Tag: Science of Parkinsons

Your appendix and Parkinson’s disease

~ Simon ~ 3 Comments

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The appendix was long considered an odd little organ in the body. It was a potentially troublesome, rather redundant appendage to the lower colon of the intestinal tract, and biologists were baffled as to its true function. Recently there were suspicions that it may be playing a role in Parkinson’s disease. This week, however, new research suggests that this may not be the case.

We have previously discussed the idea that Parkinson’s may possibly start in the gut (click here to read more on this). Some in the research community suspect that there is a particular part of the gut where it may start: the Appendix.

What is the Appendix?

The human appendix is a small (averaging 9 cm in length) tube attached to the beginning of the large intestine. Most of us only ever think of the appendix when we are affected by it in the case of Appendicitis.

 

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Source: Healthversed

The Appendix was long considered functionless, an oddity, and by some an mistake or accident of evolution. More recently, however, a new image has started to appear with regards to the appendix. And it has to do with the bacteria of the gut.

We have previously written about Helicobacter pylori and the possible associations with Parkinson’s disease, and in that post we discussed the wide variety of bacteria in the gut. These populations of bacteria are constantly changing, based on our interactions with the world around us (eg. what we are eating, geographically where we are, etc). The developing image of the appendix is that this small organ represents a safe house for bacteria, that is to say: ‘the appendix serves as a haven for useful bacteria when illness flushes those bacteria from the rest of the intestines’ (Wikipedia).

So what would this have to do with Parkinson’s disease?

We have previously discussed the idea that the gut may be one of the starting points for Parkinson’s disease. Many researchers believe that some unknown agent or causal factor is accessing the brain via the nerve fibers surrounding the gut. This theory is supported by reports that sectioning those nerves (to treat ulcers) can reduce your chance of Parkinson’s disease  (click here for more on this).

When looking at the nerve fibres surrounding the intestinal system, one can not help but notice that the appendix is densely innervated. And this is why some researchers suspect that the appendix may be playing a role in Parkinson’s disease.

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 Blood vessels of the Appendix. Source: Wikipedia

What evidence exists for a connection between the Appendix and Parkinson’s disease?

In 2014, a group of research looked at tissue of the appendix from normal people and they found something interesting.

Appendix1

Title: Alpha-synuclein in the appendiceal mucosa of neurologically intact subjects.
Authors: Gray MT, Munoz DG, Gray DA, Schlossmacher MG, Woulfe JM.
Title: Mov Disord. 2014 Jul;29(8):991-8. doi: 10.1002/mds.25779. Epub 2013 Dec 18.
PMID: 24352892

The researchers looked at biopsies of the appendix from 20 normal people (no history of Parkinson’s disease). In all cases they found high levels of the Parkinson’s disease associated protein, Alpha synuclein (Click here to read more on this), in the nerve fibres surrounding the Appendix. When they looked at other areas of the intestinal system, they found little or no alpha synuclein.

This result got a lot of attention.

A group of researchers then took a  large cohort of people  with Parkinson’s disease and asked which of them had ever had an appendectomy (removal of the Appendix).

Appendix2

Title: Appendectomy may delay Parkinson’s disease Onset
Authors: Mendes A, Gonçalves A, Vila-Chã N, Moreira I, Fernandes J, Damásio J, Teixeira-Pinto A, Taipa R, Lima AB, Cavaco S.
Journal: Mov Disord. 2015 Sep;30(10):1404-7. doi: 10.1002/mds.26311. Epub 2015 Jul 30.
PMID: 26228745

Of the 295 people with Parkinson’s disease involved in the study, 34 were found to have had an appendectomy. There was no significant difference in age of onset across the entire group of people involved in the study, but in people with late onset Parkinson’s (after the age of 55 years) the authors found that found evidence that an appendectomy significantly delayed the onset of Parkinson’s symptoms.

This result led some researchers to conclude that the appendix may have some role in Parkinson’s disease.

What was found in the study this week?

Before you rush out and order yourself an appendectomy, please read the following – This week, any role of the Appendix in Parkinson’s disease has been called into question with the publication of this study:

Appendix

Title: Appendectomy in mid and later life and risk of Parkinson’s disease: A population-based study.
Authors: Marras C, Lang AE, Austin PC, Lau C, Urbach DR.
Journal: Mov Disord. 2016 May 31. doi: 10.1002/mds.26670. [Epub ahead of print]
PMID: 27241338

The researchers involved in this study looked at the medical records of the 14 million residents of Ontario (Canada) who have health care insurance. They found 42,999 had undergone an appendectomy. When the researchers compared people with appendectomies with people without an appendectomy (the control group) and people who had a cholecystectomy (removal of the gallbladder – a surgical control group), they found no difference in the risk of Parkinson’s disease. The researchers concluded that their data did not support an association between mid to late life appendectomy and Parkinson’s disease.

These results are based on large numbers of people and it will be interesting to see how the research community reacts to them. We’ll keep you posted.

UPDATE (23/09/16): A new study came out last week from a group in Denmark that suggests Appendectomies ARE associated with a small increase in risk of developing Parkinson’s disease, but importantly this is only at 10 or more years post surgery.

Title: Appendectomy and risk of Parkinson’s disease: A nationwide cohort study with more than 10 years of follow-up.
Authors: Svensson E, Horváth-Puhó E, Stokholm MG, Sørensen HT, Henderson VW, Borghammer P.
Journal: Mov Disord. 2016 Sep 13.
PMID: 27621223

 

Today’s banner, illustrating the location of the Appendix was sourced from UCDenver

Muhammad Ali (1942-2016)

~ Simon ~ 1 Comment

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The world today is mourning the passing of the boxing great, Cassius Clay jr (aka Muhammad Ali). He was many different things to many different people – a boxer, an entertainer, a civil rights activist, an anti-war protestor, a philanthropist, a legend – but he was definitely one of the defining figures of the late 20th century.

During the last third of his life, however, he lived with Parkinson’s disease. You will find a great deal written about Ali and his sporting achievements elsewhere on the web, but today’s post here at SoPD will explore his battle with Parkinson’s.

Many famous figures throughout history have been affected by Parkinson’s disease ( Pope John Paul II, Adolf Hitler, Mao Zedong,…), but very few of them have dealt with their condition in the public eye as much as Muhammad Ali.

Ali was first diagnosed with Parkinson’s disease in 1984.

It was in September of that year – just three years into retirement from boxing – that Ali became concerned about tremors, slowness of movement, slurred speech and unexplained fatigue. He travelled with his entourage to New York, and he was evaluated for a week by Dr Stanley Fahn, M.D., a neurologist at Columbia-Presbyterian Medical Center (New York), before Fahn finally gave Ali his diagnosis.

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Dr Stanley Fahn. Source: Youtube

Given his long boxing career, Dr. Fahn suspected that the head trauma inflicted on Ali could be the cause of his condition. In fact, one of the early complaints from Ali was of numbness in his lips and face, which Dr Fahn assumed meant damage to the brain stem – most likely resulting from the boxing.

Neurodegeneration is a serious issue for boxing. 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.

In the case of Ali, however, subsequent follow up assessments over many years highlighted the steady progression of his condition, a disease course more indicative of classic Parkinson’s disease. Dr. Fahn admits, however, that – as with all cases of Parkinson’s disease – “the proof is only going to come at his autopsy”.

