Cannabis and Parkinson’s disease

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This is the kind of post that can really get someone in quite a bit of trouble.

That is, both legal and on social media trouble.

Given the online excitement surrounding a particular video that appeared on the internet last week, however, we thought that it would be useful to have a look at the research that has been done on the medicinal use of Cannabis and Parkinson’s disease.

In addition, we will assess the legal status regarding the medicinal use of Cannabis (in the UK at least).

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Cannabis being grown for medicinal use. Source: BusinessWire

This week a video appeared online that caused a bit of fuss (and hopefully not too many arrests) in the Parkinson’s community.

Here is the video in question:

The video was posted by Ian Frizell, a 55 year old man with early onset Parkinson’s disease that he has recently had deep brain stimulation (DBS) surgery to help control hid tremors (he has also posted a video regarding that DBS surgery which people might find useful – Click here to see this).

In the video, Ian turns off his DBS stimulator and his tremors quickly become apparent. He then ‘self medicates’ with cannabis off camera and begins filming again some 20-30 minutes later to show the difference. The change with regards to his tremor are very clear and quite striking.

Here at the SoPD, we find the video very interesting, but we have two immediate questions:

  1. How is this change in tremor working?
  2. Would everyone experience the same effect?

We have previously seen many miraculous treatments online (such as coloured glasses controlling dyskinesias video from a few years ago) which have failed when tested under controlled conditions (the coloured glasses did not elicit any effect in the clinical setting – click here to read more). Some of these amazing results can simply be put down to the notorious placebo effect (we have previously discussed this in relation to Parkinson’s disease – click here to read the post), while others may vary on a person to person basis.

Thus, while we applaud Mr Frizell for sharing his finding with the Parkinson’s community, we are weary that the effect may not be applicable to everyone. For this reason, we have made a review of the scientific literature surrounding Cannabis and Parkinson’s disease.

But first:

What exactly is Cannabis?

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Drawings of the Hemp plant, from  Franz Eugen Köhler’s ‘Medizinal-Pflantzen’. Source: Wikipedia

Cannabis (also known as marijuana) is a family of flowering plants that can be found in three types: sativa, indica, and ruderalis. Cannabis is widely used as a recreational drug, behind only alcohol, caffeine and tobacco in its usage. It typically consumed as dried flower buds (marijuana), as a resin (hashish), or as various extracts which are collectively known as hashish oil.

While the three varieties of cannabis (sativa, indica, and ruderalis) may look very similar, pharmacologically they have very different properties. Cannabis sativa is often reported to cause a “spacey” or heady feeling, while Cannabis indica causes more of a “body high”.  Cannabis ruderalis, by contrast, is less well used due to its low Tetrahydrocannabinol levels.

What is Tetrahydrocannabinol?

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Tetrahydrocannabinol (or THC) is one of the principle psychoactive components in Cannabis. It a chemical that is believed to be a plant defensive mechanism against herbivores. THC is a cannabinoid, a type of chemical that attaches to the cannabinoid receptors in the body, and it is this pathway that many scientists are exploring for future neuroprotective therapies for Parkinson’s disease (For a good review on the potential cannabinoid-based therapies for Parkinson’s disease, click here).

A second type of cannabinoid is Cannabidiol (or CBD). CBD is considered to have a wider scope for potential medical applications. This is largely due to clinical reports suggesting reduced side effects compared to THC, in particular a lack of psychoactivity.

So what research has been done regarding Cannabis and Parkinson’s disease?

In 2004, a group of scientists in Prague (Czech Republic) were curious to determine cannabis use in people with Parkinson’s disease, so they conducted a study and published their results:

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Title: Survey on cannabis use in Parkinson’s disease: subjective improvement of motor symptoms.
Authors: Venderová K, Růzicka E, Vorísek V, Visnovský P.
Journal: Mov Disord. 2004 Sep;19(9):1102-6.
PMID: 15372606

The researchers posted out 630 questionnaires to people with Parkinson’s disease in Prague.  In total, 339 (53.8%) completed questionnaires were returned to them. Of these, 85 people reported Cannabis use (25.1% of returned questionnaires). They usually consumed it with meals (43.5%), and most of them were taking it once a day (52.9%).

After consuming cannabis, 39 responders (45.9%) described mild or substantial alleviation of their Parkinson’s symptoms in general, 26 (30.6%) improvement of rest tremor, 38 (44.7%) alleviation of rigidity (bradykinesia), 32 (37.7%) alleviation of muscle rigidity, and 12 (14.1%) improvement of L-dopa-induced dyskinesias.

Importantly, half of the people who consumed cannabis experience no effect on their Parkinson’s disease features, and four responders (4.7%) reported that cannabis actually worsened their symptoms. So while this survey suggested some positive effects of cannabis in the treatment of Parkinson’s disease, it is apparent that the effect is different between people.

