Coffee and Parkinson’s disease – it’s not just caffeine

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Numerous epidemiologic studies have indicated that coffee consumption reduces the risk of Parkinson’s disease. For a long time, efforts have been made to determine what the magic ingredient in this popular beverage is. Many people have speculated that the stimulant caffeine is the critical active ingredient in this neuroprotective effect.

New research, however, suggests that this may not be the case.

Today’s post will review recently published results suggesting that Quercetin (and not caffeine) is the neuroprotective component in coffee.


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Kaldi the goat herder. Source: CoffeeCrossroads

Legend has it that in 800AD, an Ethiopian goat herder called Kaldi noticed that his animals were “dancing” after eating some berries from a tree that he did not recognise. Fascinated by the happy behaviour of his goats, Kaldi naturally decided to eat the berries for himself and he subsequently became “the happiest herder in happy Arabia”.

This amusing encounter was apparently how humans discovered coffee. It is most likely a fiction as the earliest credible accounts of coffee-consumption emerge from the 15th century in the Sufi shrines of Yemen, but since then coffee has gone on to become one of the most popular drinks in the world.

Stupid question: what exactly is coffee?

For a person who doesn’t drink coffee (like myself), this is actually a really interesting question. Coffee is a beverage made from ground up roasted beans, which are the seeds of berries from the Coffea plant. These are the berries:

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Coffea berries. Source: About.me

And these are the beans (unroasted):

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Unroasted Coffee beans. Source: Kopiholic

Coffee production also makes for fascinating reading (Click here for more) and why we roast the beans is equally interesting (Click here for that), but they are taking us off the topic here.

There are basically two types of coffee beans: Arabica and Robusta.

Approximately 70 percent of the coffee beans we use are Arabica. Surprisingly, the less popular Robusta actually has twice as much caffeine as Arabica. And caffeine is the stimulant that rewards people for drinking this beverage.

Caffeine is also the chemical that has long been thought to have positive effects on Parkinson’s disease, possibly even reducing the risk of the condition (more on that below).

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Fancy a cuppa? Source: Science-All

What does coffee have to do with Parkinson’s disease?

We have previously discussed the enormous contribution that the Honolulu Heart Study has made to our understanding of Parkinson’s disease (click here to read that post). Many of the earliest associations with the condition were found in that large epidemiologic study. One of those findings was that the consumption of coffee reduced one’s risk of developing Parkinson’s disease.

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Title: Association of coffee and caffeine intake with the risk of Parkinson disease.
Authors: Ross GW, Abbott RD, Petrovitch H, Morens DM, Grandinetti A, Tung KH, Tanner CM, Masaki KH, Blanchette PL, Curb JD, Popper JS, White LR.
Journal: JAMA. 2000 May 24-31;283(20):2674-9.
PMID: 10819950    (This article is OPEN ACCESS if you would like to read it)

The researchers behind this article analysed the data from the Honolulu Heart Study – an epidemiological study of 8,006 “non-institutionalized men of Japanese ancestry, born 1900-1919, resident on the island of Oahu” – and found that the age-adjusted incidence of Parkinson’s disease declined consistently with increased amounts of coffee intake (from 10.4 per 10,000 person-years in men who drank no coffee to 1.9 per 10,000 person-years in men who drank at least 28 oz/d). This and other findings in their analysis indicated that higher coffee (and caffeine) intake is associated with a significantly lower incidence of Parkinson’s disease.

Subsequent studies have replicated this association, and several have demonstrated the neuroprotective effects of caffeine (click here for a review on this topic).

So what new data has been published?

This is Prof Patrick and Prof Edith McGeer:

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Prof Patrick and Prof Edith McGeer. Source: Mcgeerandassociates

This husband and wife team of scientists are well recognised figures within the Parkinson’s disease research work, having produced many seminal scientific reports. Patrick is a particularly interesting character having played basketball for Canada in the 1948 Olympics and then a politician in the British Columbia legislature (1962-1986).

They are also authors on the article we are going to review today:

Coffee-title

Title: Quercetin, not caffeine, is a major neuroprotective component in coffee.
Authors: Lee M, McGeer EG, McGeer PL.
Journal: Neurobiol Aging. 2016 Jul 5;46:113-123.
PMID: 27479153

As we said above, for the longest time people have believed that caffeine was the active ingredient in the miraculous ability of coffee to reduce the risk of Parkinson’s disease. The researchers who published this report were particularly interested in the neuroprotective role for coffee in Parkinson’s disease and they decided to break coffee down into some of its basic components. Specifically:

  • Caffeine
  • quercetin
  • flavone
  • Chlorogenic acids (CGAs)

They tested each of these coffee components on cells (grown in petri dishes) that had been exposed to a toxin, and then assessed cell survival. Curiously, although caffeine did exhibit neuroprotective effects on the cells, it was beaten by the far superior protective effects of quercetin.

What is quercetin?

Quercetin is a flavonoid (a type of plant pigment) that is found in many fruits, vegetables, leaves and grains. Flavonoids are potent antioxidants. Antioxidants scavenge particles (called free radicals) in the body which can damage cell membranes, affect DNA, and even cause cell death. Antioxidants neutralize these free radicals. (For more on flavonoids – click here).

What does this mean?

The results are very interesting, especially if they provide us with a new potential target for therapeutic drug development. It also raises the age-old idea of antioxidants being potentially useful in the treatment of Parkinson’s disease (the previous history of this therapeutic approach has been disappointing – click here to read more on this).

But before you rush out and load up on quercetin, there are a few things to consider:

Quercetin is generally considered pretty safe. Fruits and vegetables are the primary dietary sources of quercetin, particularly citrus fruits, apples, onions, parsley, sage, tea, and red wine.

