Tag: scientist

The road ahead – Parkinson’s research in 2017

~ Simon ~ 11 Comments

road

With the end of the 2016, we thought it would be useful and interesting to provide an overview of where we believe things are going with Parkinson’s disease research in the new year. This post can be a primer for anyone curious about the various research activities, and food for thought for people who may have some fresh ideas and want to get involved with the dialogue.

Never before has so much been happening, and never before has there been greater potential for real change to occur. It is a very exciting time to be involved in this field, and it really does feel like we are on the cusp of some major discoveries.

In today’s post we will outline what to expect from Parkinson’s research in 2017.

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Things to look forward to. Source: Dreamstime

Before we start: something important to understand –

The goal of most of the research being conducted on Parkinson’s disease is ultimately focused on finding a cure.

But the word ‘cure’, in essence, has two meanings:

  1. The end of a medical condition, and
  2. The substance or procedure that ends the medical condition

These are two very different things.

And in a condition like Parkinson’s disease, where the affected population of people are all at different stages of the disease – spanning from those who are not yet aware of their condition (pre-diagnosis) to those at more advanced stages of the disease – any discussion of a ‘cure for Parkinson’s disease’ must be temporal in its scope.

In addition to this temporal consideration, everyone is different.

A ‘cure’ for one person may not have an impact on another person – particularly when genetics is included in the equation. Currently there is a clinical trial which is only being tested on people with Parkinson’s disease who have a particular genetic mutation (Click here to read more about this).

With all of that said, there are 4 key areas of ongoing/future research:

  • Defining and understanding the biology of the condition
  • Early detection
  • Slowing/halting the disease
  • Replacing what has been lost

EDITOR’S NOTE HERE: While we appreciate that this list does not take into account important research dealing with the improving the day-to-day living and quality of life of those affected by Parkinson’s disease (such as prevention of falling, etc), we are primarily focusing here on finding a ‘cure’.

Let’s now have a look at and discuss each of these key areas of research:

Defining and understanding the biology

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Complicated stuff. Source: Youtube

The first key area of research feeds into all of the others.

It is only through a more thorough understanding of the mechanisms underlying Parkinson’s disease that we will be able to provide early detection, disease halting therapies, and cell replacement options. A better conception of the disease process would open doors in all of the other areas of research.

Given the slow pace of progress thus far, you will understand that this area of research is not easy. And it is made difficult by many issues. For example, it may be that we are blindly dealing with multiple diseases that have different causes and underlying mechanisms, but display the same kinds of symptoms (rigidity, slowness of movement and a resting tremor). Multiple diseases collectively called ‘Parkinson’s’. By not being able to differentiate between the different diseases, we have enormous confounding variables to deal with in the interpretation of any research results. And this idea is not as far fetched as it may sound. One of the most common observations within a group of people with Parkinson’s disease is the variety of disease features the group presents. Some people are more tremor dominate, while others have severe rigidity. Who is to say that these are not manifestations of different diseases that share a common title (if only for ease of management).

This complication raises the possibility that rather than being a disease, ‘Parkinson’s’ may actually be a syndrome (or a group of symptoms which consistently occur together).

Recently there have been efforts to deal with this issue within the Parkinson’s research community. We have previously written about the improved diagnostic criteria for Parkinson’s disease (click here to read that post). In addition, as we mentioned above, some new clinical trials are focusing on people with very specific types of Parkinson’s disease in which the subjects have a particular genetic mutation (Click here to read more about this). Better stratification of the disease/s will help us to better understand it. And with the signing into law of the 21 century Cures Act by President Obama, the Parkinson’s research community will have powerful new data collection tools to use for this purpose – in addition to more funding for research at the National Institute of Health (Click here to red more on this).

More knowledge of the basic biology of Parkinson’s disease is critical to the road forward. Whether the Parkinson’s disease-associated proteins, like alpha synuclein, are actually involved with the cell death associated with the condition is a question that needs to be resolved. If they are simply the bio-product of an alternative (unseen) disease process is important to know.

It is impossible to know what the new year will bring for new discoveries in the basic biology of Parkinson’s disease. Compared to 20 years ago, however, when the new discoveries were few and far between, 2017 will bring with it major new discoveries every month and we’ll do our best to report them here.

Early detection for Parkinson’s disease

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Consider the impact of a pregnancy test on a person’s life. Source: Wikipedia

Ethically, the ‘early detection’ area of research can be a bit of a mine field, and for good reasons. You see, if we suddenly had a test that could accurately determine who is going to get Parkinson’s disease, we would need to very carefully consider the consequences of using it before people rush to start using it in the clinic.

Firstly there are currently no disease halting treatments, so early knowledge of future potential events may not be useful information. Second, there is the psychological aspect – such information (in light of having no treatment) may have a dramatic impact on a person’s mental wellbeing. And thirdly, such information would have huge implications for one’s general life (for example, individuals are legally bound to tell their banks and insurance companies about such information). So you see, it is a very tricky field to tackle.

Having said all of that, there are some very positive aspects to early detection of Parkinson’s disease. Early indicators (or biomarkers) may tell us something new about the disease, opening novel avenues for research and therapeutic treatments. In addition, early detection would allow for better tracking of the disease course, which would enhance our ideas about how the condition starts and changes over  time.

There are numerous tests being developed – from blood tests (click here and here for posts we wrote about this topic) to saliva tests (again, click here for our post on this topic). There are even a simple urine test (click here for our post on this) and breath analysis test (click here for more on this) being developed. And there are ever increasing brain imaging procedures which may result in early detection methods (Click here for more on this).

How does the Parkinson’s research community study early detection of Parkinson’s disease though? Well, we already know that people with rapid eye movement (REM) sleep disorder problems are more likely to develop Parkinson’s disease. Up to 45 percent of people suffering REM sleep behaviour disorders will go on to develop Parkinson’s disease. So an easy starting point for early detection research is to follow these people over time. In addition, there are genetic mutations which can pre-dispose individuals to early onset Parkinson’s disease, and again these individuals can be followed to determine common ‘biomarkers’ (aspects of life that are shared between affected individuals).  Epidemiological studies (like the Honolulu Heart study – click here for more on this) have opened our eyes to keep features and aspects of Parkinson’s disease that could help with early detection as well.

Slowing/halting Parkinson’s disease

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Source: MyThaiLanguage

One of the most significant findings in Parkinson’s disease research over the last few years has been the discovery that transplanted dopamine cells can develop Lewy bodies over time. It is very important for everyone to understand this concept: healthy embryonic cells were placed into the Parkinsonian brain and over the space of one or two decades some of those cells began to display the key pathological feature of Parkinson’s disease: dense, circular clusters of protein called Lewy bodies.

The implications of this finding are profound: Healthy cells (from another organism) developed the features of Parkinson’s disease. And this is (presumably) regardless of the genetic mutations of the host. It suggests that the disease spreads by being passed from cell to cell. There is a very good open-access article about this in the journal Nature (click here to read that article).

Slowing down the progression of Parkinson’s disease is where most of the new clinical trials are focused. There are numerous trials are focused on removing free-floating alpha synuclein (the main protein associated with Parkinson’s disease). This is being done with both vaccines and small molecules (such as antibodies). Beyond possibly slowing the disease, whether these clinical trials are successful or not, they will most definitely provide an important piece of the puzzle that is missing: is alpha synuclein involved with the spread of the disease? If the trials are successful, this would indicate ‘Yes’ and by blocking alpha synuclein we can slow/halt the spread of the disease. If the trials fail, this would suggest that alpha synuclein is not responsible, and indicate that we need to focus our research attention elsewhere.

2017 will be very big year for Parkinson’s disease as some of these clinical trials will be providing our first glimpse at resolving this major question.

Replacing what is lost

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Cell transplantation for Parkinson’s disease. Source: AtlasofScience

So if we discover a means of stopping the disease with a vaccine or a drug, this will be fantastic for people who would be destined to develop the condition… but what about those still living with the disease. Halting the condition will simply leave them where ever they are on the course of the disease – a rather unappealing situation if one is in the latter stages of the condition.

Cell transplantation is one means of replacing some of the cells that have been lost in this disease. Most of the research is focused on the dopamine neurons whose loss is associated with the appearance of the movement features of Parkinson’s disease.

Unfortunately, this area of research is more ‘blue sky’ in terms of its clinical application. It will be some time before cell transplantation has a major impact on Parkinson’s disease. And while many research groups have plans to take this approach to the clinic, there are currently just two ongoing clinical trials for cell transplantation in Parkinson’s disease:

The former is behind schedule due to the technical matters (primarily the source of the tissue being transplanted) and the latter is controversial to say the least (click here and here to read more). In the new year we will be watching to see what happens with a major research consortium called G-Force (strange name we agree). They are planning to take dopamine neurons derived from embryonic stem cells to clinical trials in 2018. Embryonic stem cells represents a major source of cells for transplantation as they can be expanded in a petri dish (millions of cells from just one cell). If they can be pushed in the right direction and they develop into dopamine neurons, they would allow people to start having some of the cells that they have lost to Parkinson’s disease to be replaced.

