patients in either arm of the study received immunosuppression, meaning that their immune systems were free to attack the injected cells (which would have been considered foreign by the body). The patients were followed up for 1 year after surgery and the success of the trial was judged on the basis of a self-report rating of clinical improvement or deterioration, scored by patients in their own homes and then sent to the investigator. The report of the study was published in the New England Journal of Medicine:

Title: Transplantation of embryonic dopamine neurons for severe Parkinson’s disease.
Authors: Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, Dillon S, Winfield H, Culver S, Trojanowski JQ, Eidelberg D, Fahn S.
Journal: New England Journal of Medicine 2001 Mar 8;344(10):710-9.
PMID: 11236774

Trial no. 2: The Tampa Bay Trial:

34 patients were randomly assigned either to receive a transplant of fetal midbrain tissue or to undergo a sham surgery. All patients received 6 months of immunosuppression after surgery. The primary endpoint for this study was a significant difference between the groups at 24 months after surgery. The report of this study was published in the journal, Annals of Neurology:

Title: A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease.
Authors: Olanow CW, Goetz CG, Kordower JH, Stoessl AJ, Sossi V, Brin MF, Shannon KM, Nauert GM, Perl DP, Godbold J, Freeman TB.
Journal: Ann Neurol. 2003 Sep;54(3):403-14.
PMID: 12953276

Both of these clinical studies failed to show any significant improvement at their endpoints. In addition, 15% – 50% of transplanted subjects developed what are called ‘graft induced dyskinesias’ (or GID’s). This is where the subjects display uncontrollable/erratic movement. Interestingly, patients under 60 years of age did show signs of improvement on when assessed both clinically (using the UPDRS-III) and when assessed using brain imaging techniques (increased F-dopa uptake on PET). But the overall negative results left a shadow over the technique for the better part of a decade.

So what is currently happening?

There are new clinical trials currently underway for cell transplantation in Parkinson’s disease. Primary amongst these is the Transeuro being conducted in Europe.

The Transeuro trial. Source: Transeuro

The Transeuro trial is an open label study, involving 40 subjects, transplanted in sites across Europe. They will receive immunosuppression for at least 12 months post surgery, and the end point of the study will be 3 years post surgery, and based on brain imaging of dopamine release from the transplanted cells (PET scans). Based on the previous double blind studies discussed above, only subject under 65 years of age have been enrolled in the study.

The European consortium behind the Transeuro trial. Source: Transeuro

Do the transplants slow down the disease?

The evidence thus far is not clear, but some of the original patients from the 1991 Sweden trial were able to stop/cut back on their L-dopa treatment. Recently, some of the patients who received transplants have pass away and their brains have been examined post-mortem. One very interesting finding is that some of the cells in the transplants (1-5%) have lewy bodies in them. This suggests that the disease is passed on to the healthy transplanted cells in some way.

Above are photos of neurons from the post-mortem brains of people with Parkinson’s that received transplants. White arrows in the images above indicate lewy bodies inside transplanted cells. Source: The Lancet

For more information on this, see these articles:

Title: Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation.
Authors: Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ, Lashley T, Quinn NP, Rehncrona S, Björklund A, Widner H, Revesz T, Lindvall O, Brundin P.
Journal: Nature Medicine. 2008 May;14(5):501-3.
PMID: 18391963

Title: Lewy body pathology in long-term fetal nigral transplants: is Parkinson’s disease transmitted from one neural system to another?
Authors: Kordower JH, Brundin P.
Journal: Neuropsychopharmacology. 2009;3 (1):254.
PMID: 19079079 (this review article is freely available)

Thus it would appear that cell transplantation will not stop the disease. At best it will simply allow us to replace the lost cells and reverse some of the motor related features of the condition. Ideally, this approach would be conducted in concert with additional therapies that slow or halt the disease (such as a vaccine possibly).

What next for cell transplantation?

Given the moral and ethical issues surrounding the use of fetal tissue, research has shifted towards using embryonic stem (ES) cells and turning them into midbrain dopamine neurons. And the results here have been very promising, with recent reports suggesting that ES cells can be converted into dopamine neurons and transplanted into rodent models of Parkinson’s disease with equal efficiency to that of fetal midbrain tissue.