That said: excessive use of quercetin can have side effects, which may include headache and upset stomach. Very high doses of quercetin can cause damage to the kidneys (doses greater than 1 g per day), and regular periodic breaks from taking quercetin is advised. Importantly, pregnant women, breastfeeding women, and people with kidney disease should avoid quercetin.

EDITOR’S NOTE: If you are considering supplementing your diet with quercetin (or any other potential therapeutic agents) please firstly discuss this change of lifestyle with your medical physician. Information provided here can under no circumstances be considered medical advice.

Having said that we shall keep an eye out for any new research of quercetin and Parkinson’s disease, and report it here.


The banner for today’s post was sourced from Phoxpopmagazine

Identical twins and Parkinson’s disease

Twins

The influence of genetics in  Parkinson’s disease is difficult to determine. If it was simply a genetic disease, identical twins – who share identical DNA – should show no difference in their susceptibility to Parkinson’s disease. They should either both develop the condition, or not. Right?

But this is not the case.

In today’s post we will review a particularly interesting pair of identical twins.


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Jeff & Jack Gernsheimer in 1982. Source: ReadingEagle 

When people ask the obvious question about the cause of Parkinson’s disease – ‘is it genetics or is it environment?’ – I have a standard answer: ‘it’s complicated’. I then tell them the curious story of identical twins Jeff and Jack Gernsheimer from eastern Pennsylvania. No other case better demonstrates the strange question of what causes Parkinson’s disease.

For almost their entire lives (69 years), Jeff and Jack have lived no more than half a mile apart. Breathing the same air, drinking the same water. They are literally neighbours – just a five-minute walk between their homes. In addition, since 1971 they have worked in the same office at a graphic design firm that they started together. The brothers were the focus of a story in the online magazine Nautilus last year. It’s a fantastic article and I fully recommend you read it.

So here’s the thing: In 2009 Jack was diagnosed with Parkinson’s disease.

To date, Jeff is yet to exhibit any signs of the condition.

Strange huh?

Two genetically identical people, living in the exact same environment and one of them develops Parkinson’s disease.

Ok, how do we explain this?

Hang on a second, slow down. I haven’t even got to the really interesting part yet:

After being diagnosed, Jack had his genome sequenced to see if there were any particular genetic mutations that might make him vulnerable to Parkinson’s disease. That analysis determined that Jack has a mutation in the most common Parkinson’s disease-associated gene: Glucocerebrosidase or GBA (which we have discussed in a previous blog post).

Interesting. So that explains the Parkinson’s disease?

No. Jack’s identical twin brother, Jeff, also has that exact same mutation.

So now we have a pair of identical twins who share the identical genetic code, live in the same environment, and have a genetic mutation associated with Parkinson’s disease, but only Jack has developed the condition while Jeff has not.

I think you will agree, it’s a really interesting tale… and with the help of modern science, it gets even more interesting.

How so?

In 2014, a research paper was published that utilized cells from both Jack & Jeff to determine what differences existed between them:

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Title: iPSC-derived dopamine neurons reveal differences between monozygotic twins discordant for Parkinson’s disease.
Authors: Woodard CM, Campos BA, Kuo SH, Nirenberg MJ, Nestor MW, Zimmer M, Mosharov EV, Sulzer D, Zhou H, Paull D, Clark L, Schadt EE, Sardi SP, Rubin L, Eggan K, Brock M, Lipnick S, Rao M, Chang S, Li A, Noggle SA.
Journal: Cell Reports. 2014 Nov 20;9(4):1173-82.
PMID: 25456120        (this article is OPEN ACCESS if you would like to read it)

EDITOR’S NOTE HERE: Monozygotic means twins from the same egg, (as opposed to dizygotic meaning twins from two eggs). And discordant means ‘at variance, or at odds’ – in medicine it is used when one identical twin has a condition and the other does not.

The researchers conducting this study took skin cells from the brothers and they turned them into brain cells via a miraculous Nobel-prize winning approach. The technique firstly involves turning the skin cells into induced pluripotent stem cells (or iPS cells).

IPS-cells

Source: Csiro

iPS cells can be used to make any cell you wish, and the researchers encouraged Jack and Jeff’s iPS cells to develop into dopamine neurons (one of the types of cells that are vulnerable in Parkinson’s disease).

When the researchers analysed the dopamine neurons from both twins, they found that both had half the normal levels GBA protein activity (an enzymatic reaction) due to the mutation in the GBA gene. The brother’s dopamine neurons also had approximately three times the normal levels of alpha-synuclein protein, and a reduced capacity to synthesize and release dopamine.

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Dopamine neurons. Source: MindsofMalady

Then the researchers noticed something interesting: the dopamine cells from Jack (the affected twin) had lower dopamine levels than Jeff’s cells. This was rather strange: identical twins should actually have similar levels – all things being equal. The researchers attributed this decrease in dopamine to an increase in the levels of monoamine oxidase B (MAO-B) in Jack’s cells.

What is MAO-B?

Good question. MAO-B is an enzyme in dopamine neurons that helps to break down excess dopamine. After a cell releases dopamine, the cell will re-collect and recycle leftover/unused dopamine. MAO-B is the enzyme that breaks dopamine down. MAO-B inhibitors (such as Rasagiline or Azilect) have been used for some time as a therapy in Parkinson’s disease. By blocking MAO-B with MAO-B inhibitors, people with Parkinson’s disease can have increased levels of dopamine as the remaining dopamine does not get broken down so quickly.

The researchers studying Jack and Jeff’s iPS dopamine neurons found that by replacing the reduced GBA and inhibiting the oversupply of MAO-B (with MAO-B inhibitors) they made the dopamine neurons healthier – with an increase in dopamine levels and increased removal of excessive alpha-synuclein (the protein that is associated with Parkinson’s disease).