Additional surveys have been conducted around the world, with similar results (Click here to read more on this).

Have there been any clinical trials?

Yes, there have.

In the 1990s, there was a very small clinical study of cannabis use as a treatment option for Parkinson’s disease, and this study failed to demonstrate any positive outcome. In the study, none of the 5 people with Parkinson’s disease experienced any effect on their Parkinson’s motor features after a week of smoking cannabis (click here for more on this).

This study was followed up by a larger study:

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Title: Cannabis for dyskinesia in Parkinson disease: a randomized double-blind crossover study.
Authors: Carroll CB, Bain PG, Teare L, Liu X, Joint C, Wroath C, Parkin SG, Fox P, Wright D, Hobart J, Zajicek JP.
Journal: Neurology. 2004 Oct 12;63(7):1245-50.
PMID: 15477546

In this randomized, double-blind, placebo-controlled study, 19 people with Parkinson’s disease randomly received either oral cannabis extract or a placebo (twice daily) for 4 weeks. They then took no treatment for an intervening 2-week ‘washout’ period, before they were given the opposite treatment for 4 weeks (so if they received the cannabis extract during the first 4 weeks, they would be given the placebo during the second 4 weeks). In all cases, the participants and the researchers were ‘blind’ to (unaware of) which treatment was being given.

The results indicated that cannabis was well tolerated by all of the participants in the study, but that it had no pro- or anti-Parkinsonian actions. The researchers found no evidence for a treatment effect on levodopa-induced dyskinesia.

In addition to this study, there has been a recent double-blind clinical study of cannabidiol (CBD, mentioned above) in the treatment of Parkinson’s disease:

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Title: Effects of cannabidiol in the treatment of patients with Parkinson’s disease: an exploratory double-blind trial.
Authors: Chagas MH, Zuardi AW, Tumas V, Pena-Pereira MA, Sobreira ET, Bergamaschi MM, dos Santos AC, Teixeira AL, Hallak JE, Crippa JA.
Journal: J Psychopharmacol. 2014 Nov;28(11):1088-98.
PMID: 25237116

The Brazilian researchers who conducted the study took 21 people with Parkinson’s disease and assigned them to one of three groups which were treated with placebo, small dose of CBD (75 mg/day) or high dose of CBD (300 mg/day). They found that there was no positive effects by administering CBD to people with Parkinson’s disease, except in their self-reported measures on ‘quality of life’.

So what does all of this mean?

Firstly, let us be clear that we are not trying to discredit Mr Frizell or suggest that what he is experiencing is not a real effect. The video he has uploaded suggests that he is experiencing very positive benefits by consuming cannabis to help treat his tremors.

Having said that, based on the studies we have reviewed above we (here at the SoPD) have to conclude that the clinical evidence supporting the idea of cannabis as a treatment for Parkinson’s disease is inconclusive. There does appear to be some individuals (like Mr Frizell) who may experience some positive outcomes by consuming the drug, but there are also individuals for whom cannabis has no effect.

One of the reasons that cannabis may not be having an effect on everyone with Parkinson’s disease is that many people with Parkinson’s disease actually have a reduction in the cannabis receptors in the brain (click here for more on this). This reduction is believed to be due to the course of the disease. If there are less receptors for cannabis to bind to, there will be less effect of the drug.

Ok, but how might cannabis be having a positive effect on the guy in the video?

Cannabis is known to cause the release of dopamine in the brain – the chemical classically associated with Parkinson’s disease (Click here and here for more on this). Thus the positive effects that Mr Frizell is experiencing may simply be the result of more dopamine in his brain, similar to taking an L-dopa tablet. Whether enough dopamine is being released to explain the full effect is questionable, but this is still one possible explanation.

There could be questions regarding the long term benefits of Mr Frizell’s cannabis use, as long term users of cannabis generally have reduced levels of dopamine being released in the brain (Click here for more on this). Although the drug initially causes higher levels of dopamine to be released, over time (with long term use) the levels of dopamine in the brain gradually reduce.

I live in the UK. Is it legal for me to try using Cannabis for my Parkinson’s disease?

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National status on Cannabis possession for medical purposes. Source: Wikipedia

The map above is incorrect, with regards to the UK at least (and may be incorrect for other regions as well).

According to the Home Office, it is illegal for UK residents to possess cannabis in any form (including medicinal).

Cannabis is illegal to possess, grow, distribute or sell in the UK without the appropriate licences. It is a Class B drug, which carries penalties for unlicensed dealing, unlicensed production and unlicensed trafficking of up to 14 years in prison (Source: Wikipedia; and if you don’t trust Wikipedia, here is the official UK Government website).

In 1999, a major House of Lords inquiry made the recommendation that cannabis should be made available with a doctor’s prescription. The government of the U.K., however, has not accepted the recommendations. Cannabis is not recognised as having any therapeutic value under the law in England and Wales.