Title: Human ESC-derived dopamine neurons show similar preclinical efficacy and potency to fetal neurons when grafted in a rat model of Parkinson’s disease.
Authors: Grealish S, Diguet E, Kirkeby A, Mattsson B, Heuer A, Bramoulle Y, Van Camp N, Perrier AL, Hantraye P, Björklund A, Parmar M.
Journal: Cell Stem Cell. 2014 Nov 6;15(5):653-65.
PMID: 25517469

The take home message regarding cell transplantation is that at present it represents one of the only ways to replace what has been lost, but as of yet there is not an approved protocol for this approach in humans. As we said above, at best this should be considered experimental, and individuals selling expensive procedures should be avoided. The future looks very bright for this field, however, and we will keep you updated as more information comes to hand.

EDITORIAL NOTE: Happy new year everyone! We look forward to bringing you all the exciting news related to the science of Parkinson’s disease in 2016.

GDNF and Parkinson’s disease

December 22, 2015 ~ Simon ~ 13 Comments

In 1991, Leu-Fen Lin and Frank Collins – both research scientists at a small biotech company in Boulder, Colorado – isolated a protein that was going to have an enormous impact on experimental therapeutic approaches for Parkinson’s disease over the next two decades. The company was called Synergen, and the protein they discovered was glial cell-derived neurotrophic factor, or GDNF.

The structure of GDNF. Source: Wikipedia

A great deal has been written about GDNF and Parkinson’s disease (there are some very good books on the story of the development of GDNF as a drug), here we will provide an overview and look at what is currently happening.

So what is GDNF?

Glial cells are the support cells in the brain. From the Greek γλία and γλοία meaning “glue”, glial cells make up more than 50% percentage of the total number of cells in the brain – though this ratio can vary across different regions.

Large neurons supported by smaller glial cells. Source: Scientific Brains

Glials cells look after the ‘work horses’ – the neurons – by maintaining the environment surrounding the neurons and supplying them with supportive chemicals, called neurotrophic factors (neurotrophic = Greek: neuron – nerve; trophikós – pertaining to food/to feed). There are many types of neurotrophic factors, some having more beneficial effects on certain types of neurons and not other. GDNF is one of these neurotrophic factors. It was isolated from a cell culture of rat glial cells (hence the name: glial cell-derived neurotrophic factor), and what became clear very quickly after it’s discovery was that it dramatically revived dying dopamine neurons (the cells classically affected in Parkinson’s disease). Leu-Fen Lin and Frank Collins’s initial results were astounding and they were published in 1993. Many studies in animal models of Parkinson’s disease followed and in almost all of those studies the results were amazing (here is a good review of the early literature).

GDNF is a member of a larger family of neurotrophic factors and three other members of that family (called neurturin, persephin, and artemin – sounds like the Three Musketeers!) have also demonstrated positive effects on dying dopamine neurons. The positive/neuroprotective effect works via a series of receptors on the surface of cells. There a receptors that are specific for each of the GDNF family members discussed above:

The GDNF family. Source: Nature

And they each exert their positive affect in combination with a protein called ret proto-oncogene (RET). RET is a receptor tyrosine kinase, which is a cell-surface molecule that initiates signals inside the cell resulting in cell growth and survival. Dopamine neurons have most of these receptors and a lot of RET.

What has happened with GDNF in the clinic?

Given the results of the initial studies with GDNF (and its family members), clinical studies/trials were set up to test if similar effects would be seen in humans.

The very first clinical trial pumped GDNF into the fluid surrounding the brain, but the drug did not penetrate very deep into the brain and had limited effect. One side effect of the treatment was a hyper-sensitivity to pain (called hyperalgesia) – patients literally couldn’t tolerate the clothes touching their bodies.

This initial failure gave rise to another clinical study at the Frenchay Hospital in Bristol (UK) in which GDNF was released inside the brain, in an area called the striatum. Tiny plastic tubes were implanted in the brain allowing for the GDNF to be pumped in.

GDNF was pumped into the striatum (green area). Source: Bankiewicz lab

Although the number of subjects in the study was very small (only 5 people with Parkinson’s), the results of that particular study were simply amazing.