Are Jeff and Jack in a unique situation?

Nope. Not at all.

Here are some other examples:

ID-twin3

Title: Pathology of PD in monozygotic twins with a 20-year discordance interval.
Author: Dickson D, Farrer M, Lincoln S, Mason RP, Zimmerman TR Jr, Golbe LI, Hardy J.
Journal: Neurology. 2001 Apr 10;56(7):981-2.
PMID: 11294946

This was a case study in which a pair of identical twins both developed Parkinson’s disease, but one of the twins was diagnosed 20 years before the other.

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Title: Identical twins with Leucine rich repeat kinase type 2 mutations discordant for Parkinson’s disease.
Authors: Xiromerisiou G, Houlden H, Sailer A, Silveira-Moriyama L, Hardy J, Lees AJ.
Journal: Movement Disord. 2012 Sep 1;27(10):1323.
PMID: 22488887                (This article is OPEN ACCESS if you would like to read it)

This second case study involved a pair of twins who both carried a mutation in the Parkinson’s associated gene, Lrrk2 (click here to read more about this gene). They both developed Parkinson’s disease, but 10 years separated their diagnoses.

Twins1

Title: Parkinson disease in twins: an etiologic study.
Authors: Tanner CM, Ottman R, Goldman SM, Ellenberg J, Chan P, Mayeux R, Langston JW.
Journal: JAMA. 1999 Jan 27;281(4):341-6.
PMID: 9929087     (This article is OPEN ACCESS if you would like to read it)

In this study, the scientists screened 19,842 white male twins enrolled in the National Academy of Sciences/National Research Council World War II Veteran Twins Registry. 163 pairs of twin were identified in which at least 1 twin had Parkinson’s disease (and medical records were available).

When diagnosis was made over the age of 50 years of age, approximately 10% of the twin pairs both had Parkinson’s disease (for both monozygotic and dizygotic twins). But when diagnosis was made under the age of 50, the monozygotic concordance was 100% – that is, all of the identical twins diagnosed under the age of 50 had Parkinson’s disease – while the dizygotic concordance remained around 10-20%. The researchers concluded that ‘this pattern strongly supports a primarily inherited cause of early-onset Parkinson’s disease’.

So how do we explain the difference seen in Jack and Jeff?

Some twins may be born with a vulnerability for Parkinson’s disease (like a genetic mutation, in the GBA or Lrrk2 gene for example), but there is some other factor/s that is influential in the initiation of the disease. And this is where scientists start talking about something called epigenetics (Epi, Greek for ‘over’ or ‘above’ and Genetics,…well, you should be able to work that one out).

Epigenetics is the study of changes in an organism that are caused by modifications or variations of gene expression rather than alteration of the genetic code itself. These variations may result from external factors that cause genes to turn on and off.

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Source: 2ndActHealth

In the case of the Gernsheimer twins, if you read the story in the online magazine Nautilus you will find that their lives were not entirely the same. There were basic differences, for examples they went to different universities and in the 1970’s Jack enlisted in the army. But there were also some larger, life-altering differences: in the late 1980’s Jack lost a son in tragic circumstances. The brothers speculate that the stress/suffering associated with that particular event may have been a catalyst for the Parkinson’s that followed. Many researchers in the Parkinson’s disease field have speculated on whether a stressful/traumatic event in their lives was the causative agent for their Parkinson’s disease.

So what does it all mean?

It means that the answer is more complicated than first assumed. And unfortunately, this is where I end up when people ask me about ‘genetics vs environment’ in the cause of Parkinson’s disease: a qualified we really don’t know. But I do always suggest that ‘Genetics vs environment’ may be too simplistic.

 


The source of today’s banner was the AutismBlog.

Pesticides and Parkinson’s disease

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Farming and country living (more specifically exposure to pesticides) has often associated with Parkinson’s disease. The findings of numerous epidemiological studies support this connection.

Recently a new study was published that lends considerable support to this idea of factors involved in causing Parkinson’s disease.


In 1986, a group of researchers in the province of Saskatchewan (Canada) made an interesting observation:

Farm

Title: Early onset Parkinson’s disease in Saskatchewan–environmental considerations for etiology.
Author: Rajput AH, Uitti RJ, Stern W, Laverty W.
Journal: Can J Neurol Sci. 1986 Nov;13(4):312-6.
PMID: 3779530

They collected the medical details of 21 people who were born & raised Saskatchewan and that later went on to be diagnosed with early onset Parkinson’s disease (that is diagnosis before the age of 40 years). When evaluating the childhood environments of those 21 people, the researchers immediately noticed that 19 of them spent the first 15 years of their lives exclusively in rural Saskatchewan.

This finding has been replicated in different parts of the world. It has also been expanded upon and there is now solid evidence pesticides, but not fungicides, were associated with Parkinson’s disease (click here to read more on this).

So what research has been done recently?

A few weeks ago, some researchers from North Carolina published interesting new results that further supports the association between exposure to pesticides and Parkinson’s disease:

Farmtitle

Title: Identification of chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration.
Authors: Pearson BL, Simon JM, McCoy ES, Salazar G, Fragola G, Zylka MJ.
Journal: Nat Commun. 2016 Mar 31;7:11173.
PMID: 27029645      (This report is OPEN ACCESS if you would like to read it)

The researchers grew mouse brain cells in petri dishes, and exposed them to hundreds of chemicals commonly found in the environment and on food. Each petri dish was exposed to just one chemical (for 24 hours), and this was done across many individual petri dishes so that many different chemicals could be tested. They then collected and analysed the RNA of the cells exposed to these chemical, allowing the researchers to access what was happening inside those cells – the molecular reactions to the chemicals. Importantly, they also compared the RNA results between samples – that is to say, they compared the effect that the different chemicals had on the cells by comparing the RNA collected from those cells.