Above we have discussed the key areas of Parkinson’s disease (dealing with ‘finding a cure’) for 2017. We would love to hear your thoughts on them. If not, here on the SoPD, then somewhere else. Please get involved with the discussion in which ever forum you choose. Speak up and add your personal account of things to the discussion.

It is only through the sharing of ideas, information, and experiences that we are going to figure out this debilitating condition.

And now we are going to change focus and discuss what we are expecting/hoping for in the new year (particularly from the clinical side of things):

Bright future ahead

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Looking ahead to better times. Source: Journey with Parkinson’s (Great blog!)

So looking ahead, what is happening:

Recently some major players have come together to focus on Parkinson’s disease:

  1. Bayer and healthcare investment firm Versant Ventures joined forces to invest $225 million in stem-cell therapy company BlueRock Therapeutics. This venture will be focused on induced pluripotent stem cell (iPSC)-derived therapeutics for cardiovascular disease and neurodegenerative disorders, particularly Parkinson’s disease (co-founders Lorenz Studer and Viviane Tabar are world renowned experts in the field of cell transplantation for Parkinson’s disease). Importantly, BlueRock has acquired rights to a key iPSC intellectual property from iPS Academia Japan, and with 4 years of funding they will be looking to make things happen (Click here to read more on this).
  2. Evotec and Celgene are also jumping into the IPS cell field, but they are collaborating to screen for novel drug targets. (Click here to read more on this).
  3. For a long time we have been hearing that the major tech company Apple is working on software and devices for Parkinson’s disease. They already provide ResearchKit and CareKit software/apps. Hopefully in the new year we will hear something about their current projects under development (Click here to read more on this).
  4. In February of 2016, seven of the world’s largest pharmaceutical companies signed up to Critical Path for Parkinson’s set up by Parkinson’s UK. It will be interesting in the new year to see what begins to develop from this initiative.
  5. Parkinson’s UK has also set up the Virtual Biotech, which is looking at providing faster means for new drugs to be brought to market. Hopefully this will take off in 2017.

In addition, there are many clinical trials starting and also announcing results. Here are the top 20 that we are keeping an eye on:

  1. Herantis Pharma, a Finnish pharmaceutical company, will begin recruiting 18 people with Parkinson’s disease for their Conserved Dopamine Neurotrophic Factor (or CDNF) clinical trial. CDNF is very similar to GDNF which we have previously discussed on this site (Click here for that post). Herantis will be collaborating with another company, Renishaw, to deliver the CDNF into the brain (Click here to read more on this trial).
  2. The results of the double-blind, placebo controlled clinical study of the diabetes drug Exenatide will be announced in 2017. We have previously discussed this therapy (click here and here for more on this), and we eagerly await the results of this study.
  3. AAV2-hAADC, which is a gene therapy treatment – a virus that works by allowing cells in the body other than neurons to process levodopa. The results of the phase one trial were successful (click here to read about those results) and the company (Voyager Therapeutics) behind the product are now preparing for phase 2 trials (Click here for more on this).
  4. Donepezil (Aricept®) is an Alzheimer’s therapy that is being tested on dementia and mild cognitive impairment in Parkinson’s disease (Click here for more on this trial).
  5. Oxford Biomedica is attempting to proceed with their product, OXB-102, which is a gene therapy treatment – a virus that modifies neurons so that they produce dopamine. Phase 1 successful, but did not show great efficacy. Phase 2 is underway but not recruiting (click here for more on this trial).
  6. Biotie is proceeding with their product, SYN120, which is new class of combination drug (dual antagonist of the serotonergic 5-HT6 and 5-HT2A receptors) which is being tested as a treatment of cognition and psychosis in Parkinson’s disease (Click here for more on this).
  7. Acorda Therapeutics is continuing to take the new inhalable form of L-dopa, called CVT-301 to the clinic. Phase 1 trials were successful (Click here and here to read more) and phase 2 trials are being planned.
  8. Related to caffeine, Istradefylline, is an A2A receptor antagonist, already approved in Japan, that is designed to reduce “off” time and suppress dyskinesias. Phase 1 testing was successful (Click here for more on this) and phase 2 trials are being planned.
  9. Another product from Biotie, Tozadenant, is an A2A receptor antagonist designed to reduce “off” time and suppress dyskinesias.
  10. UniQure was developing AAV2-GDNF – A gene therapy treatment – a virus designed to deliver GDNF (a naturally occurring protein that may protect dopamine neurons) in the brain (Click here for more on this trial). The company has recently announced cost cutting, however, and removed AAV2-GDNF from it’s list of products under development, so we are unsure about the status of this product.
  11. AstraZeneca are taking their myeloperoxidase (MPO) inhibitor, AZD3241, through phase 2 trials at the moment (Click here for more on this trial). Oxidative stress/damage and the formation of excessive levels of reactive oxygen species plays a key role in the neurodegeneration associated with Parkinson’s disease. MPO is a key enzyme involved in the production of reactive oxygen species. By blocking it, AstraZeneca hopes to slow/halt the progression of Parkinson’s disease.
  12. Genervon Biopharmaceuticals will be hopefully be announcing more results from their phase 2 clinical trial of GM 608 (Click here for more on the trial). GM 608 has been shown to protect neurons against inflammatory factors floating around in the brain. Initial results looked very interesting, though the study was very small (Click here for more on those results).
  13. Neurimmune (in partnership with Biogen) is proceeding with their product, BIIB054, which is an immunotherapy – an antibody that clears free floating alpha-synuclein in an attempt to halt the spread of the disease (Click here for more on this trial).
  14. Neuropore is continuing to move forward with their product, NPT200-11, which is a drug designed to stabilize alpha-synuclein, preventing it from misfolding and aggregating. Phase 1 trial was successful (Click here and here to read more on this). Phase 2 trials are being planned.
  15. Prothena are very pleased with their product, PRX002 (an immunotherapy – an antibody that clears free floating alpha-synuclein in an attempt to halt the spread of the disease (similar to BIIB054 described above)). Phase 1 trials were successful (Click here for more on this).
  16. Edison Pharma is currently conducting a phase  2 trial of Vatiquinone on Visual and Neurological Function in Patients with Parkinson’s Disease (Click here for more on this trial). Vatiquinone modulates oxidative stress by acting on the mitochondria on cells.
  17. Isradipine (Prescal®) – a calcium channel blocker that is approved for treatment of high blood pressure – is being tested in Parkinson’s disease by the Michael J Fox Foundation (Click here for more on this).
  18. Inosine – which is a nutritional supplement that converts to urate, a natural antioxidant found in the body – is going to be tested in a phase 3 clinical trial (Click here for more on that trial).
  19. In 2015, Vernalis has licensed its adenosine receptor antagonist programme (including lead compound V81444) to an unnamed biotech company. We are hoping to see the results of the phase 1 trial that was conducted on V81444 for Parkinson’s disease sometime in the new year (Click here to read more about that trial).
  20. And finally, we are hoping to see progress with Nilotinib (Tasigna®) – A cancer drug that has demonstrated great success in a small phase 1 trial of Parkinson’s disease. Unfortunately there have been delays to the phase 2 trial due to disagreements as to how it should be run (Click here to read more). We have been following this story (Click here and here and here to read more), and are very disappointed with the slow progress of what could potentially be a ‘game-changer’ for the Parkinson’s community. Hopefully the new year will bring some progress.

Please note that this is not an exhaustive list – we have missed many other compounds being tested for Parkinson’s disease. For example there are always alternative versions of products currently on the market being tested in the clinic (eg. new L-dopa products). We have simply listed some of the novel approaches here that we are particularly interested in.

See the Michael J Fox Foundation Pipeline page for more information regarding clinical trials for Parkinson’s disease.

EDITORIAL NOTE HERE: All of the team at the SoPD wants to wish everyone a very enjoyable festive season where ever you are. And all the very best for the new year!

Happy New Year everyone,

The team at SoPD

The banner for today’s post was sourced from Weknowyourdreams

Mmmm, Chocolate…

~ Simon ~ 5 Comments

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INTERESTING RESEARCH FINDING 1: People with Parkinson’s disease eat more chocolate than people without Parkinson’s.

INTERESTING RESEARCH FINDING 2: This difference is specific to chocolate. There is no difference in the consumption of other forms of sugary treats between the two populations.