Title: Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease.
Authors: Gill SS, Patel NK, Hotton GR, O’Sullivan K, McCarter R, Bunnage M, Brooks DJ, Svendsen CN, Heywood P.
Journal: Nat Med. 2003 May;9(5):589-95.
PMID: 12669033

The researchers reported that after just one year of GDNF treatment, there was:

a 39% improvement in the off-medication motor ability (according to the Unified Parkinson’s Disease Rating Scale (UPDRS))
a 61% improvement in how subjects perceived their ability to go about daily activities.
a 64% reduction in medication-induced dyskinesias (and they were not observed off medication)
no serious clinical side effects

Importantly, the researchers conducted brain imaging studies on the subjects and a 28% increase in striatum dopamine storage after 18 months.

And that study was followed up by an outcome report two years later, which had similar results.

Title: Intraputamenal infusion of glial cell line-derived neurotrophic factor in PD: a two-year outcome study.
Authors: Patel NK, Bunnage M, Plaha P, Svendsen CN, Heywood P, Gill SS.
Journal: Ann Neurol. 2005 Feb;57(2):298-302.
PMID: 15668979

And then the researchers published a case study of one patient, suggesting that the positive effects of GDNF were still having an impact 3 years after the drug had stopped being delivered:

Title: Benefits of putaminal GDNF infusion in Parkinson disease are maintained after GDNF cessation.
Authors: Patel NK, Pavese N, Javed S, Hotton GR, Brooks DJ, Gill SS.
Journal: Neurology. 2013 Sep 24;81(13):1176-8.
PMID: 23946313

There were two issues with this initial GDNF pump study however:

The trial was open label. Both the subjects taking part and the physicians running the study knew who was getting the drug. The study was not blind.
A larger double blind study did not find the same results.

The Amgen “Double-Blind” Trial

In 2003, based on the Bristol study results, the pharmaceutical company Amgen (which owned GDNF) initiated a double blind clinical trial for GDNF with 34 patients. Being double blind, both the researchers and the participants did not know who was getting GDNF or a control treatment. The procedure used to pump the GDNF into the brain was slightly different to that used in the Bristol study, and some have suggested that this may have contributed to the outcome of this study.

On 1st July 2004, Amgen announced that its clinical trial testing the efficacy of GDNF in treating advanced Parkinson’s had failed to demonstrate any clinical improvement after six months of use. Later that year (in September), Amgen halted the study completely citing two reasons:

Pre-clinical data from non-human primates that had been treated in the highest dosage group for six months (followed by a three-month washout period) indicated a significant loss of neurons in an area of the brain called the cerebellum (which is involved in coordinating movement)
They had detected “neutralizing antibodies” in two of the study participants.

The former was strange as it had never been detected in any other animal models previously reported, but the detection of antibodies was a more serious issue. Antibodies are made by cells to defend the body against foreign material. If the body begins to produce antibodies against GDNF, the immune system would clear the body of the GDNF drug, but also the body’s own natural supply of GDNF. The consequences of this are unknown, so Amgen decided to pull the plug on the trial.

What followed was a ugly chapter in the story of GDNF. Amgen refused to allow their study participants to continue to use GDNF when they requested it on compassion reasons. Lawyers then got involved (two lawsuits in 2005), but the judges decided in favour of Amgen.

There are many researchers around the world who still believe that GDNF represents an important treatment for Parkinson’s disease, and this has given rise to further clinical trials.

What is happening at the moment?

Currently there are several GDNF-based clinical trials being conducted. These trials have focused on three methods of delivery into the brain (specifically the striatum, which is the area of the brain where the most dopamine is released):

Gene Therapy (GT)
Encapsulated genetically modified cells (ECB)
Pump delivery

A section of human brain demonstrating the different methods

for the delivery of GDNF to the striatum. Source: EPFL

The gene therapy (GT) trials have used genetically modified viruses to deliver the GDNF family members. One of the main GT trials involved a virus that was modified so that it produced large amounts of neurturin. Subjects were injected in the brain (specifically the striatum) and then the study participants were followed for 15 months. Unfortunately, this study failed to demonstrate any meaningful improvement in subjects with Parkinson’s disease.

The Encapsulated genetically modified cells (ECB) approach for the delivery of GDNF has been developed by company called NSgene and the trial currently on-going and we are waiting to hear the results of this study.

And finally, a new pump clinical trial for GDNF trial being run in Bristol (UK). The trial is being run by a company called MedGenesis (and funded by ParkinsonsUK and the CurePDTrust). The research team in Bristol have recruited 36 people with Parkinson’s disease to take part in their 9-month trial.