What they found was very interesting.

They identified six basic groupings or clusters of chemicals which share similar mechanistic profiles. This means that the chemicals within each group caused similar RNA activity inside the exposed cells. Of particular interest to us here at the Science of Parkinson’s Disease, is that one of these groups of chemicals (cluster 2) exhibited RNA activity similar to that observed in the aged brain and certain neurodegenerative conditions.

Many of the chemicals in cluster 2 (including fenpyroximate, pyridaben and rotenone), are compounds that target the mitochondria – the power generators inside cells. Rotenone in particular has been associated with Parkinson’s disease (Click here for more on this). It would be interesting to investigate if other chemicals in this clustering have similar effects in models of Parkinson’s disease to that caused by Rotenone.

After identifying these chemicals , the researchers next turned their attention to the chemical usage and food commodity residue database collected by the United States Geological Survey, the United States Department of Agriculture (USDA) and the Food and Drug Administration (FDA). The researchers could use this database to see if what the usage trends were for many of the chemicals in cluster 2. While they found that rotenone usage is low and unchanging, many other chemicals have been used with increasing frequency. This lead the scientists to conclude that there is “significant human exposure potential to many of the chemicals in cluster 2”.

So what does it all mean?

There does appear to be a solid connection between country/rural living and Parkinson’s disease. This association has been replicated across continents and over time. And as we discussed above, we have identified chemicals used in the agricultural industry that can increase the risk of developing the condition.

The fact that the majority of the farming community do not go on to develop Parkinson’s disease, however, brings into question the strength of the association. Obviously there are additional aspects (for example, genetics) that are playing an influence.

Caution should be taken when dealing with many of the chemicals used in the agricultural industry, limiting direct exposure to an absolute minimum. It will be interesting to record if there is any decrease in the prevalence of Parkinson’s disease over time with heightened awareness about the dangers of some of the chemicals used down on the farm.


The banner for todays post was sourced from RSPB.

Juvenile-onset Parkinson’s disease

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A community in New Brunswick (Canada) was recently shocked to discover that a 2 year old boy in their midst had been diagnosed with Parkinson’s disease (Click here to read more).

Yes, you read that correctly, it’s not a typo: a 2 year old boy.

Juvenile-onset Parkinson’s disease is an extremely rare version of the condition we discuss here at the Science of Parkinson’s. It is loosely defined as being ‘diagnosed with Parkinson’s disease under the age of 20’. The prevalence is unknown, but there is a strong genetic component to form of the condition. In today’s post we will review what is known about Juvenile-onset and look at new research about a gene that has recently been discovered to cause a type of Juvenile-onset Parkinson’s disease.


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Dr Henri Huchard. Source: Wikipedia

In 1875, Dr Henri Huchard (1844-1910; a French neurologist and cardiologist) described the first case of a child who, at just 3 years of age, presented all the clinical features of Parkinson’s disease. Since that report, there have been many studies detailing the condition that has become known as ‘juvenile-onset Parkinson’s disease’.

What is juvenile-onset Parkinson’s disease?

Basically, it is a form of Parkinson’s disease that affects children and young people under the age of 20. The defining feature is the age of onset. The average age of onset is approximately 12 years of age (with the majority of cases falling between 7 and 16 years) and males are affected by this condition more than females (at a rate of approximately 5:1).

The actual frequency of juvenile-onset parkinson’s is unknown given how rare it is. When researcher look at people with early onset Parkinson’s disease (that is diagnosis before the age of 40; approximately 5% of the Parkinson’s community), they have found that between 0.5 – 5% of that group of people were diagnosed before 20 years of age. This suggests that within just the Parkinson’s community, the frequency of juvenile-onset parkinson’s is at the most 0.25% (or 2.5 people per 1000 people with Parkinson’s). Thus it is obviously a very rare condition.

It is interesting to note that Lewy bodies (the clusters of aggregated protein that classically characterise the brains of people with Parkinson’s disease) are very rare in cases of juvenile-onset parkinson’s disease. To our knowledge there has been only one case of Lewy bodies in juvenile-onset parkinson’s disease (Click here to read more on this). This suggests that the juvenile-onset form of Parkinson’s disease may differ from other forms of the condition in its underlying biology.

Do we know what causes juvenile-onset parkinson’s disease?

There is a very strong genetic component to juvenile-onset parkinson’s disease. In fact, the incidence of Parkinsonism in relatives of people with juvenile-onset parkinson’s disease is higher than in the general public AND in the relatives of people with other forms of Parkinson’s disease.

Genetic mutations in three genes are recognised as causing juvenile-onset Parkinson’s disease. The three genes are known to the Parkinson’s world as they are all PARK genes (genetic variations that are associated with Parkinson’s). Those three genes are:

  • Parkin (PARK2)
  • PTEN-induced putative kinase 1 (PINK1 or PARK6)
  • DJ1 (PARK7)

In juvenile-onset Parkinson’s disease, all of these mutations are associated with autosomal recessive – meaning that two copies of the genetic variation must be present in order for the disease to develop.

Parkin mutations account for the majority of juvenile-onset Parkinson’s disease cases. Affected individuals have a slowly progressing condition that is L-dopa responsive. Dystonia (abnormal muscle tone resulting in muscular spasm and abnormal posture) is very common at the onset of the condition, particularly in the lower limbs.

Can the condition be treated with L-dopa?

The answer is: ‘Yes, but…’

L-dopa (or dopamine replacement) treatment is the standard therapy for alleviating the motor features of Parkinson’s disease.