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Ali and a young fan. Source: Pinterest

Being diagnosed at 42 years of age basically placed Ali in the ‘young onset’ group of people with Parkinson’s disease. The average age of diagnosis for Parkinson’s disease is 65 years, but 5-10% of the Parkinson’s community is diagnosed at or below the age of 40. And there are many anecdotal bits of evidence to suggest that Ali was possibly affected by the disease before the age of 40. Ali’s trainer, Angelo Dundee, suspected that Ali’s condition was present during the last few years of his boxing. He remembers Ali gradually slowing down and the newspaper reporters having to lean in to hear what Ali was saying during some of the later interviews. Sports Illustrated senior writer William Nack also noted that “You could see back then that he was just not right”. So although Ali was diagnosed at 42 years of age, the condition may have been affecting him much earlier.

Following the diagnosis, Ali stepped away from the public eye. Parkinson’s affected both of Ali’s most defining characteristics: his moves and his voice. It would have been very understandable for a man as proud as Ali to decide to disappear completely while dealing with his condition. A decade later, however, Ali lit the Olympic caldron at the opening ceremonies of the Atlanta Games (1996), and he was rarely out of the public eye. Attending regular events not only in support of Parkinson’s disease, but also in his role of globetrotting ambassador for peace. Within the Parkinson’s community, Ali lent his name to the ‘Muhammad Ali Parkinson Research Center‘ (Phoenix) and also served as an ambassador for Parkinson’s causes.

In writing this post I have learned a great deal about Ali that I did not know. I have also enjoyed watching and re-watching many of the video interviews of Ali on the internet (Michael Parkinson’s ones are particularly good). Beyond everything the man did and the disease that later came to define him, Ali was an amazing character. It is difficult to think of his equal in the modern world of sports (or beyond).

Truly a sad day.

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Inspirational words from the man. Source: Wallpapercave

 

Today’s banner was sourced from Pinterest. And much of the information for this post was sourced from an article written about Ali by the American Academy of Neurology.

A change of dogma for Alzheimer’s disease?

~ Simon ~ 5 Comments

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This week an interesting new study dealing with the biology of Alzheimer’s was published in the journal Science Translational Medicine. It has drawn a lot of attention as it may be turning our understanding of Alzheimer’s disease on it’s head. If the results are independently replicated and verified, it could potentially have major implications for Parkinson’s disease.

For the last 30 years, a protein called beta-amyloid has been considered one of the bad boys of the most common neurodegenerative condition, Alzheimer’s disease.

What is Alzheimer’s disease?

Alzheimer’s disease is a progressive neurodegenerative condition that can occur in middle or old age. It involves a generalized degeneration of the brain, not localised to specific regions like Parkinson’s disease.

What happens in the Alzheimer’s brain?

In the brain, in addition to cellular loss, Alzheimer’s is characterised by the presence of two features:

  • Neurofibrillary tangles
  • Amyloid plaques

The tangles are aggregations of a protein called ‘Tau’ (we’ll comeback to Tau in a future post). These tangles reside within neurons initially, but as the disease progresses the tangles can be found in the space between cells – believed to be the last remains of a dying cell.

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A normal brain vs an Alzheimer’s affected brain. Source: MMCNeuro

Amyloid plaques are clusters of proteins that sit between cells. A key component of the plaque is beta amyloid. Beta-amyloid is a piece of a larger protein that sits in the outer wall of nerve cells where it has certain functions. In certain circumstances, specific enzymes can cut it off and it floats away.

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Beta-Amyloid. Source: Wikimedia

Beta-amyloid is a very “sticky” protein and for a long time it has been believed that free floating beta-amyloid proteins begin sticking together, gradually building up into the large amyloid plaques. And these large plaques were considered to be involved in the neurodegenerative process of Alzheimer’s disease.

So what was discovered this week?

This week a study was published that suggests a new (and positive) function for beta amyloid:

BetaAm

Title: Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease.
Authors: Kumar DK, Choi SH, Washicosky KJ, Eimer WA, Tucker S, Ghofrani J, Lefkowitz A, McColl G, Goldstein LE, Tanzi RE, Moir RD.
Journal: Sci Transl Med. 2016 May 25;8(340):340ra72.
PMID: 27225182

The researchers took three types of mice:

  • genetically normal mice
  • mice with no beta amyloid
  • mice producing a lot of beta amyloid

They infected all of the mice with the microbe that causes meningitis, and they found that the mice producing a lot of beta amyloid lived significantly longer than other groups of mice. They then repeated the experiment in a species of microscopic worm – called C.elegans – and found similar results. These findings suggested that beta amyloid was having a positive effect in the brain.

But then they noticed something strange.

The mice producing a lot of beta amyloid usually do not develop a lot of protein aggregation until old age, but when the researchers looked in the brains of the mice they infected with meningitis, they found significant levels of aggregation in the mice producing a lot of beta amyloid but at a young age..

This led the researchers to conduct some cell culture experiments in which they watched what was happening to the bacteria and beta amyloid. They found that the beta amyloid was sticking to the bacteria and this was leading to the formation of protein aggregates.

The results of these experiments suggested to the researchers an intriguing possibility that beta amyloid may be playing a protective in the brain – acting as an immune system for the brain – against infection.

Thus the aggregations we see in the brains of people with Alzheimer’s may not be the cause of the cell death associated with the disease, but rather evidence of the ‘brain’s immune system’ trying to fight back against unknown infectious agents. The researcher’s of the study were quick to point out that this antimicrobial action of beta amyloid is simply a new function of the protein, and it may have nothing to do with the disease itself. But it will be interesting to see where this research goes next.

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

Parkinson’s disease is only definitive diagnosed at the postmortem stage. This is done by microscopic examination of the brain. In the brains of people with Parkinson’s disease, there are protein aggregates calls Lewy bodies. These are densely packed clusters of a protein called ‘alpha synuclein‘.

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The brown spot is a Lewy body inside of a brain cell. Source: Cure Dementia

If the results of the study presented above are correct and beta amyloid is a protective protein in the brain against infection, could it not be that alpha synuclein may be playing a similar role? It is a fascinating idea that it will be interesting to test.

What are the implications of the study?

Currently, there are numerous clinical trials for Alzheimer’s disease, involving treatments that act against beta amyloid. If the study presented above is correct, and beta amyloid has a role in protecting the brain, these new treatments in clinical trial may actually be weakening the brain’s ability to fight infection.

Similarly, if alpha synuclein is found to exhibit ‘protective’ properties like beta amyloid, then the alpha synuclein vaccine clinical trials currently underway (in which the body’s immune system is primed to remove free floating alpha synuclein, in an attempt to stop the disease from spreading) may need to be reconsidered. At a minimum, investigations into whether alpha synuclein has antimicrobial properties need to be conducted.

Today’s banner was sourced from PBS.

The Autistic spectrum and Parkinson’s disease

~ Simon ~ 6 Comments

The word Autism on a cork notice board

In August of 2015, groups of scientists from North Carolina and Perth (Australia) published a report together in which they noted the high occurrence of Parkinson’s-like features in aging people with Autism.

In this post we will have a look at what links (if any) there may be between Autism and Parkinson’s disease.

Recent estimates suggest that the prevalence of Autistic Spectrum Disorders in US children is approximately 1.5 %. Autism is generally associated with children, and in this way it is almost a mirror opposite of Parkinson’s disease (which is usually associated with the elderly). A fair number of people who were diagnosed with Autism early in their lives are now reaching the age of retirement, but we know very little about what happens in this condition in the aged.

What is Autism?