Having said all of this, there has recently been an all-party group calls for the legalisation regarding cannabis for medicinal uses to be changed (click here for more on this). Whether this will happen is yet to be seen.

So the answer is “No, you are not allowed to use cannabis to treat your Parkinson’s disease”.

Except…

(And here is where things get a really grey)

There is a cannabis-based product – Sativex – which can be legally prescribed and supplied under special circumstances. Sativex is a mouth spray developed and manufactured by GW Pharmaceuticals in the UK. It is derived from two strains of cannabis leaf and flower, cultivated for their controlled proportions of the active compounds
THC and CBD.

In 2006, the Home Office licensed Sativex so that:

  • Doctors could privately prescribe it (at their own risk)
  • Pharmacists could possess and dispense it
  • Named patients with a prescription could possess

In June 2010 the Medicines Healthcare Regulatory products Agency (MHRA) authorised Sativex as an extra treatment for patients with spasticity due to Multiple Sclerosis (MS). Importantly, doctors can also prescribe it for other things outside of the authorisation, but (again) this is at their own risk.

EDITORIAL NOTE: Given that possessing cannabis is illegal and that more research into the medicinal benefits of cannabis for Parkinson’s disease is required, we here are the SoPD can not endorse the use of cannabis for treating Parkinson’s disease. 

While we are deeply sympathetic to the needs of many individuals within the Parkinson’s community and agree with a reconsideration of the laws surrounding the medicinal use of cannabis, we are also aware of the negative consequences of cannabis use (which can differ from person to person).

If a person with Parkinson’s disease is considering a change in their treatment regime for any reason, we must insist that they first discuss the matter with their trained medical physician before undertaking any changes.

The information provided here is strictly for educational purposes only.

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

The mystery deepens – Melanoma and Parkinson’s disease

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Interesting new data published today regarding the curious connection between Parkinson’s disease and melanoma.

It was interesting because the data suggests that there is no genetic connection. No obvious connection that is.

In this post we will review the study and discuss what it all means.

Melanoma

Melanoma. Source: Wikipedia

Question 1.: why are people with Parkinson’s disease are 2-8 times more likely to develop melanoma – the skin cancer – than people without Parkinson’s?

Question 2.: why are people with melanoma almost 3 times more likely to develop Parkinson’s disease than someone without melanoma?

This topic is an old favourite here at the SoPD, and we have discussed it several times in previous posts (Click here and here to read those posts). It is a really good mystery. A lot of people have looked at this issue and the connection between the two conditions has not been immediately forthcoming.

When the genetics mutations of both conditions were previously analysed, it was apparent that none of the known Parkinson’s mutations make someone more susceptible to melanoma, and likewise none of the melanoma-associated genetic mutations make a person vulnerable to Parkinson’s disease (Meng et al 2012;Dong et al 2014; Elincx-Benizri et al 2014).

So what was published today?

New genetic data! Rather than simplifying things, however, this new data has simply made the mystery….well, more of a mystery. The publication in question is:

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Title: Rare variants analysis of cutaneous malignant melanoma genes in Parkinson’s disease.
Authors: Lubbe SJ, Escott-Price V, Brice A, Gasser T, Pittman AM, Bras J, Hardy J, Heutink P, Wood NM, Singleton AB, Grosset DG, Carroll CB, Law MH, Demenais F, Iles MM; Melanoma Meta-Analysis Consortium, Bishop DT, Newton-Bishop J, Williams NM, Morris HR; International Parkinson’s Disease Genomics Consortium.
Journal: Neurobiol Aging. 2016 Jul 28.
PMID: 27640074             (This article is OPEN ACCESS if you would like to read it)

Given that previous studies have suggested that there are no obvious genetic mutations connecting Parkinson’s disease with melanoma, the researchers in this study looked for very rare genetic variations in 29 melanoma-associated genes. They did this analysis on a very large pool of genetic data, from 6875 people with Parkinson’s disease and 6065 normal healthy control subjects.

What the researchers found was only very weak connections between two conditions, based on only a few of these genetic mutations (none of which were statistically significant, which means that they could be due to chance).

One very rare genetic mutation in a gene called TYR p.V275F is very interesting. It was found to be more common in people with Parkinson’s disease than controls in 3 independent groups of data. The gene TYR produces a protein called Tyrosinase, which an important ‘rate-limiting enzyme’ in biological production in both neuromelanin and dopamine (the chemical critically associated with Parkinson’s disease).

So what does this mean?