The majority of people with juvenile-onset parkinson’s respond well to L-dopa, but in the Parkin mutation version individuals will typically begin to experience L-dopa-induced motor fluctuations (dyskinesias) early in that treatment regime.

What research is currently being done on this condition?

Given that cases are so very rare and so few, it is difficult to conduct research on this population of individuals. Most of the research that is being conducted is focused on the genetics underlying the condition.

And recent that research lead to the discovery of a new genetic variation that causes juvenile-onset Parkinson’s disease:

Juvenile

Title: Discovery of a frameshift mutation in podocalyxin-like (PODXL) gene, coding for a neural adhesion molecule, as causal for autosomal-recessive juvenile Parkinsonism.
Authors: Sudhaman S, Prasad K, Behari M, Muthane UB, Juyal RC, Thelma BK.
Journal: Journal Med Genet. 2016 Jul;53(7):450-6.
PMID: 26864383           (This article is OPEN ACCESS if you would like to read it)

The researchers who wrote this article were presented with a 10 member Indian family from Aligarh, Uttar Pradesh. Of the 8 children in the  family, 3 were affected by Parkinsonian features (tremor, slowness, rigidity and gait problems) that began between 13 and 17 years of age. The researchers conducted DNA sequencing and found that none of the three affected siblings had any of the known Juvenile-onset Parkinson’s disease genetic mutations (specifically, mutations in the genes PARK2, PINK1and DJ1).

They then compared the DNA from the three siblings with the rest of the family and found a genetic variant in a gene called podocalyxin-like (or PODXL). It must be noted that PODXL is a completely novel gene in the world of Parkinson’s disease research, which makes it very interesting. PODXL has never previously been associated with any kind of Parkinson’s disease, though it has been connected with two types of cancer (embryonal carcinoma and periampullary adenocarcinoma).

The researchers then turned to their genetic database of 280 people with Parkinson’s disease have had their genomes sequenced. The researchers wanted to determine if any genetic variants in the PODXL gene were present in other suffers of Parkinson’s disease, but had not been picked up as a major contributing factor. They found three unrelated people with PODXL mutations. All three had classical Parkinson’s features, and were negative for mutations in the Parkin, PINK1 and DJ1 genes.

The researchers concluded that the PODXL gene may be considered as a fourth causal gene for Juvenile-onset Parkinson’s disease, but they indicated that further investigations in other ethnic groups are required.

 


The banner for today’s post was sourced from ClipArtBest

Editorial note

Cambridge University applications

The scientists behind the Science of Parkinson’s disease website work at Cambridge University and are associated – through their research – with the Wellcome Trust/MRC Cambridge Stem cell institute.

sci-logo

Throughout July, the Stem cell institute is running the #MyView campaign which aims to raise awareness about all of the latest developments in stem cell research.

Of particular interest to the Parkinson’s community will be the work being conducted in Prof Roger Barker’s lab (he of the 2016 Gretschen Amphlet Memorial lecture). The Stem cell institute made a video about the research being conducted in Prof Barker’s lab – viewed through the eyes of someone with Parkinson’s disease. It provides an interesting view of the working being carried out:

We encourage all of our readers to get involved with the #myview discussion and to follow the campaign of social media via Youtube, Facebook, & Twitter.

As scientists we are always very keen to hear the views of people in the Parkinson’s community (both sufferers and carers). It is through campaigns like this that we can gain new insight from different view points.


The banner for today’s post was sourced from the Huffington Post.

Traumatic brain injury and Parkinson’s disease – an association

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A new study has found traumatic brain injury with loss of consciousness is associated with the risk of Parkinson’s disease, but (interestingly) not Alzheimer’s disease. In this post we will review the study and its findings, before considering the implications of the results.


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Image sourced from GQ

There has been a lot of talk on the interweb and various media outlets recently about the long term consequences of head injuries associated with physical sports like boxing, rugby, ice hockey and American football (click here for more on this).

Of particular concern is when individuals lose consciousness at the time of the head injury, which has been associated with worse outcomes than simply suffering a bang on the head.

A group of American researchers recently decided to assess whether there was any association between traumatic head injury with loss of consciousness and the increased risk for Alzheimer’s disease.

What they found may have profound implications for Parkinson’s disease.

TBI-title

Title: Association of Traumatic Brain Injury With Late-Life Neurodegenerative Conditions and Neuropathologic Findings.
Authors: Crane PK, Gibbons LE, Dams-O’Connor K, Trittschuh E, Leverenz JB, Keene CD, Sonnen J, Montine TJ, Bennett DA, Leurgans S, Schneider JA, Larson EB.
Journal: JAMA Neurol. 2016 Jul 11. doi: 10.1001/jamaneurol.2016.1948.
PMID: 27400367       (This study is OPEN ACCESS if you would like to read it)

The researchers collected the results of 3 large studies, collectively involving 7130 participants who had head injury data (2879 men and 4251 women; average age of 79.9 years). Of these 845 had suffered traumatic brain injuries with loss of consciousness for at least 1 hour. Interestingly, the researchers found no statistically significant association between traumatic brain injuries with loss of consciousness and risk of Alzheimer’s disease.

Next they looked at Parkinson’s disease and found that people who suffered traumatic brain injuries with loss of consciousness of more than 1 hour had a statistically significant increase in developing Parkinson’s disease (2-3 times more than normal controls).

Of the 7130 participants in the study, postmortem autopsy analysis reports were available for 1589 of the subjects. The researchers looked for the neuropathological hallmarks of Parkinson’s disease, called Lewy bodies, and they found no correlation between people who suffered traumatic brain injuries with loss of consciousness of less than 1 hour and the presence of Lewy bodies. When they looked in the brains of people who suffered traumatic brain injuries with loss of consciousness of more than 1 hour, they did find a correlation. And importantly these neuropathological events were not associated with genetic mutations.