This is one of those questions that gets people into trouble. There is a great deal of debate over how this condition should be defined/described. We here at SoPD will chose to play it safe and provide the UK National Health System (NHS)‘s description:

Autism spectrum disorder (ASD) is a condition that affects social interaction, communication, interests and behaviour. In children with ASD, the symptoms are present before three years of age, although a diagnosis can sometimes be made after the age of three. It’s estimated that about 1 in every 100 people in the UK has ASD. More boys are diagnosed with the condition than girls.

Wikipedia also has a very thorough page Autism

So what was reported in the study finding a connection between Autism and Parkinson’s disease?

Last year two groups of researchers (from North Carolina, USA and Perth, Australia) noticed an interesting trend in some of the aging Autistic subjects they were observing.

They published their findings in the Journal of Neurodevelopmental disorders:

Autism-title1

Title: High rates of parkinsonism in adults with autism.
Authors: Starkstein S, Gellar S, Parlier M, Payne L, Piven J.
Journal: Journal of Neurodev Disord. 2015;7(1):29.
PMID: 26322138         (This report is OPEN ACCESS if you would like to read it)

The article reports the findings of two studies:

Study I (North Carolina) included 19 men with Autism (with an average age of 57 years). When the researchers investigated the cardinal features of Parkinson’s disease, they found that 22 % (N = 4) of the subjects exhibited bradykinesia (or slowness of movement), 16 % (N = 3) had a resting tremor, 32 % (N = 6) displayed rigidity, and 15 % (N = 2) had postural instability issues.

In fact, three of the 19 subjects (16 %) actually met the criteria for a full diagnosis of Parkinson’s disease (one of who was already responding well to L-dopa treatment).

Study II (Perth) was a larger study, involving 32 men and 5 women (with an average age of 51 years). 46 % (N = 17) of the subjects in this study exhibited bradykinesia, 19 % (N = 7) had a resting tremor, 19 % (N = 7) displayed rigidity, and 19 % (N = 7) had postural instability problems. In study II, 12 of the 37 subjects (32 %) met the full diagnostic criteria for Parkinson’s disease.

Given this collective result, the researchers concluded that there may well be an increased frequency of Parkinsonism in the aged people with Autism. They emphasize, however, the need to replicate the study before definitive conclusions can be made.

So how could this be happening?

The short answer is: we don’t have a clue.

The results of this study need to be replicated a few times before we can conclusively say that there is a connection. There are, however, some interesting similarities between Autism and Parkinson’s disease, for example (as the NHS mentioned above) males are more affected than females in both conditions.

There are genetic variations that both Parkinson’s and Autism share. Approximately 10-20% of people with Parkinson’s disease have a genetic variation in one of the PARK genes (we have discussed these before – click here to read that post). The genetics of Autism are less well understood. If you have one child with Autism, the risk for the next child also having the condition is only 2-6% (genetically speaking, it should be a 25-50% level of risk).

There are, however, some genes associated with Autism and one of those genes is the Parkinson’s associated gene, PARK2. it has previously been reported that variants in the PARK2 gene (Parkin) in children with Autism (click here for more on this).

It would be interesting to have a look at the brains of aged people with Autism. This could be done with brain scans (DAT-SCAN), but also at the postmortem stage to see if their brains have alpha synuclein clusters and Lewy bodies – the pathological characteristics of Parkinson’s disease. These studies may well be underway – we’ll keep an eye out for any reports.

Alternative explanations?

There are alternative explanations for the connection between Autism and Parkinson’s disease suggested by this study. For example, 36 of the 56 subjects involved in the two studies were on medication for their Autism (the medication is called neuroleptics). Those medications did not appear to explain the rates of parkinsonism in either study (after excluding subjects currently on neuroleptic medications, the frequency of parkinsonism was still 20 %). Most of the subjects in both studies have been prescribed neuroleptics at some point in their lives. Thus it is possible that long-term use of neuroleptics may have had the effect of increasing the risk for parkinsonism later in life. This is pure speculation, however, and yet to be tested. Any future studies would need to investigate this as a possibility.

EDITOR’S NOTE: If you have a child or loved one on the Autism spectrum, it is important to understand that the study summarised here are novel results that are yet to be replicated. And if it turns out that adults with Autism do have a higher risk of developing Parkinson’s disease it does not necessarily mean that they will – simply that they are at greater risk than normal. It is best to consult a medical practitioner if you have further concerns.

The banner at the  today’s post was sourced from Sailing Autistic Seas.

Manna from heaven? Mannitol and Parkinson’s disease

~ Simon ~ 17 Comments

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During the forty years that the Israelites wandered the desert after leaving Egypt, they faced many hardships, most notably a scarcity of food. To resolve this particular issue, God kindly provided the Israelites with “bread from heaven”. It was a “fine, flake-like thing, fine as frost on the ground” and “It was like coriander seed, white, and the taste of it was like wafers made with honey” (Exodus, Chapter 16).

They called “manna.” Hence the phrase: Like Manna from heaven

Today’s post deals with a substance called Manna, a group of Israeli scientists, and maybe a kind of salvation for people with Parkinson’s disease.

In 2013, in the Journal of Biological Chemistry, a group of Israeli scientists published the results of a study that suggested the sweetener ‘Mannitol’ (also known as Manna sugar – I kid you not) may be useful in the treatment of Parkinson’s disease.

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A spoon full of Manna. Source: Qualifirst

What is Mannitol?

Mannitol is a colourless sweet-tasting, poorly metabolized crystalline alcohol sugar that is Food and Drug Administration (FDA)-approved as an osmotic diuretic agent.

In English: a sweetener.

Stick it on your tongue and it tastes like sugar.

Usually made from fructose and hydrogen, Mannitol increases blood glucose to a lesser extent than sucrose, and so it is commonly used as a sweetener for people with diabetes or sugar intolerance. The fact that Mannitol can be produced artificially is the only reason that it is often referred to as an ‘artificial sweetener’, but it does not fall into the same class as proper artificial sweetener, such as aspartame.

So what does the research say?

Manna-title.

Title: A blood-brain barrier (BBB) disrupter is also a potent α-synuclein (α-syn) aggregation inhibitor: a novel dual mechanism of mannitol for the treatment of Parkinson disease (PD).
Authors: Shaltiel-Karyo R, Frenkel-Pinter M, Rockenstein E, Patrick C, Levy-Sakin M, Schiller A, Egoz-Matia N, Masliah E, Segal D, Gazit E.
Journal: J Biol Chem. 2013 Jun 14;288(24):17579-88.
PMID: 23637226                              (This study is OPEN ACCESS if you want to read it)

The Israeli scientists were interested in the ability of Mannitol to inhibit the formation of alpha synuclein aggregates (clumps of the protein that is associated with Parkinson’s disease). Chemicals similar to Mannitol have exhibited protein destabilizing properties, so it was an interesting idea to test.

The researchers used different concentrations of mannitol and added it to a solution of alpha-synuclein. They left this concoction shaking for 6 days (at 37°C) and then assessed the levels of aggregation. Curiously the low levels of Mannitol had the strongest inhibitory effect, while the higher concentrations had no effect. The researchers repeated the experiments and found similar results.

Given this success, they turned their attention to an animal model of alpha synuclein: a genetically engineered fly that produces a lot of alpha synuclein. They found that Mannitol treated flies had significantly less alpha synuclein aggregation in their brain than untreated flies. This study was then repeated in genetically engineered mice (that produce too much alpha synuclein) and guess what? They found the same results.

These results led the scientists to suggest that “mannitol administration in combination with other drugs could be a promising new approach for treating PD and other brain-related diseases such as Alzheimer disease”.