Dr Stephen Gill – Professor in Neurosurgery at University of Bristol – who conducting the current GDNF-pump study

This new trial should definitively tell us if there is a future for GDNF in Parkinson’s disease. The results of the study are expected at the end of 2016.

Reasons why GDNF may not work

While we do not want to dampen any optimism regarding GDNF, we believe that it is important to supply all points of view and as much information as possible. That said, in 2012, researchers in Sweden discovered that the GDNF neuroprotective effect is blocked in cells over-expressing alpha-synuclein – the protein that clumps together in Parkinson’s disease. In agreement with this, they found that RET was also reduced in dopamine neurons in people with Parkinson’s disease. Thus, it may be that people with Parkinson’s disease have a reduced ability to respond to GDNF.

Title: α-Synuclein-induced down-regulation of Nurr1 disrupts GDNF signaling in nigral dopamine neurons.
Authors: Decressac M, Kadkhodaei B, Mattsson B, Laguna A, Perlmann T, Björklund A.
Journal: Sci Transl Med. 2012 Dec 5;4(163):163ra156.
PMID: 23220632

Luckily, the Swedish researchers also found that another protein, called Nurr1, could rescue this reduction in GDNF response. And there is now a lot of research being conducted to investigate the positive effects of GDNF and Nurr1 in combination.

We will continue to follow this area and report any new findings as they come to hand.

A call to arms

December 12, 2015December 16, 2015 ~ Simon ~ Leave a comment

While our primary goal here at the Science of Parkinson’s is to highlight and explain new research dealing with Parkinson’s disease, we are also keen to encourage the general public to get involved with efforts to cure this debilitating condition.

To this end, we would like to bring your attention to the fact that 2017 represents the 200th anniversary of the first report of Parkinson’s disease by one Dr James Parkinson:

320px-Parkinson,_An_Essay_on_the_Shaking_Palsy_(first_page)

Although there were several earlier descriptions of individuals suffering from rigidity and a resting tremor, Dr Parkinson’s 66 page publication of six cases of ‘Shaking Palsy’, is considered the seminal report that gave rise to what we now call Parkinson’s disease. The report was published in 1817.

The 200th anniversary represents a fantastic opportunity to raise awareness about the disease and a rallying point for a concerted research effort to deal with the condition once and for all. It is still a year away, but now is the time to start planning events and building awareness. We would encourage you to mark 2017 as the year of Parkinson’s disease, share this with everyone you know, and endeavour to make some small effort to help in the fight against this condition.

Parkinson’s disease and the cancer drug

December 11, 2015September 2, 2017 ~ Simon ~ 7 Comments

In October, 40,000 neuroscientists from all over the world gathered in Chicago for the annual Society for Neuroscience conference. It is one of the premier events on the ‘brain science’ calendar each year and only a few cities in the USA have the facilities to handle such a huge event.

agu20141212-16

Science conference. Source: JPL

During the five day neuroscience marathon, hundreds of lecture presentations were made and thousands of research poster were exhibited. Many new and exciting findings were presented to the world for the first time, including the results of an interesting pilot study that has left everyone in the Parkinson’s research community very excited, but also scratching their heads.

The study (see the abstract here) was a small clinical trial (12 subjects; 6 month study) that was aiming to determine the safety and efficacy of a cancer drug, Nilotinib (Tasigna® by Novartis), in advanced Parkinson’s Disease and Lewy body dementia patients. In addition to checking the safety of the drug, the researchers also tested cognition, motor skills and non-motor function in these patients and found 10 of the 12 patients reported meaningful clinical improvements.

The study investigators reported that one individual who had been confined to a wheelchair was able to walk again; while three others who could not talk before the study began were able to hold conversations. They suggested that participants who were still in the early stages of the disease responded best, as did those who had been diagnosed with Lewy body dementia.

So what is Nilotinib?

Nilotinib (pronounced ‘nil-ot-in-ib’ and also known by its brand name Tasigna) is a small-molecule tyrosine kinase inhibitor, that has been approved for the treatment of imatinib-resistant chronic myelogenous leukemia (CML). That is to say, it is a drug that can be used to treat a type of leukemia when the other drugs have failed. It was approved for this treating cancer by the FDA in 2007.

The researchers behind the study suggest that Nilotinib works by turning on autophagy – the “garbage disposal machinery” inside each neuron. Autophagy is a process that clears waste and toxic proteins from inside cells, preventing them from accumulating and possibly causing the death of the cell.