This data suggests that the connection between Parkinson’s disease and melanoma is not due to a known shared genetic mutation. This conclusion, however, leaves open many alternative possibilities. One such possibility involves the vast pieces of human DNA that are described as ‘non-coding‘. These are sections of DNA that will produce a piece of RNA, but that RNA will not be used to produce a protein (as is normal in biology 101). That non-coding RNA will, however, have functions in regulating the activity on sections of DNA or other RNAs (yeah, I know. It’s complicated. Even for me!). Importantly, these non-coding RNA can play a role in diseases. For example, it was discovered a few years ago that a non-coding RNA called BACE1-AS is produced in very large amounts in patients with Alzheimer’s disease (Click here for more on this). We are simply speculating here though.

The scientists who published the research today suggest that they will further investigate and better characterise the interesting link between the gene TYR and Parkinson’s disease, and they will now broaden their analysis of genetic regions that could be influencing the curious connection between Parkinson’s disease and melanoma. Rather than simply focusing on known genetic mutations (common or rare), they will start to dig deeper into our DNA to see what else may underlie the connection between these two conditions.

Watch this space.

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

First film footage of Parkinson’s disease

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Something different today.

I have recently been made aware of the work of Arthur Van Gehuchten (1861–1914), a Belgian anatomist who provided the world with some of the earliest films of Parkinson’s disease. The collection of footage is very precious.

In this post we share a couple of the films, which should be of interest to scientists, clinicians, historian and layman alike.

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Dopamine 2016 conference in Vienna. Source: Dopamine 2016

Two weeks ago, I attended a 4 days conference in Vienna (Austria) where everyone in the world of Dopamine (the chemical in the brain that plays such a critical role in Parkinson’s disease) collected and compared notes. It was a very interesting meeting (set in a spectacular city), with lots of fascinating new discoveries.

During the third afternoon, I was particularly intrigued by something in the introduction of a presentation. The speaker (Dr Eugene Mosharov from Columbia University) displayed some historical film footage and spoke briefly of the contribution of Arthur Van Gehuchten. I was mesmerised and I asked Dr Mosharov after the talk about the source of his film. He kindly shared the information.

The footage is part of an article published in the journal ‘Lancet’ which reviewed the work of Van Gehuchten, but also provides a nice bit of historical background which gives the films some context:

art1

Title: Moving pictures of Parkinson’s disease.
Authors: Jeanjean A, Aubert G.
Journal: Lancet. 2011 Nov 19;378(9805):1773-4.
PMID: 22106466     (This article is OPEN ACCESS if you would like to read it)

The films can be downloaded from the Lancet website, or they can be found on Youtube. Here is the first film:

And the second film:

And the third film:

Six film clips are presented with the article, but Arthur Van Gehuchten actually filmed and collected over 3 hours of short sequences, which are now housed at the Cinematek (Royal Belgian Film Archive) in Brussels.

It is remarkable to consider that there were very few treatment options available when these films were made – L-dopa was still 50 years away! While some of the content is difficult to watch considering this fact, I thought it would be of interest to acknowledge Gehuchten’s contribution and to share the films here today.

The banner of today’s post was sourced from the journal ‘Neurology‘

Update: Stem cells trial for Parkinson’s disease

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Last night surgeons at the Royal Melbourne Hospital, conducted an 8 hour surgery during which stem cells were injected into 14 sites in the brain of a 64 year old person with Parkinson’s disease. This was the first of 12 surgeries being conducted in a phase 1 clinical trial that will assess the safety of this particular type of stem cell in human.

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Surgeons at work. Source: Reuters

Some media outlets have reported the surgery as taking us ‘one step closer to a cure for Parkinson’s disease’ (Click here, here, and here to see their reports). We here at the SoP.com are less excited by this new development, having previously expressed serious concerns about this trial (Click here for that post). We believe that the preclinical data presented thus far does not support going forward to the clinic prematurely with this particular type of stem cell.

Our primary concerns arise from some of the most recent preclinical work published by the company – International Stem Cell Corporation (ISCO) – behind the trial, particularly their preclinical non-human primate work:

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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 injected in the brain with the ISCO’s stem cells (called hpNSCs). The cells are injected into two areas of the brain: the midbrain (where the dopamine cell that are lost in Parkinson’s disease normal reside) and the striatum (where the dopamine cells release their dopamine). Six 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.

When the brains were analysed at 12 months post surgery, the researchers found that less than 2% of the transplanted cells actually developed into dopamine neurons. While this is a very low number of dopamine neurons, of greater concern is that we don’t know what became of the remaining transplanted cells.

More disturbing, however, is that the authors noted extensive migration of the cells into other areas of the brain. They have also reported this phenomena in their previous study involving mice. This is represents a major concern regarding the move to the clinic. The goal of the surgery is to inject the cells into a specific region of the brain for a specific reason  – localised production of dopamine. The surgeons want the cells to stay where they are placed and for them to produce dopamine in that location. If cells are migrating away from that location and the dopamine is being produced in different areas of the brain, the therapeutic effect of the cell transplantation procedure may be reduced and there could also be unexpected side-effects (for example, dopamine being produced in the wrong areas of the brain – areas where dopamine should not be produced). Based on these findings, we still believe that proceeding to the clinic with these particular types of stem cells is premature and unwise.