Today’s post deals with a topic very dear to me and it’s relationship with Parkinson’s disease.

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Mmmm, chocolate. Source: Saucefinefoods

Everyone likes chocolate, especially at this time of the year. Curious thing is though, people with Parkinson’s seem to like chocolate even more than non-Parkinsonian people.

Why is that? We’re not sure. But some interesting research has been conducted on chocolate and Parkinson’s disease, which we shall review in this post.

But first:

What is chocolate?

Silly question. Fascinating answer.

The word “chocolate” comes from the word xocolātl. This word is from the Aztec language (Nahuatl), and is a combination of the words xococ (meaning ‘sour or bitter’), and ātl (‘water or drink’). This is because for the vast majority of it’s existence, chocolate has been consumed as a drink.

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“Don’t touch my jar of xocolātl!” Source: Ancient-origins

Fermented beverages made from chocolate date back to 1900 BC in Mesoamerica. The Aztecs believed that cacao seeds were a divine gift from the god of wisdom, ‘Quetzalcoatl’. In fact, the seeds were so precious to the Aztecs that they once had so much value that they were used as a form of currency.

Chocolate was introduced to Europe in the 16th century by the Spanish who added sugar or honey to counteract the natural bitterness. Since then, it has had a rather successful rise in popularity.

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Chocolate: it’s popular stuff. Source: WallPapersCraft

How is chocolate actually made?

Chocolate comes from the beans of the Theobroma cacao tree – an evergreen native to the tropical regions of Central and South America. The beans are produced in pods, like these:

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Pods of the of Theobroma cacao tree. Source: Wikipedia

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Seeds inside the pod. Source: Wikipedia

Cacao beans are harvested from the pods, and then allowed to ferment over a period two weeks. Two things happen during this process: 1. outside of the pod, the beans are exposed to the warm heat which kills the germinating seed, and 2. natural yeasts – which like the heat – grow and help to develop complex flavours.

After this fermentation period, the beans are then sun-dried, which helps to preserve them for shipping. Next, the beans are roasted, which helps to further develop complex flavours and to remove unpleasant acidic compounds developed in the fermentation process. This is followed by mechanically separating the valuable nibs (interior of the bean) from the useless shells.

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Cacao nibs. Source: HuffingtonPost

The nibs must then be refined, which involves extensive grinding. The raw cocoa liquor is then “conched“. This is the stage where the general characteristic tastes, smells and textures of chocolate are developed. Conching is a lengthy process which drives off the rest of the acidic flavoring compounds. The process also helps coat the ground up cocoa particles with fat to reduce the viscosity of the molten chocolate.

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Conching. Source: Instructables

Finally, the conched product is tempered which gives chocolate it’s gloss and affects how it melts in your hands/mouth. Tempering is necessary because cocoa butter can crystallise into at least six different forms (form V being the most desired). Each of these forms have different stability and properties. Form V has the most popular texture and ‘feeling in the mouth’, in addition it does not melt too quickly in the hand.

Why is chocolate soooo good?

No one is entirely sure. Chocolate contains many different chemicals which help in making chocolate tasty and (dare we say it) addictive. Among the most important ingredients are stimulants like phenylethylamine and caffeine (all in very small quantities), which can give you a positive boost.

Importantly, chocolate also contains a feel-good chemical called anandamine, which functions in the brain by binding to cannabinoid receptors (these are the same receptors that chemicals in marijuana bind to). Its name actually comes from ananda, the Sanskrit word for “bliss”. Normally anandamide is broken down quite quickly after it is produced, but some researchers believe that the anandamide in chocolate makes the natural anandamide in our brain persist for longer, giving us a longer-lasting “chocolate high”.

And what is the difference between dark and white chocolate?

Ok, now don’t be upset, but technically speaking white chocolate is not really a chocolate.

It is made without any cocoa powder or solids, containing just cocoa butter mixed with milk and sugar. Without the cocoa powder, chocolate has no colour thus it’s white. In addition, white chocolate doesn’t have many of the ‘happy’ ingredients likes caffeine.

Not actually being a chocolate makes white chocolate very useful, however, in research (as you shall see below). Given that it is missing many of the key components of normal chocolate (eg. cocoa, caffeine, etc), white chocolate can be used as a control substance in studies looking at the effect of chocolate on various conditions.

Are there health benefits of eating chocolate?

Mum always told me that chocolate was bad for me, but recent scientific research has altered this perception. Studies of the Kuna Indians of the San Blas islands of Panama, who consume large amounts of a natural cocoa beverage, have found lower blood pressures, better renal function and decreased cardiovascular mortality relative to mainland Panamanian control populations (Click here to read more on this).

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Kuna indians. Source: Superfoodsrx

The prevalence of hypertension in Kuna indians who have migrated to urban areas on mainland Panama is significantly higher (10.7% of the population compared with just 2.2% of those still on the islands). This is believed to be partly due to the reduction in cacao intake – Kuna indians on the islands eat 10 times more than their mainland equivalents.

Interesting. But what does all of this have to do with Parkinson’s disease?

Right. Down to business. In 2009, this research report was published:

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Title:  Chocolate consumption is increased in Parkinson’s disease. Results from a self-questionnaire study.
Authors: Wolz M, Kaminsky A, Löhle M, Koch R, Storch A, Reichmann H.
Journal: J Neurol. 2009 Mar;256(3):488-92. doi: 10.1007/s00415-009-0118-9.
PMID: 19277767

These researchers conducted a survey of 274 people with Parkinson’s disease and 234 age-matched controls. They found that people with Parkinson’s disease ate approx. 100g of chocolate per week (on average) compared to just 57.3g for the control subjects.

Using measures of mood (such as the Beck’s Depression Inventory survey), the researchers found that this increased consumption of chocolate was independent of feelings of depression. This interesting observations lead the researchers to conduct this clinical study:

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Title:  Comparison of chocolate to cacao-free white chocolate in Parkinson’s disease: a single-dose, investigator-blinded, placebo-controlled, crossover trial.
Authors: Wolz M, Schleiffer C, Klingelhöfer L, Schneider C, Proft F, Schwanebeck U, Reichmann H, Riederer P, Storch A.
Journal: J Neurol. 2012 Nov;259(11):2447-51. doi: 10.1007/s00415-012-6527-1.
PMID: 22584952

The researchers in this study (the same people who published the survey study above) tested the effects of 200g of (80% cacao) chocolate on Parkinsonian motor scores (as measured by UPDRS). They assessed 26 people with moderate non-fluctuating Parkinson’s disease at both 1 and 3 hours after eating the chocolate. The researchers used white chocolate as the control treatment in the study, and they (the assessors) were blind to which treatment each subject received.

At 1 hour after consumption, the researchers noted a mild decrease in both treatment groups (most statistically in the dark chocolate group) when compared to the measures taken at baseline (that is before the actual study started). Similar results were observed in the measures taken at 3 hours post consumption. The researchers also took blood samples and found no differences in β-phenylethylamine blood levels (we’ll come back to this shortly).

Altogether, while there was an improvement in motor performance after eating chocolate, the results indicated no difference between dark chocolate and white cacao-free chocolate on Parkinson’s motor function.

What is β-phenylethylamine?

β-phenylethylamine is a naturally occurring chemical in the body, which is produced in chocolate during the thermal processing of cocoa (click here for more on this). Functionally, β-phenethylamine is similar to amphetamine in its action, as it leads to the release of dopamine. Interestingly, people with Parkinson’s disease have almost 50% less β-phenethylamine in the fluid surrounding their brains (Click here to read more on this). Thus, in addition to any stimulant effect of caffeine, increasing β-phenethylamine levels by eating chocolate may be causing an increase in dopamine levels in the brains of people with Parkinson’s disease – resulting in better motor scores.

But the researchers in the clinical study of chocolate reviewed above did not register any change in blood levels of β-phenethylamine. Again, perhaps longer term usage is required in order to detect a significant rise.

What does it all mean?

Here at the SoPD, we feel that the effect of chocolate on Parkinson’s disease have not been fully explored. More research is required. And we are not just saying this because everyone likes chocolate.

Firstly, it would be interesting to replicate what has already been done, particularly the survey of chocolate consumption to determine if people with Parkinson’s disease really do eat more chocolate! This is the most interesting observation reported thus far and needs to be replicated. It would be interesting to determine if the difference pre-dates diagnosis – that is to say, do people who develop Parkinson’s disease eat more chocolate when they are younger (before they are diagnosed)? Could chocolate be actually having a negative effect on the development of the disease?

Second, if a longer term analysis of chocolate and Parkinson’s disease indicates an effect, it would be interesting to further investigate individual ingredients. If we are investigating the ingredients of coffee to assess beneficial components for Parkinson’s disease (click here for more on this), the same analysis of chocolate should be conducted.