It is believed that that aggregation of alpha synuclein (and the presence of Lewy bodies) is one of the pathological hallmarks of Parkinson’s disease, and thus any substance that inhibits that aggregation would potentially be beneficial.While there is a lot of experimental evidence to suggest that aggregated alpha synuclein is involved in the cell death associated with Parkinson’s disease, it is yet to be determined that inhibiting that aggregation would be beneficial. There are clinical trials going on as we write, so we should have an answer to this issue shortly.

A warning regarding Mannitol 

Before you rush out and start loading up on Mannitol there are a few things you should know about it.

It is used medically, usually to treat increased pressure within the skull.

It should not be abused, however, as it can have an osmotic effect (in particular, attracting water from the intestinal wall). Consumed in excess, it will cause diarrhea, abdominal pain, and excessive gas.

In addition to intestinal problems, Mannitol has also been associated with worsening heart failure, electrolyte abnormalities, or low blood volume. We also do not know what effect it may have on absorption of L-dopa and other Parkinson’s disease medications.

EDITORIAL NOTE HERE: Whenever we discuss new experimental drugs and treatments on SoPD, we point out to the reader that what we are presenting here is experimental research. Under absolutely no circumstances should anyone reading this matter consider it medical advice. Much of what is presented are novel results that need to be replicated and verified before being considered gospel (this certainly applies to the current post). Before considering or attempting any change in your treatment regime, please consult with your doctor or neurologist. 

The Header for today’s post is a depiction of manna from heaven. Source: History.com

The debate surrounding a new Stem cell transplantation trial for Parkinson’s

~ Simon ~ 7 Comments

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In December last year, the Australian government gave official clearance for an American company – International Stem Cell Corporation – to conduct a stem cell based clinical trial at the Royal Melbourne Hospital in Melbourne. This news was greeted with both excited hope from the Parkinson’s support community, but also concern from the Parkinson’s research community. In this post we will explore exactly what is going on.

Before reading on it may be wise for those unfamiliar with transplantation therapy in Parkinson’s disease to read our previous post about the topic, where we discuss the concept and the history of the field. Click here to read that post.

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On the 14th December, the ‘Therapeutics Goods Administration’ (TGA) of Australia passed a regulatory submission from International Stem Cell Corporation (ISCO) for its wholly owned subsidiary, Cyto Therapeutics, to conduct a Phase I/II clinical trial of human stem cell-derived neural cells in patients with moderate to severe Parkinson’s disease. The hospital where the trial will be conducted -the  Royal Melbourne Hospital in Melbourne – gave ethical approval in March this year for the trial to start and the company is now recruiting subjects.

What are the details of the trial?

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Cyto Therapeutics (the subsidiary of ISCO) is planning a Phase I/IIa clinical study. This will evaluate the safety of the technique and provide some preliminary efficacy results. They are going to transplant human parthenogenetic stem cells-derived neural stem cells (ISC-hpNSC, for an explanation of this, please see below) into the brains of 12 patients with moderate to severe Parkinson’s disease. The study will be:

  • an open-label (meaning that everyone knows what they are being treated with),
  • single center (Royal Melbourne Hospital in Melbourne),
  • uncontrolled (there wil be no sham/placebo treated group for comparison)
  • an evaluation of three different doses of neural cells (from 30,000,000 to 70,000,000)

Following the transplantation procedure, the patients will be monitored for 12 months at specified intervals, to evaluate the safety and biologic activity of ISC-hpNSC. The monitoring process will include various neurological assessments and brain scans (PET) performed at baseline (as part of the initial screening assessment), and at 6 and 12 months post surgery.

What are ISC-hpNSCs?

Transplantation of cells is theoretically a good way of replacing the tissue that is lost in neurodegenerative conditions, like Parkinson’s disease. Previous (and the current Transeuro) clinical trials have usually used tissue dissected from aborted fetuses to supply the dopamine neurons required for the transplantations. Obviously there are major ethic and moral issues/problems with this approach. There are also procedural issues with these trials (surgeries being cancelled as not enough tissue is available – tissue from at least three fetuses is required for each transplant).

Growing dopamine cells in petri dishes solves many of these problems. Millions of cells can be grown from a small number of starting cells, and there are no ethical issues regarding the fetal donors. As a result, there has been a major effort in the research community to push stem cells to become dopamine neurons that can be used in transplantation procedures.

Embryonic stem (ES) cells are of particular interest to researchers as a good starting point because the cells have the potential to become any type of cell in the body – they are ‘pluripotent’. ES cells can be encouraged using specific chemicals to become whatever kind of cell you want.

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Embryonic stem cells in a petridish. Source: Wikipedia

Embryonic stem cells are derived from a fertilized egg cell. The egg cell will divide, to become two cells, then four, eight, sixteen, etc. Gradually, it enters a stage called the ‘blastocyst’. Inside the blastocyst is a group of cell that are called the ‘inner stem cell mass’, and it is these cells that can be collected and used as ES cells.

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The process of attaining ES cells. Source: Howstuffworks

The human parthenogenetic stem cells-derived neural stem cells (hpNSC) that are going to be used in the Melbourne trial are slightly different. The hpNSCs come from an unfertilized egg – that is to say, no sperm cell is involved. The egg cell is chemically encouraged to start dividing and then becoming a blastocyst. This process is called ‘Parthenogenesis’, and it actually occurs naturally in some plants and animals.  Proponents of the parthenogenic approach suggest that this is a more ethical way of generating ES cells as it does not result in the destruction of a viable organism.

What has been the response to the announced trial?

In general, the response from the Parkinson’s community has been very positive. The announcement of the trial was greeted by numerous support groups as a positive step forward (for some examples see Parkinson’s UK and the stem cellar blog).

So why then is the research community concerned about the study?

Basically the research community is concerned that this trial will be a repeat of the infamous Colorado/Columbia Trial and Tampa Bay trial back in the 1990s (two double-blind studies which initially suggested no positive effect from transplantation). Both of these studies have been criticised for methodological flaws, but more importantly longer term follow-ups with patients have suggested that the period of observation was too short (12-24 months post transplant), and longer term the transplants have had more positive outcomes – the cells simply required a longer period of time to fully develop into mature neurons. This last detail is important when considering the new trial in Australia – the trial will only follow the subjects for a period of one year.

There are concerns that the absence of paternal genes in parthenogenic stem cells has not been thoroughly investigated (remember that these cells only have the genes from the female egg cell). Paternal genes are believed to be more dominant that female genes during development (Click here for more on this). They may play an important role in the development of dopamine neurons, but this has never been investigated. As a result, researchers are asking if it is wise to move to the clinic before such issues are addressed.

There is also concerns that the preclinical research supporting the trial from the companies involved (ISCO and Cyto Therapeutic) is lacking. While there has been some research into the use of parthenogenic stem cells in models of Parkinson’s (Click here for an example), the research from the company involved in this trial is limited to just a couple of peer-reviewed publications.

The research community has begun expressing their concerns in editorial comments in various journals – the most recent being in the Journal of Parkinson’s disease (Click here to read that article – it is open access).

What preclinical research is supporting the trial?

As far as we here at the SoPD are aware (and we would be very pleased to be corrected on this), there is one research article on the company website dealing with the production of dopamine neurons, and that study did not deal with transplantation. It simply described the recipe from making dopamine neurons.