The process of autophagy – Source: Wormbook

Waste material inside a cell is collected in membranes that form sacs (called vesicles). These vesicles then bind to another sac (called a lysosome) which contains enzymes that will breakdown and degrade the waste material.

Some details about the study:

The study was run at the Georgetown University Medical Center
The patients were given increasing doses of Nilotinib (150mg to 300mg/day) that were are significantly lower than the doses of Nilotinib used for CML treatment (800-1200mg/day).
The researchers took cerebrospinal fluid (CSF; the liquid surrounding the brain) and blood samples at the start of the study, 2 and 6 months into the study.
Nilotinib was detected in the CSF, indicating that it had no problem crossing the protective blood-brain-barrier – the membrane covering the brain that blocks many drugs from entering.
Participants exhibited positive changes in various cerebrospinal fluid biomarkers with statistically significant changes in an important protein called, Tau, which have been shown to increase with the onset of dementia.
The researchers found a significant reduction (>60%) in levels of α-Synuclein detected in the blood, but no change in CSF levels of α-Synuclein.
The investigators report that one individual confined to a wheelchair was able to walk again; three others who could not talk were able to hold conversations.

If the outcomes of this study are reproducible, then we here at the Science of Parkinson’s are assuming that Nilotinib is working by turning on the garbage disposal system of the remaining cells in the brain and allowing them to function better. This would suggest that there is a certain level of dysfunction in those remaining cells, which would be expected as this is a progressive disease. The study researchers reported that the small, daily dose of nilotinib turns on autophagy for about four to eight hours, and if that is enough to have such remarkable effects, then this treatment deserves more research.

The results of the study are intriguing and the participants of the study will continue to be treated and followed to see if the improvements continue.

BUT before we go getting too excited:

While these results sound extremely positive, there are several issues with this study that need to be considered before we celebrate the end of Parkinson’s disease.

Firstly, this study was an open-label trial – that means that everyone involved in the study (both researchers and subjects) knew what drug they were taking. There was also no control group or control treatment for comparative analysis in the study. Given these conditions there is always the possibility that what some of the subjects were experiencing was simply a placebo effect. Indeed the lead scientist on the project, Dr Fernando Pagan, pointed out that “It is critical to conduct larger and more comprehensive studies before determining the drug’s true impact.”

In addition, according to Novartis (the producer of the drug), the current cost of Nilotinib is about $10,360 (£6,900) per month for the daily 800mg dose used for cancer treatment. Even if the dose used in this study was only 150 to 300 mg/daily, it would still make this treatment extremely expensive.

Thirdly, Nilotinib has a number of adverse side-effects when used as an anti-cancer drug (at 800mg/day). These include headache, fatigue, nausea, vomiting, diarrhea, constipation, muscle/joint pain, skin issues, flu-like symptoms, and reduced blood cell count. It may not be the nicest of treatments to tolerate.

There are important reasons for optimism, however, with the results of this study:

In 2010, a group of researchers published a paper demonstrating the neuroprotective effects of another cancer drug very similar to Nilotinib. That drug was ‘Gleevec’

Title: Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin’s ubiquitination and protective function.
Authors: Ko HS, Lee Y, Shin JH, Karuppagounder SS, Gadad BS, Koleske AJ, Pletnikova O, Troncoso JC,Dawson VL, Dawson TM.
Journal: Proc Natl Acad Sci U S A. 2010 Sep 21;107(38):16691-6.
PMID: 20823226

And that Gleevec publication was followed up a couple of years ago with a second study demonstrating the neuroprotective effects of another Abl-inhibitor: Nilotinib!

Title: The c-Abl inhibitor, nilotinib, protects dopaminergic neurons in a preclinical animal model of Parkinson’s disease.
Authors: Karuppagounder SS, Brahmachari S, Lee Y, Dawson VL, Dawson TM, Ko HS
Journal: Sci Rep. 2014 May 2;4:4874.
PMID: 24786396

These studies provided a strong rationale for testing brain permeable c-Abl inhibitors as potential therapeutic agents for the treatment of PD. The phase 2 trial at Georgetown will be starting in early 2016 and we will be watching this trial very closely.

“Red hair, sir, in my opinion, is dangerous”

December 6, 2015December 6, 2015 ~ Simon ~ 4 Comments

The quote entitling this post is from a PG Wodehouse book ‘Very Good, Jeeves!’.