I’m going to go off now and contemplate some of this with a piece of dark chocolate…

The banner for today’s post was sourced from pngimg.

Blood transfusions and Parkinson’s disease

~ Simon ~ Leave a comment

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Donating blood helps to save lives. And an awful lot of blood is needed on a daily basis: In the England alone, over 6,000 blood donations are required every day to treat patients.

There has been concerns over the years about what can be transmitted via blood donation (from donor to recipient). The good news is that we now know that Parkinson’s disease is not.

Today’s post looks at recent research investigating this issue and discusses the implications of the findings.

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Blood transfusions save lifes. Source: New York Times

The average adult human carries approx. 10 pints (about 6 litres) of blood in his body. So much blood, that we actually have an excess – we can survive with a little less. And this allows us to donate blood to blood banks on a regular basis (approx. every 8 weeks). Roughly 1 pint can be given during each blood donation and our bodies will have no trouble replacing it all.

These donations can be used in blood transfusions, replacing blood that has been lost via accident or during surgical procedures. It may surprise you that blood transfusion (from human to human) has been practised for some time. The very first blood transfusion was performed by an obstetrician named Dr. James Blundell in the late 1820’s.

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Dr. James Blundell. Source: Wikpedia

The exact date of that first procedure is the subject of debate, but Blundell wrote up his experience in the journal Lancet in 1829:

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Blundell’s article in the journal Lancet. Source: Wikipedia

Since that time, blood transfusions have gradually become an everyday occurrence at hospitals all over the world. And as we suggested above a lot of blood is used on a daily basis, keeping people alive. Determining whether each donation of blood is safe to use is obviously a critical step in this process, and all donated blood is tested for HIV, hepatitis B and C, syphilis and other infectious diseases before it is released to hospitals. But for a long time there has been a lingering concern that not everything is being detected and filtered out.

In fact there has been a serious concern that some neurodegenerative conditions like Alzheimer’s and Parkinson’s disease may be transmissible. If these diseases are being caused by ‘prion-like behaviour’ from the particular proteins involved with these conditions (eg. beta amyloid and alpha synuclein, respectively), then there is a very real possibility that such rogue proteins could be transferred via blood transfusions.

This was a concern (note the past tense) until July of this year when this research report was published (with a rather mis-leading title):

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Title: Transmission of neurodegenerative disorders through blood transfusion. A cohort study
Authors: Edgren G, Hjalgrim H, Rostgaard K, Lambert P, Wikman A, Norda R, Titlestad KE, Erikstrup C, Ullum H, Melbye M, Busch MP, Nyrén O.
Journal: Ann Intern Med. 2016 Sep 6;165(5):316-24.
PMID: 27368068

The researchers in this study took all of the data from the enormous nationwide registers of blood transfusions in Sweden and Denmark – collectively almost 1.5 million people have received transfusions in these two countries between 1968 and 2012 – and compared the medical records of the recipients to those of the donors (you have to love the Scandinavians for the medical databases!). Approximately 3% of the recipients received a blood transfusion from a donor who was diagnosed with one of the neurodegenerative diseases included in this study (Alzheimer’s, Parkinson’s and Motor neurone disease (or Amyotrophic lateral sclerosis – ALS). There was absolutely no evidence of transmission of any of these diseases.

For the statistic lovers amongst you, the hazard ratio for dementia in recipients of blood from donors with dementia versus recipients of blood from healthy donors was 1.04 (95% CI, 0.99 to 1.09). Estimates for individual diseases, Alzheimer disease and Parkinson disease were 0.99 (CI, 0.85 to 1.15) and 0.94 (CI, 0.78 to 1.14), respectively.

These statistics mean that if Parkinson’s disease is being transmitted via a blood transfusion, it is an extremely rare event.

So what does this mean for our understanding of Parkinson’s disease?

Well, we already know that you can’t catch Parkinson’s disease from your spouse (Click here to read more on this) and there is a lot of other evidence to suggest that Parkinson’s disease is not contagious (Click here to read more on this). So this is one less thing for carers, family members and friends to worry about.

But if Parkinson’s disease is not caused by some contagious agent, this knowledge has major implications for our understanding of the disease. Previous lab-based research has pointed toward a ‘Prion’-like nature to alpha synuclein (the protein most associated with Parkinson’s disease. Prions being small infectious agents made up entirely of protein material, that can lead to disease that is similar to viral infection. And researchers actually found that if you inject specific types of alpha synuclein into the muscles of mice, those animals would start to develop cell loss in the brain (Click here to read more about this).

If Parkinson’s disease is a ‘prion’ condition, then we have to ask one important question: why isn’t it being transmitted via blood transfusion? Alpha synuclein is certainly found in the blood of people with Parkinson’s disease.

It could be that an infectious agent initiated the condition many years ago and it has very slowly been developing (similar to chronic infections resulting from Hepatitis – click here to read more on this).

Research like we have reviewed today may result in a serious re-think of our theory of Parkinson’s disease.

The banner for today’s post was sourced from CampusCluj

The biology of immortality and Parkinson’s disease

~ Simon ~ 1 Comment

 

 

live-forever

A research paper was published in the prestigious journal Cell this week that has some people excitedly suggesting that we are one step closer to living longer.

Age is the no. 1 correlate with neurodegenerative conditions like Parkinson’s disease. A better understanding of the ageing process would greatly aid us in understanding these conditions.

In today’s post we will review the research paper in question and discuss what it will mean for Parkinson’s disease.

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Henrietta Lacks with her husband David. Source: HuffingtonPost

The lady in this photo is basically immortal.

Henrietta Lacks was an African American woman who died in October, 1951, but (it could be argued) lives in almost every research institute in the world. Henrietta died with cervical cancer, and during her treatment, she had a (unethical) biopsy conducted on her tumor which give rise to the first human immortalised cell line that is named after her: Hela cells (Henrietta Lacks).

And I kid you not when I say that there are samples of Hela cells in a freezer in almost every research institute in the world. Since the 1950s, scientists have grown 20 tons (and counting) of her cells (Source). And some of our greatest advances have been made with Hela cells, for example in 1954, Jonas Salk used HeLa cells in his research to develop the polio vaccine.

Unwittingly, Henrietta achieved immortality.

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Hercules fighting off death. Source: ProactionaryTranshumanist

We humans have a strange fascination with immortality. It could be argued that it underlies our religions, and also drives us to achieve great things during our live times.

During the last three decades, science has begun probing the biology of ageing with the goal of helping us to understand how and why our bodies degrade over time in the hope that it will lead to better treatments for disease that predominantly affect the elderly.

Last week research groups from Spain and the Salk institute in California published the results of a study that may be considered the first tentative steps towards actually extending life and perhaps reversing the ageing process.

This is the article:

cell-title-5

Title: In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming.
Authors: Ocampo A, Reddy P, Martinez-Redondo P, Platero-Luengo A, Hatanaka F, Hishida T, Li M, Lam D, Kurita M, Beyret E, Araoka T, Vazquez-Ferrer E, Donoso D, Roman JL, Xu J, Rodriguez Esteban C, Nuñez G, Nuñez Delicado E, Campistol JM, Guillen I, Guillen P, Izpisua Belmonte JC.
Journal: Cell. 2016 Dec 15;167(7):1719-1733.
PMID: 27984723

In their study, the researchers used something called the ‘Yamanaka factors’ to try and reverse the ageing process in mice.

What are the Yamanaka factors?

This is Prof Shinya Yamanaka:

yamanaka-s

Source: Glastone Institute

He’s a dude.

In 2012 he and Prof John Gurdon (University of Cambridge) were awarded the Nobel prize for Physiology and Medicine for the discovery that mature cells can be converted back to stem cells. Prof Gurdon achieved this feat by transplanting a young nucleus into an old cell, while Prof Yamanaka did the same thing with the ‘Yamanaka factors’.

The Yamanaka factors are a set of 4 genes (named Myc, Oct3/4, Sox2 and Klf4) that when turned on in a mature cells (like a skin cell) can force the cell to ‘de-differentiate’ back into an immature cell that is capable of becoming any kind of cell. This induced un-programmed state means that the once adult cell has changed into something similar to an embryonic stem cell.

This new cell is called an induced pluripotent stem (IPS) cell – ‘pluripotent’ meaning capable of any fate.

So what did the researchers in the Cell paper do with the Yamanaka factors?

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A lab mouse. Source: USNews

They genetically engineered mice that produced the Yamanaka factors in every cell in the body. They could turn on the Yamanaka factors by adding a special chemical to the drinking water of the mice for 2 out of every 7 days.

By turning on the 4 genes in this manner, the researchers found that they could extend the life span of the mice by 30%. In human terms, this would increase the average age of death from the current 80 years to 105 years!