SciRep-title

Title: Deriving dopaminergic neurons for clinical use. A practical approach.
Authors: Gonzalez R, Garitaonandia I, Abramihina T, Wambua GK, Ostrowska A, Brock M, Noskov A, Boscolo FS, Craw JS, Laurent LC, Snyder EY, Semechkin RA.
Journal: Sci Rep. 2013;3:1463.
PMID: 23492920                 (This article is OPEN ACCESS if you would like to read it)

(One important caveat here – the research published in this study was conducted using both embryonic stem cells (WA-09 cell line) and hpNSCs, but there is no indication in the text as to which cells were used for each result or whether the different types of pluripotent cells gave the same results. The text is unclear on this)

The company also published a study last year in which they transplanted the hpNSCs into both a rodent and primate model of Parkinson’s disease:

Gonzalez-title

Title: Proof of concept studies exploring the safety and functional activity of human parthenogenetic-derived neural stem cells for the treatment of Parkinson’s disease.
Authors: Gonzalez R, Garitaonandia I, Crain A, Poustovoitov M, Abramihina T, Noskov A, Jiang C, Morey R, Laurent LC, Elsworth JD, Snyder EY, Redmond DE Jr, Semechkin R.
Journal: Cell Transplant. 2015;24(4):681-90.
PMID: 25839189

The researchers in this study grew the hpNSCs in petridishes and pushed the cells towards becoming dopamine neurons, and then transplanted them into ten Parkinsonian rats and two Parkinsonian primates. Several months after transplantation, the researchers found the hpNSCs inside the brain and some of them had become dopamine neurons. There was, unfortunately, no indication as to how many of the hpNSCs survived the transplantation procedure. Nor any indication as to how many of them actually became dopamine neurons.

In addition, no behavioural data is presented in the study so there is no evidence that the cells had any functional effect. The researchers did measure the amount of dopamine in the brain, but those result suggested that there was only marginally more dopamine in the transplanted animals than the control animals (which had lesioned dopamine systems and saline injections rather than hpNSCs). Thus there is very evidence that the cells are functional inside the brain.

The researchers wrote in the report that “Most of the engrafted hpNSCs were dispersed from the graft site and remained undifferentiated”. This is not an ideal situation for a cell being transplanted into a particular region of the brain. Nor is it ideal for an undifferentiated cell to be going to the clinic.

And given that these two papers form the bulk of what has been published by the company with regards to their Parkinson’s disease work, researchers are concerned that the company is moving so aggressively to trial.

To be completely fair, ISCO has stated in a press release from April 2014, that their hpNSCs have been tested in 18 Parkinsonian primates. They suggested that those transplanted animals presented “significant improvement in the main Parkinson’s rating score”. Given that those results have never been made public, however, we are unclear as to what they actually mean (what is the “main Parkinson’s rating score”?).

 

We will follow the proceedings here at the Science of Parkinson’s with great interest.

FULL DISCLOSURE – The author of this blog is associated with research groups conducting the current Transeuro transplantation trials and the proposed G-Force embryonic stem cell trials planned for 2018. He has endeavoured to present an unbiased review of the current situation, but ultimately he is human and it is difficult to remain unbiased. He shares the concerns of the Parkinson’s scientific community that the research supporting the current Australian trial is lacking in its thoroughness. 

It is important for all readers of this post to appreciate that cell transplantation for Parkinson’s disease is still experimental. Anyone declaring otherwise (or selling a procedure based on this approach) should not be trusted. While we appreciate the desperate desire of the Parkinson’s community to treat the disease ‘by any means possible’, bad or poor outcomes at the clinical trial stage for this technology could have serious consequences for the individuals receiving the procedure and negative ramifications for all future research in the stem cell transplantation area. 

The header is of a scan of a brain after surgery. Source: Bionews-tx

UPDATE: 26/05/2016
ISCO has published further pre-clinical data this week regarding the cells that will be transplanted in their clinical trial. The data presented is from 18 transplanted monkeys:

Title: Neural Stem Cells Derived from Human Parthenogenetic Stem Cells Engraft and Promote Recovery in a Nonhuman Primate Model of Parkinson’s Disease.
Authors: Gonzalez R, Garitaonandia I, Poustovoitov M, Abramihina T, McEntire C, Culp B, Attwood J, Noskov A, Christiansen-Weber T, Khater M, Mora-Castilla S, To C, Crain A, Sherman G, Semechkin A, Laurent LC, Elsworth JD, Sladek J, Snyder EY, Jr DE, Kern RA.
Journal: Cell Transplant. 2016 May 20. [Epub ahead of print]
PMID: 27213850     (This article is OPEN ACCESS if you would like to read it)

In this study, 12 African Green monkeys with induced Parkinson’s disease (caused by the neurotoxin MPTP) were transplanted with hpNSCs in the midbrain and the striatum. 6 additional monkeys with induced Parkinson’s disease received saline as a control condition. Behavioural testing was conducted and the brains were inspected at 6 and 12 months.

Behaviourally, there was very little difference between the animals that were transplanted versus the control animals when they were compared at 12 months of age. This suggests that the transplant procedure is safe, but may not be having an effect at 12 months.

An inspection of the brain suggested that 10% of the transplanted cells survive to 12 months of age, and a few of them become dopamine neurons.

Some concerns regarding this new study:
Again the researchers have chosen to use saline injections as their control condition. It would be useful to see a comparison of hpNSCs with other types of transplanted cells (eg. fetal tissue or embryonic stem cells) – for a fairer comparison of efficiency.

The biochemical readings (the amount of dopamine in the brain) suggest an small increase in dopamine levels following transplantation, but only in one or two areas of the brain. Most of the analysed regions show no difference. And there is no comparison with a normal brain so it is difficult judge how truly restorative this procedure is. The increases that are observed may be minimal compared to what they should be in a normal brain.

Less than 2% of the transplanted cells became dopamine neurons. This is a bit of a worry given that we don’t know what the rest of the transplanted cells are doing. And the authors noted extensive migration of the cells into other areas of the brain. They reported this in their previous study. This is cause for real concern leading up to their clinical trial. The cells are being transplanted into a specific region of the brain for a specific reason (localised production of dopamine). If that dopamine is being produced in different areas of the brain, there may be unexpected side-effects from the procedure.

Another cause for concern leading up to the clinical trial is that the follow up period for the trial is only 12 months. Given that so little improvement has been seen in these monkeys over 12 months, how do the investigators expect to see significant changes in human over 12 months? The cells may well have an effect long term, but from the behavioural results presented in this new study, it is apparent that it will be extremely difficult to judge efficacy within 12 months.

Even when trying to view the study with an unbiased eye, it is difficult to agree with the researchers conclusion that the results “support the approval of the world’s first pluripotent stem cell based Phase I/IIa study for the treatment of Parkinson’s disease”. The lack of effect over 12 months and the migration of the transplanted cells suggest a serious rethink of the planned clinical study is required.

Finding PARK16

~ Simon ~ 4 Comments

o-GENETICS-facebook

The genetics of any disease is very complicated. We are, however, gradually identifying the genetic mutations/variations that are associated with Parkinson’s disease and coming to understand that role of those genes in the condition. This week, researchers have identified a mutation underlying one form of Parkinson’s disease, which is associated with the name PARK16.

In this post we will review what the scientists have found and what it means.

Parkinson's-disease-regulatory-network-The-genes-and-miRNAs-implicated-in-PD-pathology

A map of some of the genetic interactions associated with Parkinson’s disease. Source: Pubmed

As the image above demonstrates the genetic interactions underlying some forms of Parkinson’s disease are extremely complicated. And it is important to note, dear reader, that that schematic provides only a partially completed picture. It maps out only a portion of the interactions that we know of, and we can only guess at the interactions that we don’t know of. Complicated right?