So what does it all mean? 

 

The results indicate that traumatic brain injuries with loss of consciousness of more than 1 hour could significantly increase a person’s risk of Parkinson’s disease. The crucial  detail in the results is the ‘loss of consciousness of more than 1 hour’. Traumatic head injury can often result in disruption to the blood-brain-barrier (the protective film surrounding the brain), which may result in certain pathogens entering the brain. So the more severe the injury, perhaps the longer the barrier is disrupted. Why this event may relate solely to Parkinson’s disease and not Alzheimer’s disease, however, remains to be determined.

It would be interesting to assess how this finding relates to the greater Parkinson’s community. That is to say, determine how many of the people with Parkinson’s disease have a head injury with loss of consciousness in their past medical records?

Reading this study, one cannot help thinking of the recent passing of Boxing great Muhammad Ali. Ali died this year having spent the last third of his life living with Parkinson’s disease. Many boxing careers have probably involved one or two severe head injuries with loss of consciousness, so why are there not more cases of Parkinson’s disease in the boxing community? Many retired boxers suffer from what is called Dementia pugilistica – a neurodegenerative condition with Alzheimer’s-like dementia. Some estimates suggest that 15-20% of boxers may be affected, with symptoms usually starting 12-16 years after the start of a career in boxing. Some very famous boxers have been diagnosed with this condition, including world champions Floyd Patterson, Joe Louis, Sugar Ray Robinson and boxer/coach Freddie Roach.

The difference between the results of today’s study and dementia pugilistica may lie in the repeated nature of the injuries in boxers and the length of time individuals were unconscious. It will be interesting to see what becomes of this research.

 

 


The banner for today’s post was sourced from the Huffington Post

Bees! Bees! Hark to your bees!

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The title of today’s post comes from a Rudyard Kipling poem, and it seemed appropriate as we review the results of a clinical study for Parkinson’s disease…involving bees!  Much has been written about the medicinal properties of the lovely honey that bees make. The healing properties of the sweet produce of our little friends seems to cure all ailments.

Today’s post, however, is not about honey.

No, today’s post is about the other thing bees are known for: their sting!


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Source: Gizmodo

Earlier today a group of researchers in Paris (France), published the results of a clinical trial in which they gave bee venom to people with Parkinson’s disease for 11 months.

Beetitle

Title: Bee Venom for the Treatment of Parkinson Disease – A Randomized Controlled Clinical Trial.
Authors: Hartmann A, Müllner J, Meier N, Hesekamp H, van Meerbeeck P, Habert MO, Kas A, Tanguy ML, Mazmanian M, Oya H, Abuaf N, Gaouar H, Salhi S, Charbonnier-Beaupel F, Fievet MH, Galanaud D, Arguillere S, Roze E, Degos B, Grabli D, Lacomblez L, Hubsch C, Vidailhet M, Bonnet AM, Corvol JC, Schüpbach M.
Journal: PLoS One. 2016 Jul 12;11(7):e0158235.
PMID: 27403743        (This study is OPEN ACCESS if you would like to read it)

No! What? Bee Venom? Really?

Yeah, I know. Weird, right? But there is actually some logic to the idea.

Bee venom has recently become in vogue for all kinds of health associated products (eg. face masks, etc – click here for more on this), but preclinical experiments have also demonstrated that it can have beneficial effects in models of Parkinson’s disease.

Bee venom (or Apitoxin as it known to the science types) contains some interesting components, one of which is called Apamin.

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Apamin. Source: Wikipedia

Apamin is the only component of bees venom that can pass through the blood-brain-barrier and enter into the brain. Once inside the brain, Apamin selectively blocks structures on the membrane of cells called ‘calcium channels’.

Calcium channels allow calcium (surprise) to enter a cell, and control many physiological functions including neurotransmitter release, muscle contraction and cell survival. It has already been demonstrated in models of Parkinson’s disease that Apamin has neuroprotective properties on the dopamine neurons in the brain:

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Title: Bee venom and its component apamin as neuroprotective agents in a Parkinson disease mouse model.
Authors: Alvarez-Fischer D, Noelker C, Vulinović F, Grünewald A, Chevarin C, Klein C, Oertel WH, Hirsch EC, Michel PP, Hartmann A.
Journal: PLoS One. 2013 Apr 18;8(4):e61700.
PMID: 23637888               (this article is OPEN ACCESS if you would like to read it)

The researchers in this preclinical study demonstrated that bee venom was protective in models of Parkinson’s disease. When they tested Apamin alone, however, they found that it reproduced the protective effects only partially. They concluded that other components of bee venom must be enhancing the protective action of Apamin.

So what happened in the clinical trial?

The researchers in France conducted a randomized double-blind study (meaning that nobody – researchers included – knew who was getting the bee venom or the saline control solution). They took 40 people with early stage Parkinson disease (Hoehn & Yahr stages 1.5 to 3) and assigned them to either monthly bee venom injections or equivalent injections of saline.

After 11 months of monthly injections, the researchers found that bee venom did not significantly decrease the motor features of Parkinson’s disease (as judged by UPDRS III scores during ‘off’ condition). In addition, brain imaging (DAT-scan) did not differ significantly between treatment groups over the 11 months.

The researchers did, however, see improvements in some of the cognitive measures in subjects receiving the bee venom (albeit non-significant).

In their concluding remarks, the researchers questioned whether lack of significant effect was due to the low frequency of injections (once per month). Maybe the subjects in the trial were simply receiving too little of the treatment for it to have an effect. With the support of more preclinical experimental results, they propose that a larger study is warranted with a higher administration frequency and possibly higher individual doses of bee venom.