Not only did they not the increase in the life span of the mice, but the researchers also found that the reprogramming of cells improved the regenerative ability of the cells in the aged mice. They even demonstrated this in human cells carrying the Yamanaka factors.

The study is very artificial – the mice and the human cell lines were engineered to produce the Yamanaka factors, which does not happen in normal nature – and we won’t be seeing any clinical trial for this kind of approach anytime soon. But the results will have big implications for the field of neurodegeneration.

Ok, but what has all this got to do with Parkinson’s disease?

Remember that the no. 1 correlate (association) with Parkinson’s disease is age. That is to say, your risk of developing Parkinson’s disease increases with age.

So this begs the question: if we had a better understanding of the ageing process (or even just a concept of what ageing is), could we beat off Parkinson’s disease?

Until the research paper reviewed above was published last week, this was all just silly hypothetical stuff. Now that we can extend the lives of mice by 30%, however, do we need to start actually considering the hypothetical as possible?

Science has brought us along way and provided us with many wonderful things (I would be lost without my Apple ipod). But we are now interesting a strange new world where science is going beyond normal basic biology and this may allow us to reverse what was previously un-negotiable facts. We can argue till the cows come home over the ethics of letting people live longer, but there is tremendous potential to use this technology to deal with the neurodegenerative conditions currently affecting us.

This is all very speculative, but it will be interesting to see where this leads. Stay tuned.

The banner for today’s post was sourced from TechieKids

A brave new world: 21st Century Cures Act

~ Simon ~ 4 Comments

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In one of his last acts as President, this week Barrack Obama signed into law the 21st Century Cures Act. Enacted by the 114th United States Congress, the new law will have enormous implications for the American health system and for the Parkinson’s community.

In today’s post we’ll review the new law and what it will mean for Parkinson’s disease.

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An early version of the hypocratic oath. Source: Wikipedia

It may surprise you, but contrary to popular belief the phrase “First do no harm” (Latin: Primum non nocere) does not appear in the Hippocratic oath that medical practitioners are suppose to abide to.

Not now, nor in the original form.

The closest we get to it is (Greek) noxamvero et maleficium propulsabo (“I will utterly reject harm and mischief”). Despite this, the basic idea of ‘not doing harm’ has been part of the foundation of medical practise since the oath was first written around the 3rd century BCE.

The idea of ‘doing no harm’, however, presents a double-edge sword for practitioners when they are faced with patients prepared to try anything to cure themselves of a crippling condition. Does the practitioner knowingly consent to allowing a subject to take a treatment that could have negative side-effects or no effect at all?

The example above is provided simply to set the stage for the discussion below. For we are about to embark on a new age when practitioners will potentially be faced with this dilemma on an ever more frequent basis.

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The United States Capitol. Source: SpotHeroBlog

The ‘Science of Parkinson’s’ is politically neutral.

We do, however, investigate proposals and new legislations that will affect the Parkinson’s community, particularly those affecting the research world.

With that said, on the 13th December 2017, President Barrack Obama signed into law one of the most sweeping efforts to provide additional support and funding for health conditions that we have seen for some time. The 21st Century Cures Act (catchy name huh?) is going to have a big impact.

What is in the new law?

The law focuses on cancer, Alzheimer’s disease, opioid addiction, medical devices, access to new drugs, and mental health.

The new law provides $4.8 billion for three of the Obama administration’s key research programs over the next 10 years: Vice President Joe Biden’s cancer moonshot, the BRAIN Initiative, and the Precision Medicine Initiative. It will also give states $1 billion to fight the opioid crisis currently affecting certain areas of the country, and deliver an additional $500 million to the Food and Drug Administration (FDA).

In addition, the ‘Cures’ law will create new databases that will access health records and allow for a greater collection of information focused on certain diseases. Of particular interest to us is the creation of the ‘National Neurological Conditions Surveillance System’ at the Centers for Disease Control and Prevention (CDC), which will collect demographic information on people living with neurological diseases, like Parkinson’s disease.

Critically, the ‘Cures’ law will speed up the regulatory process for getting new treatments and devices approved for the clinic. Currently it can take up to a decade and a billion dollars to get new drugs from the lab bench to the clinic. Patient groups have been lobbying hard for this and they will be very happy with the Act being passed into law.

Who benefits from this new law?

With every new law there are winners and losers:

Winners:

1. Pharmaceutical and Medical Device Companies. The law will give the FDA new authority to request fewer studies from those companies trying to bring new products to the clinic. In theory this should speed up the approval process. Critics worry that this will result in a lowering of standards and bring products to the clinic that haven’t been properly tested (According to disclosures, 58 pharmaceutical companies, 24 device companies and 26 “biotech products and research” companies have spent more than $192 million on lobbying for this new law).

2. Patient groups. As we mentioned above, patient advocacy groups have lobbied very hard for this new law (spending $4.6 million according to disclosures). The law also includes the allowance for more patient input in the drug development and approval process. This aspect alone will be a boost to the clout of such groups.

3.  Health information technology companies. The law urges federal agencies and health providers nationwide to use electronic health records systems and to collect data to enhance research and treatment (the only caveat here is that this section is unfunded by the new law). Computer companies were apparently very keen on this aspect of the new law, however, as they too have been lobbying hard.

We wanted to write that Medical schools and research hospitals may benefit since the law provides $4.8 billion over 10 years in additional funding to the federal government’s main biomedical research organisation, National Institutes of Health (NIH). It should be noted, however, that these funds are not guaranteed and will be subject to annual appropriations. So we’ll hold off stating that research is a winner until this is resolved.

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President Obama hard at work. Source: Fastcompany

Losers:

1.  Preventive medicine groups. $3.5 billion — about 30 percent — of the Prevention and Public Health Fund will be cut. This fund was established under ‘Obamacare’ to promote prevention of Alzheimer’s disease, hospital acquired infections, chronic illnesses and other ailments. Obviously certainly things have to be cut in order to fund other aspects of this new law, but this particular cut is going to hurt some affected groups.

2.  The FDA. While the FDA will be given an additional $500 million (through to 2026), this amount is not enough to cover the additional workload resulting from the law. In addition, the agency has been pushing hard for extra funding to deal with deteriorating facilities, but there was nothing to cover this in the new law.

In addition, the FDA has to deal with the renewal of a controversial voucher system which rewards companies that receive approval for new treatments dealing with ‘rare pediatric diseases‘. Upon approval the company will receive a voucher that can be redeemed later and allows the company to receive a priority review of a marketing application for a different product.

3.  Randomised clinical trials. The gold standard for testing the safety and efficacy of new drugs and devices is the randomised clinical trial. The new law, however, directs the FDA to evaluate the use of “real world evidence” for approval of new indications for FDA-approved drugs. This may result in randomised clinical trials will become less important for drug and device approval.

Currently getting a drug or a medical device approved by the FDA and into the clinic, companies have to go through a rigorous screening process, included randomized double-blind clinical trials. With the 21st Century Cures Act, that process will be sped up by allowing the use of anecdotal evidence and observational data to clear a drug for approval. That is to say, patient feedback might be used to help get drugs into the clinic more quickly.

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Source: DunnHumby

Getting treatments to the clinic sooner is a good though, right?

Critics of the new law, such as Public Citizen’s Health Research Group, are worried that the new law is relaxing the standards too much. For example they believe the designation of  “breakthrough” devices is too broad, and could lead to clearance of devices that aren’t ready for the market.

Neutral as we are here at the SoPD, we have to agree that there is the potential for real problems here. While we are as desperate as everyone else in the Parkinson’s community for new treatment, we have to be sure that those novel therapies are safe. Any lowering of standards will increase the likelihood of ineffective treatments coming to market.

What does it all mean for Parkinson’s disease?

There are a lot of positives for the Parkinson’s community resulting from this new law:

1.  The development of infrastructure to collect data on neurological diseases to better understand Parkinson’s is a good thing.

As the Micheal J Fox Foundation (MJFF) points out, we currently do not have really accurate information about how many people are living with Parkinson’s disease, let alone where they are located or who they are based on gender, ethnicity, etc. Critical pieces of information might be missing from our understanding of the disease based on the absence of such information.

2.  Extra funding for the Obama administration research initiatives to further our knowledge of the brain and developing individualized treatments is a good thing.

The ‘Cures law’ has allocated $1.5 billion over the next ten years to the NIH for the BRAIN Initiative. This will have benefits for Parkinson’s research. In addition, $30 million has been allocated for clinical research to further the field of regenerative medicine using stem cells.

3.  Speeding up the regulatory process and accounting for ‘real world observations’

The new law will make it easier for companies to bring new treatments to the clinic. Reducing the number of tests, and thus reducing the regulatory cost, may result in pharmaceutical companies being prepared to take more treatments to the FDA for approval.