Approximately 10-15% of cases of Parkinson’s disease are associated with a genetic variation in the DNA that renders an individual vulnerable to the condition.

The region of DNA in which a mutations occurs is called the ‘Locus’. There are more than 20 loci (these  regions of mutations) now associated with Parkinson’s disease. The loci are referred to as ‘PARK genes’.

What are the PARK genes?

Below is a table of the first 15 PARK genes to be associated with Parkinson’s disease:

jkma-54-70-i001-l

A list of the PARK genes. Source: JKMA

The PARK genes in the table are numbered 1 to 15 (16-20 are not mentioned here), and their genetic location is indicated under the label ‘Chromosome’ (this tells us which chromosome the locus is located on and where on that chromosome it is). The specific gene and protein that are affected by the mutation are also labelled (for example the gene (and protein) associated with PARK8 is Lrrk2). It is interesting to note that the gene responsible for making the protein alpha synuclein (SNCA) has two PARK gene loci within it (PARK 1 and PARK4), further emphasizing the importance of this gene in the disease.

You may also notice that there are a lot of unknowns under the labels ‘protein function’ and ‘Pathology’ (with regards to Parkinson’s disease), this is because we are still researching these genes. Furthermore, PARK3 and PARK11 both have question marks beside the genes associated with these loci, indicating that we are still not sure if these are the genes responsible for the dysfunction we observed in these forms of Parkinson’s disease.

Obviously the PARK  genes list is a work in progress.

That said, this week researchers from the University of Tehran (Iran) published a report about the gene they believe is responsible for the dysfunction associated with PARK16 mutations:

Adora1-title

Title: Mutation in ADORA1 identified as likely cause of early-onset parkinsonism and cognitive dysfunction.
Author: Jaberi E, Rohani M, Shahidi GA, Nafissi S, Arefian E, Soleimani M, Moghadam A, Arzenani MK, Keramatian F, Klotzle B, Fan JB, Turk C, Steemers F, Elahi E.
Journal: Mov Disord. 2016 May 2.
PMID: 27134041

The researchers had two siblings (brothers) referred to them that had been diagnosed with early onset Parkinson’s disease (2 siblings from a family of 8 children). Both of the siblings were in their early 30s, but had exhibited Parkinson’s-like features since their early 20s. They had responded to L-dopa therapy, but involuntary movements (L-dopa-induced dyskinesias) had started to appear after just 2 years of treatment.

Naturally the researchers were keen to determine if there was a genetic reason for this situation. To this end, they conducted whole genome analysis to determine what genetic variations the two siblings shared.

They took DNA from white blood cells of the 10 family members (two parents and eight children), and sequenced the genomes for analysis. What they found was two regions of DNA that were the same in the two affected siblings, but different in the rest of the family. In one of these regions was in the gene ADORA1, which encodes a receptor for a particular protein that can influence dopamine release. Importantly, the ADORA1 gene is located within the domain of the PARK16 locus.

When the researcher checked the sibling’s genetic variation inside the ADORA1 gene on a database of 60,000 normal individuals, they found only one other individual who was partially affected by it, suggesting that this mutation is very rare. Based on these findings, the researchers concluded that variations in ADORA1 may explain some of the cases of PARK16 -associated Parkinson’s disease.

So what does it all mean?

It means that we have another piece of the puzzle, and each week other pieces are falling into place. ADORA1 may not be the only genetic variant within the PARK16 locus, but it will explain some cases of PARK16 Parkinson’s disease. Next we need to work out what the variation does to the gene function of ADORA1.

And that will hopefully be a future blog post.

Blood test for Parkinson’s disease?

~ Simon ~ 2 Comments

 

blood-cells

Last week there was a press release from La Trobe University in Melbourne, Australia regarding the development of a new blood test for Parkinson’s disease. The announcement is a little bit odd as the results of the study are still being peer-reviewed (press announcements usually come after the publication of results). But the Parkinson’s community is excited by the idea of new diagnostic aids, especially those that can maybe tell us something new about the disease.

In this post, we will review what we know at present, and we will follow up this post once the results are eventually published.

As we have previously written, the diagnosis of Parkinson’s is rather difficult, with a 10-15% error rate becoming apparent when brains are analysed at the postmortem stage. Thus any new diagnostic tools/tests that can aid in this effort would be greatly appreciated.

La_Trobe_University_logo.svg

A group at La Trobe University in Melbourne have been studying the blood of people with neurodegenerative conditions, and have now announced that they may have a blood test for Parkinson’s disease.

preview

The La Trobe University team: (left to right) Professor Paul Fisher, Dr Sarah Annesley and Dr Danuta Loesch-Mdzewska. Source: La trobe

So what do we know thus far?

The test has been conducted on blood taken from a total of 38 people (29 people with Parkinson’s disease and 9 in a control group). Professor Paul Fisher – one of the lead scientists in the study – has reported that the tests have proven ‘very reliable’.

What does the test measure?

The test is apparently looking at the mitochondria in the blood cells.

And what are mitochondria?

A mitochondrion (singular) is a small structure inside a cell that is responsible for respiration and energy production. It is one of the powerhouses of the cell. Cells have lots of mitochondria (plural) because cells need lots of energy. But when the mitochondria start failing, the cell dies. As the mitochondria fails, they send out toxic chemical signals that tell the cell to begin shutting down.

biobook_cells_4

A schematic of a mitochondria, and where they are inside a cell. Source: Shmoop

The researchers at La Trobe found in their blood tests that there was no damage to the mitochondria of patients with Parkinson’s disease. That in itself is an interesting observation, but what they found next has larger implications:

“Based on the current literature we were expecting reduced oxygen consumption in the mitochondria, which leads to a buildup of toxic byproducts, but what we saw was the exact opposite,” Prof Fisher was quoted as saying. “We were able to show the mitochondria were perfectly normal but were working four times as hard, which also leads to increased production of poisonous byproducts to occur.”

A test that can measure these ‘hyperactive’ mitochondria is very useful as it can both identify people with Parkinson’s disease, but it may also help us to better understand the condition. Prof Fisher and his colleagues, in addition to taking the test forward, are also trying to understand the underlying mechanisms of the ‘hyperactive mitochondria’ – what is causing them to become the way they are.

What is going to happen now?

The scientists at La Trobe would like to repeat and expand on the results (after they are published), and the Michael J Fox foundation and Shake It Up Australia have given La Trobe University more than $640,000 to further develop the research. The plan is to now test 100 subjects – 70 people with Parkinson’s disease and a control group of 30. Prof Fisher is hoping that a test may be available for the clinic in five years time.

What about other neurodegenerative conditions?

So here’s the catch with the information provided thus far – the researchers have not had the funding to test whether this hyperactivity in the mitochondria is occurring exclusively in people with Parkinson’s. That is to say, they haven’t tested whether the effect is also present in people with other neurodegenerative diseases, such as Alzheimer’s, Huntington’s, or ALS. And this is where a little bit of the excitement comes out of the announcement.

But even if the hyperactivity in the mitochondria is shared between certain neurodegenerative diseases, a test highlighting the effect would still be very useful, especially if it can aid us in early detection of these conditions.

As we said above, we will be following this story closely and will report back here as and when information becomes available.

Stay tuned.

An update on the connection between Melanoma and Parkinson’s disease

~ Simon ~ 3 Comments

We have previously discussed the strange connection between Melanoma and Parkinson’s disease (click here to read that post).

Melanoma

That post included the curious observations that:

  • People with Parkinson’s disease are 2-8 times more likely to develop melanoma than people without Parkinson’s.
  • People with melanoma are almost 3 times more likely to develop Parkinson’s disease than someone without melanoma.