We have previously discussed the curious connection between melanoma and Parkinson’s disease. There is also a well known connection between melanoma and red hair. And believe it or not, there is another really strange relationship between Parkinson’s disease and red hair.

Title: Genetic determinants of hair color and Parkinson’s disease risk.
Authors: Gao X, Simon KC, Han J, Schwarzschild MA, Ascherio A.
Journal: Ann Neurol. 2009 Jan;65(1):76-82.
PMID: 19194882

In 2009, researchers from Harvard University found a relationship between hair color and risk of Parkinson’s disease, when they examined the records of 131,821 US men and women who participated in the two large longitudinal studies, the Health Professionals Follow-up Study (HPFS) and the Nurses’ Health Study (NHS).

The HPFS, which started in 1986, sends questionnaires to US health professionals (dentists, optometrists, etc) – aged 40-75. Every couple of years, members of the study receive questionnaires dealing with diseases and health-related issues (e.g. smoking, physical activity, etc). The questionnaire is supplemented by another questionnaires which is sent every four years, that deals with dietary information.

The NHS study – which was established in 1976 and then expanded in 1989 – has also collected questionnaire-based information from 238,000 registered nurses. Similar to the HPFS, every two years the study participants receive a questionnaire dealing with diseases and health-related topics.

In their study, the investigators found 264 of the male and 275 of the female responders to the HPFS and NHS questionnaires had been diagnosed with Parkinson’s disease. Of these individuals, 33 were black haired, 418 had brown hair, 62 were blond and 26 were redheads. Given that redheads make up just 1% of the general population but 5% of the people who were diagnosed with Parkinson’s disease in their study, the authors suggested that red haired people have a higher risk of developing Parkinson’s disease. Interestingly, they found a stronger association between hair color and Parkinson’s disease in younger-onset of PD (that is being diagnosed before 70 years of age) than those with age of onset greater than 70 years. When they took health and age related matters into account, the authors concluded that people with red hair are almost four times more likely to develop Parkinson’s disease than people with black hair.

NOTE: This result does not mean that people with red hair are definitely going to develop Parkinson’s disease, it simply suggests that they may be more vulnerable to the condition. And we should add that this result have never been replicated and we are not sure if anyone has ever attempted to reproduce it with a different database.

So how does (or could) this work?

The short answer is: we really don’t know.

The long answer involves explaining where there are no connections:

Red hair results from a genetic mutation. 80% of people with red hair have a mutation in a gene called MC1R – full name: melanocortin-1 receptor. Another gene associated with red hair is called HCL2 – ‘Hair colour 2’. We know that the connection between red hair and Parkinson’s disease is not genetic, as there is no association between MC1R mutations and Parkinson’s disease (for more on this, click here). We are not sure about HCL2, but this gene has never been associated with any disease.

What we do know is that redheads:

are more sensitive to cold (for more on this, click here)
are less responsive to subcutaneously (under the skin) administered anaesthetics (for more on this, click here)
suffer more from toothaches (for more on on this, click here)
are more sensitive to painkillers (for more on this, click here)
require more anesthetic for surgery (for more on this, click here)

Common myths associated with red hair include:

redheads bled more than others (this is not true – click here)…but they do bruise easier!
redheads are at greater risk of developing endometriosis (this is not true – click here)
redheads are more frequently left-handed (I can find no evidence for this, so I’ll put it in the myth basket until corrected).

There is also a strange link between red hair and multiple sclerosis, but it is too complicated to understand at the moment (women with red hair are more vulnerable to multiple sclerosis than men with red hair, for more on this, click here).

How any of these findings relates to Parkinson’s disease is unclear – we provide them here for those who are interested in following up this curious relationship.

One important caveat regarding this study is that incidence rates of Parkinson’s disease in countries with very high levels of red hair do not support the relationship (PD & red hair). In Scotland, approx. 10% of the population have red hair (source), and yet the England has a higher incidence of Parkinson’s disease (28.0/10,000 in England vs 23.9/10,000 in Scotland – source).

It may well be, however, that there is no direct connection between red hair and Parkinson’s disease. And until the results of the 2009 study mentioned above are replicated or supported by further findings, we here at the ‘Science of Parkinson’s disease’ shall consider this simply as a curious correlation.