In addition, the FDA will now be required to take patient perspectives into account in the drug approval process and the new law tasks the agency with creating a framework for collecting patient experience data.

This data will be collected from various sources (patients, family members and caregivers, patient advocacy organizations, disease research foundations, researchers and drug manufacturers), and it will detail a patient’s experience with a disease or therapy, taking into account the impact it has on their lives.

By involving patients/carers/families in this manner, it is hoped that government regulators will be more in touch with the community’s experiences and priorities as new drugs and devices enter late-stage clinical testing and move toward FDA approval.

What does it all mean?

It will be interesting to see how this new law impacts medical regulators globally. The US FDA is already considered to be a ‘fast mover’ when compared with other regulatory bodies. Whether these international counterpart will follow suit will be interesting to watch.

Bring treatments to market quicker, having more information regarding disease, and having a more patient-centric approach are all good aspects to this new law. As we have suggested above, however, there will be new potential for the system to be abused. Profit motivated companies will naturally look to game this new law to get their products to market.

And this may well result in medical practitioners being confronted by that double-edged sword dilemma we discussed at the start of this post. For now, all we can really so is sit back and see what happens.

If we thought 2016 was full of surprises, we can only imagine what 2017 will bring!

The banner for today’s post was sourced from Fanshare

Get more EGCG. Drink green tea.

~ Simon ~ 12 Comments

green-tea-leaves

We have previously written about the benefits of drinking coffee in reducing one’s chances of developing Parkinson’s disease (Click here for that post). Today, however, we shift our attention to another popular beverage: Tea.

Green tea in particular. Why? Because of a secret ingredient called  Epigallocatechin Gallate (or EGCG).

Today’s post will discuss why EGCG may be of great importance to Parkinson’s disease.

cup and teapot of linden tea and flowers isolated on white

Anyone fancy a cuppa? Source: Expertrain

INTERESTING FACT: after water, tea is the most widely consumed drink in the world.

In the United Kingdom only, over 165 million cups of tea were drunk per day in 2014 – that’s a staggering 62 billion cups per year. Globally 70 per cent of the world’s population (over the age of 10) drank a cup of tea yesterday.

Tea is derived from cured leaves of the Camellia sinensis, an evergreen shrub native to Asia.

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The leaves of  Camellia sinensis. Source: Wikipedia

There are two major varieties of Camellia sinensis: sinensis (which is used for Chinese teas) and assamica (used in Indian Assam teas). All versions of tea (White tea, yellow tea, green tea, etc) can be made from either variety, the difference is in the processing of the leaves.

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The processing of different teas. Source: Wikipedia

There are at least six different types of tea based on the way the leaves are processed:

  • White: wilted and unoxidized;
  • Yellow: unwilted and unoxidized but allowed to yellow;
  • Green: unwilted and unoxidized;
  • Oolong: wilted, bruised, and partially oxidized;
  • Black: wilted, sometimes crushed, and fully oxidized; (called “red tea” in Chinese culture);
  • Post-fermented: green tea that has been allowed to ferment/compost (“black tea” in Chinese culture).

(Source: Wikipedia)

More than 75% of all tea produced in this world is considered black tea, 20% is green tea, and the rest is made up of white, Oolong and yellow tea.

What is the difference between Green tea and Black tea?

Green tea is made from Camellia sinensis leaves that are largely unwilted and heated through steaming (Japanese style) or pan-firing (Chinese style), which halts oxidation so the leaves retain their color and fresh flavor. Black tea leaves, on the other hand, are harvested, wilted and allowed to oxidize before being dried. The oxidation process causes the leaves to turn progressively darker.

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

In 2006,this research paper was published:

egcg-1-title

Title: Small molecule inhibitors of alpha-synuclein filament assembly
Authors: Masuda M, Suzuki N, Taniguchi S, Oikawa T, Nonaka T, Iwatsubo T, Hisanaga S, Goedert M, Hasegawa M.
Journal: Biochemistry. 2006 May 16;45(19):6085-94.
PMID:16681381

In this study, the researchers tested 79 different chemical compounds for their ability to inhibit the assembly of alpha-synuclein into fibrils. They found several compounds of interest, but one of them in particular stood out: Epigallocatechin Gallate or EGCG

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The chemical structure of EGCG. Source: GooglePatents

Now, before we delve into what exactly EGCG is, let’s take a step back and look at what is meant by the “assembly of alpha-synuclein into fibrils” (???).

Alpha Synuclein

We have previously written a lot about alpha synuclein (click here for our primer page). It is a protein that has been closely associated with Parkinson’s disease for some time now. People with mutations in the alpha synuclein gene are more vulnerable to developing Parkinson’s disease, and the alpha synuclein protein is found in the dense circular clumps called Lewy bodies that are found in the brains of people with Parkinson’s disease.

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

What role alpha synuclein plays in Parkinson’s disease and how it ends up in Lewy bodies is the subject of much research and debate. Many researchers, however, believe that it all depends on how alpha synuclein ‘folds’.

The misfolding of alpha synuclein

When a protein is produced (by stringing together amino acids in a specific order set out by RNA), it will then be folded into a functional shape that do a particular job.

Alpha synuclein is slightly different in this respect. It is normally referred as a ‘natively unfolded protein’, in that is does not have a defined structure. Alone, it will look like this:

PBB_Protein_SNCA_image

Alpha synuclein. Source: Wikipedia

By itself, alpha synuclein is considered a monomer, or a single molecule that will bind to other molecules to form an oligomer (a collection of a certain number of monomers in a specific structure). In Parkinson’s disease, alpha-synuclein also aggregates to form what are called ‘fibrils’.

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Microscopic images of Monomers, oligomers and fibrils. Source: Brain

Oligomer versions of alpha-synuclein are emerging as having a key role in Parkinson’s disease. They lead to the generation of fibrils and may cause damage by themselves.

oligomers

Source: Nature

It is believed that the oligomer versions of alpha-synuclein is being passed between cells – and this is how the disease may be progressing – and forming Lewy bodies in each cells as the condition spreads.

For this reason, researchers have been looking for agents that can block the production of alpha synuclein fibrils and stabilize monomers of alpha synuclein.

And now we can return to EGCG.

What is EGCG?

Epigallocatechin Gallate is a powerful antioxidant. It has been associated with positive effects in the treatment of cancers (Click here for more on that).

And as the study mentioned near the top of this blog suggested, EGCG is also remarkably good at blocking the production of alpha synuclein fibrils and stabilizing monomers of alpha synuclein. If the alpha synuclein theory of Parkinson’s disease is correct, then EGCG could be the perfect treatment.

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EGCG blocks the formation of oligomers. Source: Essays in Biochemistry

And there have been many studies replicating this effect:

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Title: EGCG remodels mature alpha-synuclein and amyloid-beta fibrils and reduces cellular toxicity
Authors: Bieschke J, Russ J, Friedrich RP, Ehrnhoefer DE, Wobst H, Neugebauer K, Wanker EE.
Journal: Proc Natl Acad Sci U S A. 2010 Apr 27;107(17):7710-5. doi: 10.1073/pnas.0910723107.
PMID: 20385841            (This article is OPEN ACCESS if you would like to read it)

In this particular study, the researchers found that EGCG has the ability to not only block the formation of of alpha synuclein fibrils and stabilize monomers of alpha synuclein, but it can also bind to alpha synuclein fibrils and restructure them into the safe form of aggregated monomers.

And again, what has Green tea got to do with Parkinson’s disease?

Green tea is FULL of EGCG.

In the production of Green tea, the picked leaves are not fermented, and as a result they do not go through the process of oxidation that black tea undergoes. This leaves green tea extremely rich in the EGCG, and black tea almost completely void of EGCG. Green tea is also superior to black tea in the quality and quantity of other antioxidants.

What clinical studies have been done on EGCG and Parkinson’s disease?

Two large studies have looked at whether tea drinking can lower the risk of Parkinson’s disease. Both studies found that black tea is associated with a reduced risk of Parkinson’s disease, but one of the studies found that drinking green tea had no effect (Click here and here for more on this). Now the positive effect of black tea is believed to be associated with the high level of caffeine, which is a confounding variable in these studies. Even Green tea has some caffeine in it – approximately half the levels of caffeine compared to black tea.

The levels of EGCG in these studies were not determined and we are yet to see a proper clinical trial of EGCG in Parkinson’s disease. EGCG has been clinically tested in humans (Click here for more on that), so it seems to be safe. And there is an uncompleted clinical trial of EGCG in Huntington’s disease (Click here for more) which we will be curious to see the results of.

So what does it all mean?

Number 1.