ISCO is yet to make a press release about this overnight surgery (we can hopefully expect it later today given US time zones). The surgeons who conducted the surgery, however, have reiterated that this study is just a phase 1 trial to determine the safety of these cells in human. The transplanted subjects will be monitored for 12 months.

We will follow the proceedings here at the Science of Parkinson’s and keep you updated.

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 shares the concerns of the Parkinson’s scientific community that the research supporting the current Australian trial does not support the trial moving into the clinic. 

EDITORIAL NOTE – 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 banner for today’s post is of a scan of a brain after surgery. Source: Bionews-tx

Vaccine for Parkinson’s – AFFiRiS update

 

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Interest press release from the biotech company AFFiRiS last week (Click here for the press release) regarding their clinical trial of a vaccine for Parkinson’s disease. We have previously outlined the idea behind the trial (Click here for that post) and the team at Michael J Fox foundation also provide a great overview (Click here for that – MJF are partly funding the trial). In today’s post we will briefly review what results AFFiRiS has shared.

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Vaccination. Source: WebMD

Vaccination represents an efficient way of boosting the immune system in the targeting of foreign or problematic agents in the body. For a long time it has been believed that the protein Alpha Synuclein is the ‘problematic agent’ involved in the spread of Parkinson’s disease inside the brain. Alpha synuclein is required inside brain cells for various normal functions. In Parkinson’s disease, however, this protein aggregates for some reason and forms circular clusters inside cells called Lewy bodies.

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A lewy body (brown with a black arrow) inside a cell. Source: Cure Dementia

It has been hypothesized (and there is a lot of experimental evidence available to support the idea) that released alpha synuclein – freely floating between brain cells  – may be one method by which Parkinson’s disease spread through the brain. With this in mind, groups of scientists (like those at AFFiRiS) are attempting to halt the spread of the condition, by training the immune system to target free-floating alpha synuclein. Vaccination is one method by which this is being attempted.

AFFiRiS is a small biotech company in Vienna (Austria) that has an ongoing clinical trial program for a vaccine (called ‘AFFITOPE® PD01A’) against alpha synuclein. The subjects in the study (22 people with Parkinson’s disease) received four vaccinations – each injection given four-weeks apart – and then the subjects were observed for 2-3 years (6 additional subjects were included in the study for comparative sake, but they did not receive the vaccine.

 Last week the company issued a press release regarding a phase 1 trial (AFF008), which indicated that PD01A is safe and well tolerated, and causing an immune response (which is a good thing) in 19 of 22 (86%) of vaccinated subjects. In 12 of those 19 (63%) participants with and immune response, the researchers found alpha-synuclein antibodies in the blood, suggesting that the body was reacting to the injected vaccine and producing antibodies against alpha synuclein (for more on what antibodies are, click here).

The scientists also conducted some exploratory efficacy assessments – to determine if they could see if the vaccine was working clinically and slowing down the disease. Eight of the 19 (42%) subjects with an immune response, had no increase of their dopaminergic medication (eg. L-Dopa) over the course of the observational period (average three years per subject). And five of those eight subjects had stable clinical motor scores at the end of the study.

The company also conducted parallel laboratory-based experiments which indicate that AFFITOPE® PD01A-induced antibodies are binding to alpha-synuclein in various models of Parkinson’s disease.

The company will be presenting the results on a poster at the 4th World Parkinson Congress in Portland, Oregon, USA on September 21.

So this is a good result right?

It is easy to get excited by the results announced in the press release, but they must be taken with a grain of salt. This is a Phase I trial which is only designed to test the safety of a new therapeutic agent in humans. From this point of view: Yes, the study produced a good result – the vaccine was well tolerated by the trial subjects.

Drawing any other conclusions, however, is not really possible – the study was not double-blind and the assignment of subjects to the treatment groups was not randomize. In addition, the small sample size makes it very difficult to make any definitive conclusions. It must be noted that of the 22 people with Parkinson’s disease that started the study, only five exhibited stabilized clinical motor scores at the end of the study. It may be too soon to tell if the vaccine is having an effect in most of the people involved in the study. Thus longer observation periods are required – which the company is currently undertaking with their follow-up study, AFF008AA. The results of that study are expected in middle-late 2017.

We shall keep you posted.

The banner for today’s post was sourced from AFFiRiS

One year in

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On the 8th September 2015, we kicked this blog off with the goals of:

  • Trying to answer any questions you may have about Parkinson’s disease.
  • Report each week on interesting/exciting research in the world of Parkinson’s disease.
  • Interview Parkinson’s disease researchers, providing a face to the people doing the work.
  • Help you to understand this disease better.