Will this happen?

It is unclear at present.

In the study, 4 subjects had immune system responses to the bee venom, so it may be wise to firstly establish what components of bee venom are having any beneficial effect before proceeding with further clinical trials.


The banner for today’s post was sourced from modern.scot

Nilotinib and Parkinson’s disease – an update

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We have previously discussed news briefings regarding a cancer drug that displayed interesting results in a pilot clinical study of Parkinson’s disease (click here to read that post). Today we will delve more deeply into the results of that particular study and consider what they mean.


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Nilotinib (Tasigna) from Novartis. Source: William-Jon

In October of last year, at the Society for Neuroscience meeting in Chicago, a presentation of data from a clinical trial got the Parkinson’s community really excited. The study was investigating the effects of a cancer drug called ‘Nilotinib’ (also known as Tasigna) on Parkinson’s disease and the initial results were rather interesting.

The results of the pilot clinical study for Nilotinib were published today in the Journal of Parkinson’s disease:

Nilo-title

Title: Nilotinib Effects in Parkinson’s disease and Dementia with Lewy bodies
Authors: Pagan F, Hebron M, Valadez E, Tores-Yaghi Y,Huang X, Mills R, Wilmarth B, Howard H, Dunn C, Carlson A, Lawler A, Rogers S, Falconer R, Ahn J, Li Z, & Moussa C.
Journal: Journal of Parkinson’s Disease, vol. Preprint
PMID: Yet to be allocated              (This article is OPEN ACCESS if you would like to read it).

The study was setup to determine safety of using Nilotinib in Parkinson’s disease dementia or dementia with Lewy bodies.

What is Nilotinib?

Nilotinib is a drug that can be used to treat a type of leukemia when the other cancer drugs have failed. It was approved for this treating cancer by the FDA in 2007.

The researchers behind the current study believe that Nilotinib works by turning on autophagy – the “garbage disposal machinery” inside brain cells. 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.

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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.

The researchers suggest that Nilotinib may be working in Parkinson’s disease by helping affected cells to better clear away the build up of unnecessary proteins, which helps cells to function more efficiently.

What happened in the clinical study?

Twelve people with either Parkinson’s disease dementia or dementia with Lewy bodies were randomized given either 150 mg (n = 5) or 300 mg (n = 7) daily doses of Nilotinib for 24 weeks. After the treatment period the subjects were followed up for 12 weeks. All of the subjects were considered to have mid to late stage Parkinson’s features (Hoehn and Yahr stage 3–5). One subject was withdrawn from the study at week 4 due to a heart attack and another discontinued at 5 months due to unrelated circumstances.

An important question in the study was whether Nilotinib could actually enter the brain. Various tests conducted on the subjects suggesting that the drug had no problem crossing the ‘blood brain barrier‘ and having an effect in the brain. The levels of Nilotinib in the brain peaked at 2 hrs after taking the drug and the levels of the target protein (called p-Abl) were reduced by 30% at 1 hr. This level of activity remained stable for several hours.

The motor features of Parkinson’s disease were assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS) and the investigators observed an average decrease of 3.4 points and 3.6 points at six months (week 24) compared to the baseline measures (scores from the start of the study) with 150 mg and 300 mg Nilotinib, respectively. A decrease in motor scores represent a reduction in Parkinson’s motor features.

The really remarkable result, however, comes from the testing of cognitive performance, which was monitored with Mini Mental Status Examination (MMSE). The researchers report an average increase of 3.85 and 3.5 points in MMSE at six months (24-week) compared to baseline, for 150 mg and 300 mg of Nilotinib, respectively. This means that the mental processing of the subjects improved across the study.

The motor and cognitive results were complemented by measures of proteins in blood and cerebrospinal fluid samples taken from the subjects. The researchers saw increases in dopamine related proteins (suggesting that more dopamine was present in the brain) and stabilization of alpha synuclein levels.

The researchers concluded that these observations warrant a larger randomized, double-blind, placebo-controlled trial to truly evaluate the safety and efficacy of Nilotinib.

Here at the SoPD, we are inclined to agree.

So what does all this mean?

The results of the study are very interesting, and the researchers should be congratulated on the outcome (and presentation of all the data in the report). As they themselves acknowledge, the study was open labelled – meaning that everyone in the study knew that they were getting the treatment – so the placebo effect could be at play here.

One intriguing note in the report was that most of the participants in the study ‘experienced increased psychotic symptoms (hallucination, paranoia, agitation) and some dyskinesia whilst on Nilotinib’ suggesting an increase in dopamine levels in the brain. The researchers used medication (monoamine oxidase (MAO)-B inhibitors) to help control these side effects.

Obviously a larger, double-blind study is required to determine whether the effect of the drug in Parkinson’s disease is real. The Michael J. Fox Foundation, the Van Andel Research Institute (Michigan, USA) and the Cure Parkinson’s Trust are collaborating on the development program for a double-blind, placebo-controlled clinical trial of nilotinib, which it is hoped will begin in 2017.

 


The banner for today’s banner was sourced from Wikimedia 

The GDNF trial (Bristol) initial results

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We learned today that the phase 2 GDNF clinical trial in Bristol (UK) has failed to meet the primary efficacy end point. That is to say, the initial results suggest that the drug has not worked. In this post we will review what we know and discuss what will happen next.


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

We have previously discussed GDNF and Parkinson’s disease (Click here to read that post). This drug was considered the great hope for Parkinson’s disease and a lot was riding on the results. Today’s announcement is extremely unwelcomed news, but it is not necessarily the end of the road for GDNF.

What is GDNF?