It means that if the alpha-synuclein theory of Parkinson’s disease is correct, then more research should be done on EGCG. Specifically a double-blind clinical trial looking at the efficacy of this antioxidant in slowing down the condition.

Number 2.

It means that I now drink a lot of green tea.

Usually mint flavoured (either Teapigs or Twinnings – please note: SoPD is not a paid sponsor of these products, though some free samples would be appreciated!).

It’s very nice. Have a try.

The banner for today’s post was sourced from WeightLossExperts

Something different – Government funding for Parkinson’s research

~ Simon ~ Leave a comment

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Here at SoPD we try to remain politically neutral.

That said, we do have a vested interest when it comes to political events and their impact on government research funding for Parkinson’s disease (or simply medical research in general).

In the wake of the recent BREXIT vote in the UK and the poll-defining victory of Mr Donald Trump in the US presidential elections, there have been many in the research community who are expressing concerns about the future of research funding.

In this post we thought it would be interesting to have a look at US and UK Government research funding and where things may be heading after the election of Mr Trump and the BREXIT vote.

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US Federal R&D spending over time. Source: Business insider

What is the current situation for federal research funding in the USA?

According to the American Association for the Advancement of Science (AAAS), the US federal government appropriates almost $140 billion per year to research and development. That is a remarkably big number (it is more than the entire GDP of Hungary!).

The grandeur of this number, however, hides a disturbing fact. That $140 billion is down from a 2010 peak of about $160 billion (in constant dollars – inflation adjusted). And this reduction in funding has had trickle down effects.

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The NIH headquarters in Maryland, USA. Source: NPR

The National Institute for Health (NIH) is one of the largest funders of medical research in the world. In 2015 it had a budget of $31,381 million. More than 83 percent of their budget goes to more than 300,000 research personnel at over 3,000 universities, medical schools, and other research institutions in the USA and around the world (Source: NIH). Few other research funding institutions wield the kind of power that the NIH has.

Again, however, the impressive numbers hides a secret.

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NIH funding from 2003 – 2015. Source: FASEB

As displayed in the graph above, from 2003 to 2015, NIH funding from the US government dropped by 22% of its capacity to fund research due to budget cuts, sequestration, and inflationary losses.

In very real terms, medical research funding from the US federal Government has been falling – and this started long before the global financial crisis.

What is the current situation for Government research funding in the UK?

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Research funding in the UK. Source: Keith’s Blog

The UK spends approximately £25bn per year on research.While not as impressive as our cousins across the pond, that number is still a large chunk of change. Approximately 1/3 (£7.98bn) comes from the UK Government. And again that sounds like a lot of money, but here is the terrible truth of the matter:

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Science research funding as a % of GDP. Source: Scienceogram

At a time where the population is ageing and requiring more assistance due to conditions like Parkinson’s disease, we are spending less (based on GDP) on research than most of our neighbours. Yes, we are still recovering for the global economic crisis (9 years and counting, dear bankers), but the trend for the UK in the graph above is of some concern. Especially when you consider that back in the 1980s the UK was spending over 2% of GDP on research:

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The difference in % of GDP spent on research between 1985 and 2007. Source: Keith’s Blog

For academic research, there are seven Research Councils that receive funding from the Government’s Science Budget. Each year, they invest around £3 billion in research, covering the full spectrum of academic disciplines. This arrangement may change shortly, with all of the seven councils coming together under one umbrella: Research UK (but that is an entirely different controversy – click here for more on this).

A total investment of £26.3 billion has been planned by the Government between 2016/17 to 2020/21 (Source: Gov.uk), but this may well change in the wake of BREXIT. All eyes in the UK are focused on the Autumn budget statement on Wednesday 23 November. This will be the first confirmation from Theresa May’s government as to their stance on research funding.

In addition to Government funding of research, the UK research community has benefitted considerably from belonging to the EU. Between 2007 to 2013, the UK contributed nearly £4.3bn towards EU research projects, BUT it received nearly £7bn back over the same period. That £2.7bn excess was equivalent to more than £400m in research funds a year. By leaving the EU, this enormous stream of funding is now in jeopardy.

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The UK is the leading country in terms of number of projects won from Horizon 2020. Source: LSE

We remain fully paid-up members of Horizon 2020, the EU’s eighth Framework Programme for funding research and innovation, and as the graph above shows we are one of the most successful countries in the EU with regards to projects being awarded funding. The Horizon 2020 scheme has a total budget of just over €70 billion for funding research until 2020. But beyond that…

Critically for researchers, the lack of clarity in the UK position with the EU leaves the potential for international collaborations up in the air.

So what is the outlook for the US?

The good news is that historically new Republicans presidents generally spend more on research than democrats:

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New president spending on research. Source: ChicagoPolicyReview

The bad news is that much of that increase is predominantly on the defence research side of things (Click here to read more on this – the original study).

Mr Trump has given little indication regarding his thoughts on research funding. And it is difficult to get any real sense of where things may be going based on the mass media news outlets, which seem to be more interested in scandal rather than in depth investigative journalism.

Mr Trump has been quoted as saying:

“Though there are increasing demands to curtail spending and to balance the federal budget, we must make the commitment to invest in science, engineering, healthcare, and other areas that will make the lives of Americans better, safer and more prosperous. We must have programs such as a viable space program and institutional research that serve as incubators to innovation and the advancement of science and engineering in a number of fields.”

Adding, however:

“In a time of limited resources, one must ensure that the nation is getting the greatest bang for the buck. We cannot simply throw money at these institutions and assume that the nation will be well served.”

Source: Science Debate

Mr Trump appears to be intent on bringing the US federal deficit under control. But he has also indicated plans for cutting taxes (for all incomes), eliminating the estate tax, and providing a significant child care credit. He believes that the increased economic activity resulting from these cuts would counteract that drop in tax income. Such policies do not bode well for research funding (an easy section of the budget to reduce).

With regards to neurodegeneration research, during the election campaign Mr Trump told a New Hampshire audience that Alzheimer’s was a “total top priority” for him. So there may be some hope there for closely associated Parkinson’s disease (we can hope).

We will simply have to wait and see.

And what is the outlook for the UK?

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The winning team in the BREXIT vote. Source: Telegraph

The UK’s public finances have worsened by approximately £25 billion since the March Budget (source: Independent), with the impact of the BREXIT vote apparently being a major contributing factor. This hole in the finances is going to require the Government to borrow more and spend less, which may well impact research funding in the up coming Autumn budget statement. And the Autumn statement is causing very real concerns for many in the research community (Click here for a recent editorial in the journal Nature).

To counter any reduction in the levels of Government research funding, incentives could be put in place for commercial/industrial resources to step in. The pharmaceuticals industry accounts for 48% of all corporate research funding in the UK, and much of this funding is at the University research institute level.

With regards to the huge pot of EU funding that could be lost, the UK could ‘buy-back’ into the EU research programmes as an ‘Associated Member’. But this approach would have several major drawbacks:

  • No political say into the formation and direction of future research funding programmes.
  • A 12% contribution of funds requirement for just a 16% gain of competitive funds.
  • Any changes to UK immigration policies at any stage would cause major disruption to future programmes.

Obviously clarity is required. We will wait to see what the Autumn statement brings.

EDITORIAL NOTE: I have tried to remain unbiased here, ignoring much of the negative comments in the media regarding Mr Trump’s proposed policies and the BREXIT related scaremongering in the UK. It is however difficult to sort through the mess and differentiate fact from opinion. This post was never intended to be a post, just a personal investigation of the state of play in research funding for Parkinson’s disease. But I decided to share it here for general interest (and I hope it was of interest). It is a very serious matter.

The banner for today’s post was sourced from Lucas Jackson/Reuters

Inhaling L-dopa

~ Simon ~ 7 Comments

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For more than 50 years, L-dopa (a critical ingredient used by the brain to produce the chemical dopamine) has been one of the primary therapies used in the treatment of Parkinson’s disease. Over those years, there have been several different versions of L-dopa, providing advantages over previous forms. Last week, the results of clinical trials involving a new inhalable version of L-dopa were published.

In this post we will review the results of those studies.

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Inhalers. Source: Verywell

The motor features (a resting tremor in one of the limbs, slowness of movement, and rigidity in the limbs) of Parkinson’s disease begin to appear when most of the dopamine producing neurons in the brain have been lost (specifically, >60% of the midbrain dopamine neurons). Thus for the last 50 years the primary means of treating Parkinson’s disease has been via dopamine replacement therapies.

Why don’t we just inject people with dopamine?

The chemical dopamine has a very difficult time crossing the blood-brain barrier, which is a thick membrane surrounding the brain. This barrier protects the brain from unwanted undesirables (think toxic chemicals), but it also blocks the transfer of some chemicals that exert a positive impact (such as dopamine).