On the first goal, we have fielded many questions and hope that we have provided satisfactory answers (thus far, no complaints). On the second, we are pleased to have published 63 posts over the past year – more than once per week (rather miraculous considering the requirements of work and family). As for interviewing researchers, we have held back on this, but will be looking to initiate something in this next 12 months – it is a question of format rather than availability of interviewees. We are thinking about posting some videos and this may be a better format for readers to meet the researchers behind the science.

On the final goal, well… only you the reader can judge how we are doing in that regard. We hope that we are providing useful information.

Looking forward to another year of Parkinson’s Science!

The team@SoPD

The banner for today’s post was sourced from PlusQuotes

 

Game changer for Alzheimer’s?

TOP-L-Concussion Front Page

Exciting results published this week regarding a small phase 1b clinical trial of a new treatment for Alzheimer’s disease. In this post, we shall review the findings of the study and consider what they may mean for Parkinson’s disease.

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An Alzheimer’s brain scans on the left, compared to a normal brain (right). Source: MedicalExpress

Alzheimer’s disease is the most common neurodegenerative disease, accounting for 60% to 70% of all cases of dementia. It is a progressive neurodegenerative condition, like Parkinson’s disease, affecting approximately 30 million people around the world.

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

  • Neurofibrillary tangles
  • Amyloid plaques

 

 

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A schematic demonstrating the difference between healthy and Alzheimer’s affected brains. Source: MmcNeuro

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.

Amyloid plaques are clusters of proteins that outside the 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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The releasing of Beta-Amyloid. Source: Wikimedia

Beta-amyloid is a very “sticky” protein and 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. Thus, for a long time scientists have attempted to reduce the amount of free-floating beta-amyloid in the brain. One of the main ways they do this is with antibodies.

What are antibodies?

An antibody is the foundation of our immune system. It is a Y-shaped structure, that is used to alert the body when a foreign or unhealthy agent is present.

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An artist’s impression of a Y-shaped antibody. Source: Medimmune

Two arms off the Y-shaped antibody have what is called ‘Antigen binding sites‘. An antigen is a molecule that is capable of inducing a response from the immune system (usually a foreign agent, but it can be a sick/dying cell).

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A schematic representation of an antibody. Source: Wikipedia

There are currently billions of antibodies in your body -each with specific sets of antigen binding sites – awaiting the presence of their antigen. Antibodies are present in two forms: secreted, free floating antibodies, and membrane-bound antibodies. Secreted antibodies are produced by B-cells, which are part of the immune system. And it’s this secreted form of antibody that modern science has used to produce new medicines.

Really? How does that work?

Scientists can make antibodies in the lab that target specific proteins and then inject those antibodies into a patient’s body and trick the immune system into removing that particular protein. This can be very tricky, and one has to be absolutely sure of the design of the antibody because you do not want any ‘off-target’ effects – the immune system removing a protein that looks very similar to the one you are actually targeting.

These manufactured antibodies are used in many different areas of medicine, particularly cancer (over 40 antibody preparations have been approved by the U.S. Food and Drug Administration for use in humans against cancers). Recently, large pharmaceutical companies (like Biogen) have been attempting to use these manufactured antibodies against other conditions, like Alzheimer’s disease.

Which brings us to the study published this week:

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Title: The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease.
Authors: Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, O’Gorman J, Qian F, Arastu M, Li M, Chollate S, Brennan MS, Quintero-Monzon O, Scannevin RH, Arnold HM, Engber T, Rhodes K, Ferrero J, Hang Y, Mikulskis A, Grimm J, Hock C, Nitsch RM, Sandrock A.
Journal: Nature. 2016 Aug 31;537(7618):50-6.
PMID: 27582220

In this study, the researcher conducted a 12-month, double-blind, placebo-controlled trial of the antibody Aducanumab. This antibody specifically binds to potentially harmful beta-amyloid aggregates (both small and large). At the very start of the trial, each participants was given a brain scan which allowed the researchers to determine the baseline level of beta-amyloid in the brains of the subjects. 

All together the study involved 165 people, randomly divided into five different groups: 4 groups received the 4 different concentrations of the drug (1, 3, 6 or 10 mg per kg) and 1 group which received a placebo treatment. Of these, 125 people completed the study which was 12 months long. Each month they received an injection of the respective treatment (remember these are manufactured antibodies, the body can’t make this particular antibody so it has to be repeated injected).

After 12 months of treatment, the subjects in the  3, 6 and 10 mg per kg groups exhibited a significant reduction in the levels of beta-amyloid protein in the brain (according to brain scan images), indicating that Aducanumab – the injected antibody – was doing it’s job. Individuals who received the highest doses of Aducanumab had the biggest reductions in beta-amyloid in the brain. Interestingly, this reduction in beta-amyloid in the brain was accompanied by a slowing of the clinical decline as measured by tests of dementia.  Individuals treated with the placebo saw neither any reduction in their brain levels of beta amyloid nor their clinical decline.