And we have no idea why (there is no shared genetic predisposition for the two conditions).

Research published this week, however, may begin to explain part of the connection:

Melanoma-title

Title: Parkinson disease (PARK) genes are somatically mutated in cutaneous melanoma.
Authors: Inzelberg R, Samuels Y, Azizi E, Qutob N, Inzelberg L, Domany E, Schechtman E, Friedman E.
Journal: Neurol Genet. 2016 Apr 13;2(3):e70.
PMID: 27123489     (This research article is OPEN ACCESS if you would like to read it)

In this study, the scientists looked at somatic mutations in cells from 246 tissue samples of melanoma.

What are somatic mutations?

Somatic mutations are genetic alteration that have been acquired by a cell that can then be passed to the progeny of that mutated cell (via cell division). These somatic mutations are different from ‘germline’ mutations, which are inherited genetic alterations that are present in the sperm and egg that were used in making each of us.

germlinesomatic1

Somatic vs Germline mutations. Source: AutismScienceFoundation

In the 246 samples analysed, the researchers found 315,914 somatic mutations in 18,758 genes. Yes, that is a lot, but what was very interesting was their discovery of somatic mutations in many of the PARK genes.

What are PARK genes?

There are a number (approx. 20) genes that are now recognised as conferring vulnerability to developing Parkinson’s disease. These genes are referred to as PARK genes. They include the gene that makes the protein Alpha synuclein ( SNCA ) and many others with interesting names (like PINK1 and LRRK2). Approximately 15% of cases of Parkinson’s are believed to occur because of a mutation in one (or more) of the  PARK genes. As a result there is a lot of research being conducted on the PARK genes.

Were all of PARK genes mutated in the Melanoma samples?

Somatic mutation in 14 of the 15 PARK genes (that the researchers analysed) were present in the melanoma samples. This means that after the skin cells turned into melanoma cancer cells, they acquired mutations in some of the PARK genes. Overall, 48% of the analysed samples had a mutation in at least 1 PARK gene, and 25% had mutations in multiple PARK genes (2–8 mutated genes). One PARK gene in particular, PARK 8, was more significantly present in the melanoma cells than the others. PARK8 is also known as Leucine-rich repeat kinase 2 or LRRK2 (we have previously discussed Lrrk2 – click here to read that post). Three additional PARK genes (PARK2, PARK18, and PARK20) were also significantly present, but not as significant as Lrrk2.

So what does it all mean?

The researchers speculate in the discussion of their report about what the findings could mean, but it is interesting to note that many of the PARK genes are susceptible to acquiring mutations (particularly  Lrrk2). And this is important to consider when thinking about our development as individual human beings – even though you may not born with a particular mutation for Parkinson’s disease (you haven’t inherited it from our parents), somewhere along the developmental pathway (from egg fusing with sperm to full grown adult) you could acquire some of these mutations which would make you vulnerable to Parkinson’s disease.And here we should note that skin and brain share the same developmental source (called the ectoderm). A mutation in a PARK gene could occur during your development and you would never know.

We thought this was a very interesting study – certainly worthy of reporting here.

Helicobacter pylori and Parkinson’s disease

~ Simon ~ 11 Comments

In her best selling book, ‘Gut’, author Giulia Enders wrote the following:

Gut book

‘Although doctors had known since the 1960s that patients with Parkinson’s disease have an increased incidence of stomach problems they did not know the nature of the connection between sore stomachs and trembling hands. It took a study of different population groups on the Pacific island of Guam to throw light on the subject. In some parts of the island, there was an astonishingly high incidence of Parkinson-like symptoms among the population. Those affected suffered from trembling hands, facial paralysis and motor problems. Researchers realised that the symptoms were most common in areas where people’s diets included cycad seeds. These seeds contain neurotoxins – substances that damage the nerves. Helicobacter pylori can produce an almost identical substance. When laboratory mice were fed with an extract of the bacteria without being infected with the living bacterium itself, the displayed very similar symptoms to the cycad eating Guamanians.’

While finding her book a very interesting read, we here at the Science of Parkinson’s were a little worried as to how the general audience would interpret this passage (“So Helico… whatever causes Parkinson’s disease?!?”).

But then this week a new study was published regarding Helicobacter pylori and Parkinson’s disease. And so we thought we’d do a post on it.

In 1982, two Australian scientists – Robin Warren and Barry Marshall – made an interesting discovery.

ILoad672___source

Barry Marshall (left) and Robin Warren. Source: AustraliaUnlimited 

They were studying the association between bacterial infection and peptic ulcers. Their research was ridiculed by the establishment who did not believe that bacteria could even live in the harsh acidic environment of the gut let alone influence or affect it. The general consensus was that stomach ulcers were caused by stress, fatigue, and too much acid.

After some unsuccessful initial experiments, Marshall took the rather bold step of making himself a guinea pig in his own study: he drank a petri dish containing cultured Helicobacter pylori.

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A petri dish of Helicobacter pylori. Yummy! Source: Liofilchem

Yes, I know how crazy that sounds, but that is what happened. And the resulting events changed the way we look at the intestinal system forever.

Marshall had expected the bacteria to take months (if not years) to embed and start to grow, so it came as a bit of a surprise when several days later he began feeling nausea and his mother commented about his bad breath. After a week, Marshall had a biopsy, which demonstrated severe inflammation and the growing of Helicobacter pylori bacteria in his gut. Warren and Marshall were awarded the Nobel prize in Medicine in 2005 for this work.

Since their discovery, we have discovered a small universe of microbes living in our intestinal system (and most of it is still waiting to be discovered). Importantly – as Miss Elders’ book emphasises – we are learning more and more about how the biological system living in our gut is influencing our bodies, both our normal and abnormal states of being.

There are even theories of Parkinson’s disease arising from our growing knowledge of the ‘microbiota’ (what scientists called the eco-system in our guts) and how it could be playing a role in the disease. And many of those theories involve Helicobacter pylori.

What is Helicobacter pylori?

Helicobacter pylori is a spiral shaped bacterium that lives in the stomach and duodenum (that is the section of intestine just below stomach). Don’t be disturbed by that, the population of all microbes outnumber the cells in our body by approximately 10 to 1, and without them we wouldn’t last very long. And Helicobacter pylori are present in the gut of at least 50% of us (though 85% of people never display the symptoms of an infection).

o_helicobacter-pylori

Helicobacter pylori. Source: Helico

So are Helicobacter pylori involved in Parkinson’s disease?

There have been numerous studies that have assessed the Helicobacter pylori populations in the guts of people with Parkinson’s disease (for a very good open access review on this, please click here). These studies are difficult to judge, however, as the rate of Helicobacter pylori is very high and varies somewhat around the world. Different strains of Helicobacter pylori may be having different effects, but this is yet to be determined.

Helicobacter pylori does appear to have an effect, however, with regards to the standard treatment of Parkinson’s disease: L-dopa.

In 2001, Italian researchers noticed fluctuations in the absorption of L-dopa in six Helicobacter pylori infected people with Parkinson’s disease, but not in Helicobacter pylori-negative people with Parkinson’s disease. This was interesting, but even more interesting was that the ratings of these subjects (their UPDRS scores) decreased when they were treated with medication to eradicate Helicobacter pylori.