When dopamine is blocked from entering the brain, other enzymes can convert it into another chemical called ‘norepinephrine’ (or epinephrine) and this conversion can cause serious side effects in blood pressure and glucose metabolism.

In addition, any dopamine that does find its way into the brain is very quickly broken down by enzymes. Thus, the amount of time that dopamine has to act is reduced, resulting in a very limited outcome. And these reasons are why doctors turned to L-dopa instead of dopamine in the treatment of Parkinson’s disease.

What is L-dopa?

Basically, Levodopa (L-dopa) is a chemical intermediary in the production of dopamine. That is to say, you need L-dopa to make dopamine. L-dopa is very stable inside the body and crosses the blood-brain-barrier very easily.

In the UK, a commonly used version is known as  ‘Sinemet®‘(produced by Merck).

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The chemical structure of L-dopa. Source: Wikipedia

The best way to understand what L-dopa is probably be to explain the history of this remarkable chemical.

The history of L-dopa

Until the 1950s there were few treatment options for Parkinson’s disease, but a young scientist in Sweden was about to change that.

This is Arvid Carlsson.

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Prof Arvid Carlsson. Source: Alchetron

He’s a dude.

In 1957, he discovered that when he injected the brains of rabbits with a neurotoxin (reserpine) it killed the dopamine neurons (and the animals exhibited reduced movement). He also discovered that by injecting the dopamine precursor –L-dopa – into those same animals, he was able to rescue their motor ability. Importantly, he found that the serotonin precursor (called 5-hydroxytryptophan) was not capable of reversing the reduction in motor ability, indicating that the effect was specific to L-dopa.

Here is the 1957 report:

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Title: 3,4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists.
Authors: Carlsson A, Lindqvist M, Magnusson T.
Journal: Nature. 1957 Nov 30;180(4596):1200. No abstract available.
PMID: 13483658       (the article on the Nature website – access required)

This was a fantastic discovery. A Nobel prize winning discovery in fact.

But what to do with it?

At the time, we did not know that dopamine was depleted in Parkinson’s disease. And people with Parkinson’s continued to suffer.

It was not until 1960 that the critical discovery of Parkinson’s disease was made by another young European scientist. Carlsson’s research (and that of others) inspired the Austrian researcher, Oleh Hornykiewicz to look at dopamine levels in people with Parkinson’s disease.

And what he found changed everything.

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Prof Oleh Hornykiewicz. Source: Kurienwissenschaftundkunst

In his study, Hornykiewicz found very high levels of dopamine in the basal ganglia of normal postmortem adult brains, but a marked and consistent reduction (approx. 10-fold) in six postmortem cases of Parkinsonisms. The basal ganglia is one of the main regions of the brain that dopamine neurons communicate with (releasing dopamine there).

 

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Title: Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system
Authors: Ehringer H, Hornykiewicz O.
Journal: Parkinsonism Relat Disord. 1998 Aug;4(2):53-7. No abstract available.
PMID: 18591088

Importantly, Hornykiewicz did not stop there.

In November 1960, Hornykiewicz approached Walther Birkmayer, a doctor at a home for the aged in Vienna, and together they began some clinical trials of L-dopa in July 1961. Birkmayer injected 50 to 150 mg intravenously in saline into 20 volunteers with Parkinsonism. In their report, Birkmayer and Hornykiewicz wrote this regarding the results:

“The effect of a single intravenous injection of l-dopa was, in short, a complete abolition or substantial relief of akinesia. Bedridden patients who were unable to sit up, patients who could not stand up when seated, and patients who when standing could not start walking performed after l-dopa all of these activities with ease. They walked around with normal associated movements, and they could even run and jump. The voiceless, aphonic speech, blurred by palilalia and unclear articulation, became forceful and clear as in a normal person. For short periods of time the people were able to perform motor activities, which could not be prompted to any comparable degree by any other known drug”

Despite their initial excitement, Birkmayer and Hornykiewicz found that the response to L-dopa was very limited in its duration. In addition, subsequent trials by others were not able to achieve similar results, with many failing to see any benefit at all.

And that was when George stepped into the picture.

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Dr George Cotzias…and yes, he is holding a brain. Source: New Scientist

Dr George Cotzias was a physician working in New York who became very interested in the use of L-dopa for Parkinson’s disease. And he discovered that by starting with very small doses of L-dopa, given orally every two hours and gradually increasing the dose gradually he was able to stabilize patients on large enough doses to cause a dramatic changes in their symptoms. His studies led ultimately to the Food and Drug Administration (FDA) approving the use of L-dopa for use in PD in 1970. Cotzias and his colleagues were also the first to describe L-dopa–induced dyskinesias.

How does L-dopa work?

When you take an L-dopa tablet, the chemical will enter your blood. Via your bloodstream, it arrives in the brain where it will be absorbed by cells. Inside the cells, another chemical (called DOPA decarboxylase) then changes it into dopamine. And that dopamine is released, and that helps to alleviate the motor features of Parkinson’s disease.

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The production of dopamine, using L-dopa. Source: Watcut

Outside the brain, there is a lot of DOPA decarboxylase in other organs of the body, and if this is not blocked then the effect of L-dopa is reduced in the brain, as less L-dopa reaches the brain. To this end, people with Parkinson’s disease are also given Carbidopa (Lodosyn) which inhibits DOPA decarboxylase outside of the brain (Carbidopa does not cross the blood-brain-barrier).

How does the L-dopa inhaler work?

The company behind this new product, Acorda Therapeutics, spent many years developing a powdered version of levodopa that could be delivered to the lungs. Early on in this developmental process the scientists realised a problem: while normal asthma inhalers only need to release micrograms of their medicine to the lungs, a L-dopa inhaler would need to deliver 1,000 times more than that to have any effect. The huge amounts were needed to ensure that enough L-dopa would get from the lungs into the brain to be effective. Thus, the ARCUS inhaler delivers 25 to 50 milligrams in two breaths.

The inhaler contains capsules of L-dopa, which are designed to break open so that the powder can escape. By sucking on the inhaler (see image below), the open capsule starts spinning, releasing the levodopa into the air and subsequently into the lungs.

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The ARCUS inhalation technology. Source: ParkinsonsLife

Pretty straightforward, right? Nice idea, cool design, easy to use.

But does it work?

What were the results of the clinical trials?

inhaler

Title: Preclinical and clinical assessment of inhaled levodopa for OFF episodes in Parkinson’s disease.
Authors: Lipp MM, Batycky R, Moore J, Leinonen M, Freed MI.
Journal: Sci Transl Med. 2016 Oct 12;8(360):360ra136.
PMID: 27733560     (This article is OPEN ACCESS if you would like to read it)

In their research report, the scientists provided data from three studies: preclinical, phase one clinical, and phase two clinical. In the preclinical work, they measured the levels of L-dopa in dogs who had inhaled levodopa powder. When they looked at blood samples, they found that levodopa levels peaked in all of the animals 2.5 min after administration. This represented a very quick route to the blood system, as dogs that were given levodopa plus carbidopa orally did not exhibit peak blood levodopa levels until 30 min after administration.

In the phase one (safety) clinical trial, 18 healthy persons were enrolled, and again comparisons were made between inhaled CVT-301 and orally administered carbidopa/levodopa. This study demonstrated that CVT-301 was safe and had a similar rapidity of action as in the preclinical dog study.

Next, the researchers conducted a phase two (efficacy) clinical study. This involve 24 people with Parkinson’s disease inhaling CVT-301 as a single 50mg dose during an OFF episode (periods of no prescribed medication). 77% of the CVT-301 treated subjects showed an increase in plasma levodopa within 10 min. By comparison, only 27% of a group of subjects taking oral doses of carbidopa/levodopa at a 25-mg/100-mg dose achieved the same levels within that time. Improvements in timed finger tapping and overall motor function (as measured by the Unified Parkinson’s Disease Rating Scale) were observed between 5 and 15 minutes after administration.

The most common adverse event was cough, but all of the coughing events were considered mild to moderate, generally occurring at the time of inhalation. In most cases, they were resolved rapidly and became less frequent after initial dosing.

So what does it all mean?

Inhalation of L-dopa may represent a novel means of treating people with Parkinson’s disease, especially those who struggle with swallowing pills. The most obvious benefit is the speed with which the subjects see results.

The amount of L-dopa being used is very high, however, and we will be interested to see the results of more long term studies before passing judgement on the inhaler approach. We’ll keep you informed as more information comes to hand.

The banner for today’s post is sourced from the BBC

One year in

~ Simon ~ Leave a comment

happy_birthday

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

 

Nilotinib update – new trial delayed

~ Simon ~ 3 Comments

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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.