The authors considered this study strong justification for larger phase III trials. Two of them are now in progress, with completion dates expected around 2020.

So this is a good thing right?

Yes, this is a very exciting result for the Alzheimer’s community. But the results must be taken with a grain of salt. We have discussed beta-amyloid in a previous post (Click here for that post). While it has long been considered the bad boy of the Alzheimer’s world, the function of beta-amyloid remains the subject of debate. Some researchers worry about the medical removal of it from the brain, especially if it has positive functions like anti-microbial (or disease fighting) properties.

Given that the treatment is given monthly and can thus be controlled, we can sleep easy knowing that disaster won’t befall the patients receiving the antibody. And if they continue to demonstrate a slowing/halting of the disease, it would represent a MASSIVE step forward in the neurodegenerative field. I guess what I am saying is that it is too soon to say. It will be interesting, however, to see what happens as these patients are followed up over time. And the two phase 3 clinical trials currently ongoing, which involve hundreds of participants, will provide a more definitive idea of how well the treatment is working.

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

Yeah, so let’s get back to our area of interest: Parkinson’s disease. Biogen is the pharmaceutical company that makes the Alzheimer’s antibody (Aducanumab) discussed above. Biogen is also currently conducting a phase 1 safety trial (on normal healthy adults) of an antibody that targets the Parkinson’s disease associated protein, alpha synuclein. We are currently waiting to hear the results of that trial.

Several other companies have antibody-based approaches for Parkinson’s disease (all of them targeting the protein alpha synuclein). These companies include:

There are some worries regarding this approach, however. For example, alpha synuclein is highly expressed in red blood cells, and some researchers worry about what affects the antibodies may have on their function. In addition, alpha synuclein has been suspected of having anti-viral properties – reducing viruses ability to infect a cell and replicate (click here to read more on this). Thus, removal of alpha synuclein by injecting antibodies may not necessarily be a good thing for the brain’s defense system.

Unlike beta-amyloid, however, most of alpha synuclein’s activities seem to be conducted within the walls of brain cells, where antibodies can’t touch it. Thus the hope is that the only alpha synuclein being affected by the antibody treatment is the variety that is free floating around the brain.

The results of the Alzheimer’s study are a tremendous boost to the antibody approach to treating neurodegenerative diseases and it will be very interesting to watch how this plays out for Parkinson’s disease in the near future.

Watch this space!

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Is there something in my eye?

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Some people say that the eyes are the gateway to the soul.

Maybe. I don’t know. Poetic stuff though.

Research published recently, however, suggests that the eyes may also provide a useful aid in the diagnosis of Parkinson’s disease. In today’s post we will review what results have been published and try to understand what they mean for our understanding of this condition.

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A schematic of the human eyeball. Source: NIDDK image library

The fact that you can see and read this page is a miraculous thing.

Amazing not just because light is entering your eye, being focused on a particular point in the back of the eyeball and then being turned into a signal that is transmitted to your brain for further analysis, but also because of all the other activities involved with sight. The muscle movements, for example, which are required for turning the eyeball the small fractions necessary for reading this sentence from left to right.

And then there is also the blood supply, keeping the whole system working. This feature is of particular interest to today’s post, as research published last week suggests that there are differences in the blood flow of the eyeball between people with and without Parkinson’s disease.

The anatomy of an eyeball

The human eyeball is – on the macro level – a fairly simple structure.

You have the Iris, which regulates the amount of light entering the eye. At the centre of the iris, you have a central opening called the pupil, which can dilate and constrict as required. Covering these is the cornea, a transparent circular skin. These structures all sit over the lens which helps to refract incoming light and focus it onto the retina. And the retina, of course, is the light sensitive layer that lines the interior of the eye – allowing us to see.

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The anatomy of the eye. Source: GemClinic

Within the retina are specialised cells of two sorts:

  • Rod cells (about 125 million of them per eye) which are necessary for seeing in dim light.
  • Cone cells (6-7 million of these) which can be further divided into three types, each sensitive to different primary colours – red, green or blue.

These specialised ‘photoreceptive’ cells send signals down through the layers of the retina to what are called retinal ganglion cells which are the key conduits in the sending of information to the brain.

All of these cells require a constant blood supply, from arteries and veins spreading across the retina, and this a key part of our discussion today (see below).

So what have eyeballs got to do with Parkinson’s disease?

Good question. People with Parkinson’s disease often complain of from visual issues, such as reduced visual acuity, low contrast sensitivity and disturbed colour vision.