HP1-title

Title: Reduced L-dopa absorption and increased clinical fluctuations in Helicobacter pylori-infected Parkinson’s disease patients.
Authors: Pierantozzi M, Pietroiusti A, Sancesario G, Lunardi G, Fedele E, Giacomini P, Frasca S, Galante A, Marciani MG, Stanzione P.
Journal: Neurol Sci. 2001 Feb;22(1):89-91.
PMID: 11487216

Other studies have reported similar observations, including this study:

HP2-title

Title: Helicobacter pylori infection and motor fluctuations in patients with Parkinson’s disease.
Authors: Lee WY, Yoon WT, Shin HY, Jeon SH, Rhee PL.
Journal: Mov Disord. 2008 Sep 15;23(12):1696-700.
PMID: 18649391

The researchers in this study found that the onset time of L-dopa was longer, and the duration of the effect was shorter in people with Parkinson’s disease who also have  an Helicobacter pylori infection (compared to people with Parkinson’s disease who are Helicobacter pylori negative). This data supports the idea that Helicobacter pylori may be disrupting the absorption of L-dopa. And again, after administering antibiotic treatment to people with Parkinson’s disease to eradicate Helicobacter pylori, the ‘onset’ time decreased and the duration of the L-dopa effect increased when compared to the pretreatment measures.

So there appears to be some indication that Helicobacter pylori may be affecting the situation in Parkinson’s disease.

But is there any evidence that Helicobacter pylori causes Parkinson’s disease?

To our knowledge, there has been one study that has suggested any kind of causative role for Helicobacter pylori in Parkinson’s disease. That study was presented at the Annual general meeting of the American Society for Microbiology at New Orleans in 2011:

ASM_Logo_Fnl

Title: Helicobacter pylori Infection Induces Parkinson’s Disease Symptoms in Aged Mice.
Authors: Block: M. F. Salvatore, S. L. Spann, D. J. Mcgee, O. A. Senkovich, T. L. Testerman;
University: Louisiana State Univ. Hlth.Sci. Ctr.- Shreveport, Shreveport, LA.
Poster Presentation Number: 136

Poster Abstract:
Background: H. pylori has long been known to cause gastritis and ulcers, but mounting evidence suggests that this organism contributes to several extragastric diseases, including idiopathic Parkinson’s disease. It has been hypothesized that cholesteryl glucosides produced by H. pylori are the cause of neurotoxicity; however chronic inflammation may also cause neurological damage. We have recently developed a mouse model of H. pylori-mediated Parkinson’s disease which approximates many features of human disease, including locomotor dysfunction, decreased dopamine in certain brain regions, and increased susceptibility of older animals to Parkinsonian symptoms. Our experiments also revealed that a mutant strain causes more severe disease than the isogenic wild-type strain. AlpA and AlpB have previously been identified as adhesins.
Methods: We measured five locomotor activity parameters in aged mice persistently colonized with H. pylori SS1 AlpAB and in mice fed whole, killed H. pylori. Following euthanasia, we measured dopamine and tyrosine hydroxylase content in the substantia nigra and dorsal striatum. We also measured effects of the AlpAB mutation on H. pylori adherence and pathogenesis.
Results: Long-term administration of food containing killed H. pylori causes locomotor deficits similar to those seen in H. pylori-infected animals. We found that AlpA and AlpB bind host laminin. Contrary to expectations, the AlpAB mutant causes severe inflammation in gerbils.
Conclusions: The finding that feeding killed H. pylori causes locomotor deficits similar to those seen with active infection supports the hypothesis that products produced by H. pylori are neurotoxic. Our results also suggest alterations in laminin binding by the AlpAB strain could impact interactions with the host. This new mouse model offers an unprecedented opportunity to examine the mechanisms through which H. pylori contributes to Parkinson’s disease in humans.

(Click here for the original abstract)

Unfortunately this research has not been formally published (in a peer-reviewed fashion or otherwise), so many of the details regarding the study are unknown to us. The implications, however, are very interesting and exciting. It would be a worthwhile endeavour for the study to be independently replicated.

But there was a study published last week that raised some interesting possibilities regarding a role for Helicobacter pylori in the onset of Parkinson’s disease:

Helico-title

Title: Augmentation of Autoantibodies by Helicobacter pylori in Parkinson’s Disease Patients May Be Linked to Greater Severity.
Authors: Suwarnalata G, Tan AH, Isa H, Gudimella R, Anwar A, Loke MF, Mahadeva S, Lim SY, Vadivelu J.
Journal: PLoS One. 2016 Apr 21;11(4):e0153725.
PMID: 27100827     (this research article is OPEN ACCESS if you want to read it)

The researchers in this study took  blood from 30 Helicobacter pylori-positive people with Parkinson’s disease and 30 age- and gender-matched Helicobacter pylori-negative people with Parkinson’s disease. They then analysed the blood for autoantibodies (we’ve discussed these before in a previous post). Interestingly, some of the autoantibodies that were found to be elevated in Helicobacter pylori-positive group included antibodies that recognize proteins essential for normal brain function (such as Nuclear factor I subtype A (NFIA), Platelet-derived growth factor B (PDGFB) and Eukaryotic translation initiation factor 4A3 (eIFA3)). This suggests that Helicobacter pylori may be causing the immune system to attack proteins that are required, thus making people with Parkinson’s more vulnerable.

Finally, back to Miss Elder’s passage in her book ‘Gut’:

In the passage at the start of this post, we would suggest that Miss Elders may have been referring to ‘Lytico-bodig’ (also known as amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC) – coined by Hirano and colleagues in 1961). ALS-PDC is a neurodegenerative disease of unknown causes that exists in the United States territory of Guam. In fact, during 1950s, it was one of the leading causes of death for the Chamorros people of of Guam.

As the name suggests the disease has elements of several neurodegenerative conditions, and it is considered a separate condition to Parkinson’s disease. There is no treatment for ALS-PDC. The Parkinsonian drug L-DOPA alleviates only some of the symptoms of ALS-PDC, and window of efficacy is a lot shorter (only 1-2 hours) than that of Parkinson’s disease. ALS-PDC occurs within families, but no genetic connection has been found yet, so most scientists believe it is predominantly environment-based.

β-Methylamino-L-alanine (BMAA), is a neurotoxin produced by a bacteria called cyanobacteria and it has long been considered the culprit behind ALS-PDC. Miss Elders is correct that cycad seeds contain high levels of BMAA, and so too do animals that like eating the fleshy covering of the cycad seeds, such as flying foxes. Flying foxes were a popular dinner in Guam, but little did those consuming the meat realise that their meal probably contained high levels of BMAA. One theory of ALS-PDC causation is basically ‘Eat enough of those dinners across a lifetime and…’. But this theory is not supported by the evidence – flying foxes have been hunted to near extinction in Guam, but the rates of ALS-PDC have disappeared in parallel.

It is also interesting to note that high concentrations of BMAA are present in shark fins. Ignore any comments about the ‘libido enhancing properties’ and avoid shark fin soup.

While we here are very excited by the largely unexplored depths the gastrointestinal system and of the role that it could be playing in Parkinson’s disease, we think that Miss (soon to be Dr) Giulia Enders’ suggestion that Helicobacter pylori and Parkinson’s disease are intimately connected is a bit flimsy. Certainly unproven.

It is dangerous to write definitely about medically related research as it will often result in some individuals going off and self-testing all manner of different treatments in a desperate attempt to ‘cure themselves’.Sometimes this ‘definitive style’ is the suggestion of the editorial staff, hoping to cause something sensational and sell more books.

We are of the mind that more research is required in order to determine the role of bacteria (not just Helicobacter pylori) in Parkinson’s disease.

Having said all this, we still think that soon-to-be-Dr Enders’ book is a good read!