Glial cell-derived neurotrophic factor (or GDNF) is a neurotrophic factor (neurotrophic = Greek: neuron – nerve; trophikós – pertaining to food/to feed). It is a chemical produced in the brain. GDNF has previously been found to have miraculous effects on some of the neurons in the brain that are most affected by Parkinson’s disease (particularly the dopamine neurons).

Given the amazing results in laboratories around the world, clinical trials were set up for people with Parkinson’s disease. The first study had astounding results, but a larger follow up study failed to replicate those results and so a third GDNF clinical trial was initiated: the Bristol GDNF study

What is the Bristol GDNF study?

The Bristol GDNF study run by the the North Bristol NHS Trust, was funded by Parkinson’s UK, with support from The Cure Parkinson’s Trust. The company MedGenesis Therapeutix supplied the GDNF and additional project resources/funding. MedGenesis Therapeutix itself has funding support from the Michael J. Fox Foundation for Parkinson’s Research.

The study involved participants having GDNF (or a placebo drug) pumped directly into their brains, into an area called the putamen. The putamen is where the greatest loss of dopamine occurs in people with Parkinson’s disease.

All together there were 41 people with Parkinson’s disease enrolled in the clinical trial. The trial was divided into two phases and the first of those is now complete. During the first phase 35 participants received either GDNF or a placebo drug over 9-months in a double blind fashion

What does double blind mean?

It means that neither the researchers nor the participants know which drug they are receiving. Everyone is ‘blind’ to the treatment. Single blind studies involve the researchers being aware of the treatment allocation, but the participants are blind. Single blind studies can be affected by what is called ‘investigator bias’ – where the investigators start to think that they see an effect when there may not be an effect. Double blind is considered the gold standard, but there are problems with this type of study as well.

If phase one has finished what is phase two of the trial?

The second phase of the study will involve all participants receiving GDNF. This part is already underway.

What was the “primary efficacy end point”?

The press release from the company behind the study, MedGenesis, suggested that:

‘The primary endpoint of the study is the percentage change from baseline in the practically defined OFF-state Unified Parkinson’s Disease Rating Scale (UPDRS) motor score (part III) after nine months of double-blind treatment’

With the limited information we currently have, we are assuming that the researchers were looking for a significant improvement in the motor symptoms rating scale (‘UPDRS’) of the subjects when compared to how they were at the start of the trial (‘baseline’). The subject’s motor features were assessed during periods when they were not taking their medication (‘OFF-state’), and the initial indications are that the researchers failed to see any improvement.

Is this negative result the end of the world?

NO. Most definitely not.

There are many reasons why the trial may have failed to achieve its primary end point, and the researchers have emphasized that they need time to analyse all of the results. It will be interesting to see the final analysis (and we will summarise it here when it is available – end of 2016 apparently).

It will also be important to follow up the participants to determine if there are any delayed positive outcomes. It may take longer than 9 months to see improvements (fetal transplant studies, for example, usually require 2-3 years before improvements are observed).

 

Maybe GDNF just needs a bit more time. We will keep you updated as more information comes to hand.


For more on the study, please see Parkinson’s UK and MedGenesis.

A gut feeling about gut feelings

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At the Movement Disorders meeting held in Berlin two weeks ago, there was an interesting presentation dealing with a topic close to our hearts (literally).

In a previous post, we have discussed research suggesting that people (Danes) with vagotomies (severing of the nerves from the stomach to the brain) have a reduced risk of Parkinson’s disease – supporting the idea that perhaps the gut is a one site of disease initiation (click here to read that post).

At the meeting in Berlin, however, data was presented that failed to replicate the findings in a separate group of people (Sweds!).

Vagotomy

Title: Vagotomy and Parkinson’s disease risk: A Swedish register-based matched cohort study
Authors: B. Liu, F. Fang, N.L. Pedersen, A. Tillander, J.F. Ludvigsson, A. Ekbom, P. Svenningsson, H. Chen, K. Wirdefeldt
Abstract Number: 476 (click here to see the original abstract – OPEN ACCESS)

The Swedish researchers collected information regarding 8,279 individuals born in Sweden between 1880 and 1970 who underwent vagotomy between 1964 and 2010 (3,245 truncal and 5,029 selective). For each vagotomized individual, they  collected medical information for 40 control subjects matched for sex and year of birth (at the date of surgery). They found that vagotomy was not associated with Parkinson’s disease risk.

Truncal vagotomy was associated with a lower risk more than five years after the surgery, but that result was not statistically significant. The researcher suggested that the findings needs to be verified in larger samples.

Differences between the studies?

The Danish researcher analysed medical records between 1975 and 1995 from 5339 individuals had a truncal vagotomy and 5870 had superselective vagotomy. The Sweds on the other hand, looked over a longer period (1964 – 2010) but at a smaller sample size (3,245 truncal and 5,029 selective).

Conclusions?

We must note here that the current research has not been peer-reviewed and we are presenting it here for interests sake. But it come after a series of correspondence regarding the original Danish paper were published in the journal Annals of Neurology. Those letters to the editor were from a group of researchers (believe it or not, mainly Norwegians) reported that an analysis of the same data sets used in the original study failed to find a significant difference between the groups – that is, no protective effect for vagotomies in Parkinson’s disease.

This Scandinavian debate has important implications for Parkinson’s disease, bringing in to question the idea that Parkinson’s disease may begin in the gut. Recently, there have also been several reports published suggesting that alpha synuclein present in colonic biopsies may not be as useful in diagnosing Parkinson’s disease as previously proposed.

And this is why the path of science is such a long one – interesting new findings need to be replicated before they can be added to our understanding of the world around us. And if those interesting results can not be replicated, then we have to ask ‘why?’

Watch this space.