And there has been some research into the eyes with regards to Parkinson’s disease. A few weeks ago, this particular study was published:

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Title: The retina as an early biomarker of neurodegeneration in a rotenone-induced model of Parkinson’s disease: evidence for a neuroprotective effect of rosiglitazone in the eye and brain.
Authors: Normando EM, Davis BM, De Groef L, Nizari S, Turner LA, Ravindran N, Pahlitzsch M, Brenton J, Malaguarnera G, Guo L, Somavarapu S, Cordeiro MF.
Journal: Acta Neuropathol Commun. 2016 Aug 18;4(1):86. doi: 10.1186/s40478-016-0346-z.
PMID: 27535749       (This article is OPEN ACCESS if you would like to read it)

The researchers in this study used a rodent model of Parkinson’s disease (rotenone-induced). In this model, the animals started losing dopamine cell loss in the brain at 60 days after the model of Parkinson’s disease was chemically induced.

The scientists examined the eyes of the rats at 10, 20, 40 and 60 days of the study. At the 20 day time point, the researchers began to see increased retinal ganglion cell death and swelling of the retinal layers in the eyes. These changes were obviously occurring well before the cell loss is observed in the brain, which leads the authors to ask whether the eyes could potentially used as an early indicator of Parkinson’s disease.

Of particular interest in this study was the use of Rosiglitazone to protect the retinal cells (AND the dopamine neurons in this rodent model of Parkinson’s disease). Rosiglitazone is an anti-diabetic drug. It works as an insulin sensitizer, by binding to fat cells and making them more responsive to insulin (we have previously discussed the curious relationship between Parkinson’s disease and diabetes (click here for more on this), and this result reinforces that connection). The scientists found that giving the drug once every 3 days had very beneficial effects of the survival of the retinal cells. They also observed significant neuroprotection after delaying the treatment for 10 days and then just giving one round of treatment, suggesting that a lot of the drug is not required for positive results.

EDITORIAL NOTE HERE: Before readers start to get any crazy ideas about sourcing and self medicating with Rosiglitazone, it is important to note that there are serious side effects associated with this class of drug. It has been associated with heart disease and stroke (click here to read more), and it should only be taken by people with diabetes and under the strict supervision of a qualified physician. It it mentioned here purely for educational purposes.

So obviously what is required is an examination of the eyes of people with Parkinson’s disease

Yep. And conveniently, in the same week as the previous study came out, this second study was also published:

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Title: Evaluation of Retinal Vessel Morphology in Patients with Parkinson’s Disease Using Optical Coherence Tomography.
Authors: Kromer R, Buhmann C, Hidding U, Keserü M, Keserü D, Hassenstein A, Stemplewitz B.
Journal: PLoS One. 2016 Aug 15;11(8):e0161136.
PMID: 27525728          (This article is OPEN ACCESS if you would like to read it)

The researchers examined 49 people with Parkinson’s disease and 49 age- and sex-matched healthy controls. Blood vessels within the retina were identified and then divided into arteries and veins, based on their shape (using computer software). The results of the study indicate significant differences in the morphology of retinal veins in people with Parkinson’s disease when compared to controls.

Interestingly, the retinal effect was more significant on the side of the body firstly affected by Parkinson’s disease (a very common feature of Parkinson’s is that initially the condition will affect one side of the body more than the other).

What does it all mean?

For generations, we have focused on the clinical motor features of Parkinson’s disease (slowness, rigidity, and a resting tremor) when trying to determine if someone has the condition. Now we are learning that there may be other parts of the body that we should be investigating, which could not only provide us with novel diagnostic tools for earlier detection of the disease, but those areas may also provide us with new insights into disease onset and spread as well.

I may be getting a bit ahead of myself here but the possibilities are exciting and we’ll keep you abreast of these new findings as they come to us.

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

Nilotinib update – new trial delayed

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It is with great frustration that we read today of the delayed start to the phase 2 clinical trial of the re-purposed cancer drug Nilotinib for Parkinson’s disease (click here for a story outlining the background, and click here for the Michael J Fox Foundation statement).

We have previously  discussed both the preclinical and clinical research regarding Nilotinib and its use in Parkinson’s disease (click here and here for those posts). And the Parkinson’s community certainly got very excited about the findings of the small phase 1 unblinded clinical trial conducted by researchers at Georgetown University in 2015.

With the recent failure of the GDNF trial in Bristol, what the Parkinson’s community (both suffers and researchers alike) needs to do is refocus on moving ahead with exciting new projects, like Nilotinib. To hear that the follow-up trials for Nilotinib, however, will be delayed until 2017 (TWO YEARS after the initial results were announced) due to disagreements regarding the design of the study and who is seemingly in charge of the project, is both baffling and deeply disappointing.

Currently it appears that parties involved in the follow-up clinical trial have decided to go their separate ways, with the researchers at Georgetown University looking to conduct a single site phase 2 study of 75 subjects (if they can access the drug from supplier Novartis), while the Michael J Fox backed consortium will set up a multi-site phase 2 study.

We will continue to follow this situation as it develops and will report events as they happen.

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:

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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