Diabetes and Parkinson’s

A reader recently asked for an explanation of some recent research regarding diabetes and Parkinson’s.

You see, a significant proportion of the Parkinson’s community have glucose intolerance issues and some live with the added burden of diabetes. That said, the vast majority of diabetics do not develop PD. Likewise, the vast majority of people with Parkinson’s do not have a diagnosis of diabetes.

There does appear to be a curious relationship between Parkinson’s and diabetes, with some recent research suggests that this association can be detrimental to the course of the condition. 

In today’s post we will look at what what diabetes is, consider the associations with Parkinson’s, and we will discuss the new research findings.

Foreman and Ali. Source: Voanews

1974 was an amazing year.

On October 30th, the much-hyped heavyweight title match – the ‘Rumble in the Jungle’ – between George Foreman and Muhammad Ali took place in Kinshasa, Zaire (Democratic Republic of the Congo).

Stephen King. Source: VanityFair

A 26-year-old author named Stephen King published his debut novel, “Carrie” (April 5, with a first print-run of just 30,000 copies).

Lucy. Source: Youtube

The fossil remains of a 3.2 million years old hominid skeleton was discovered in Ethiopia (November 24th). It was named ‘Lucy’ – after the song “Lucy in the Sky with Diamonds” by The Beatles which was played repeatedly in the expedition camp the evening after the team’s first day of work on the site (Source).

And Richard Nixon becomes the first US president to resign from office (August 9th).

President Richard Nixon. Source: Fee

In addition to all of this, in December of 1974, a small study was published in the Journal of Chronic Diseases.

It dealt with Parkinson’s and it presented a rather startling set of findings:

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Ibudilast: A Phosphodiesterase inhibitor

A reader recently asked me about an experimental drug called Ibudilast.

It is a ‘Phosphodiesterase 4 inhibitor’.

Recently there was a very interesting result in a clinical trial looking at Ibudilast in a specific neurodegenerative condition. Sadly for the reader that condition was not Parkinson’s, in fact very little research has been done on Ibudilast in Parkinson’s

In today’s post we will look at what Phosphodiesterase inhibitors are, how they work, and discuss why Ibudilast may not be such a good experimental treatment for Parkinson’s.

On April 21-27th, 2018, the American Academy of Neurology (AAN) will hold their 70th Annual Meeting in Los Angeles (California).

I will not be at the meeting, but I will definitely be keeping an eye out for any news regarding the results of one particular clinical trial. At the meeting, a biopharmaceutical company called MediciNova Inc. will be presenting data regarding one of their clinical trials.

The presentation, entitled “Ibudilast – Phosphodiesterase Type 4 Inhibitor – Bi-Modal Therapy with Riluzole in Early Cohort and Advanced Amyotrophic Lateral Sclerosis (ALS) Patients – Final Report and Future Directions“ (Source) will be presented by principal investigator of the clinical study, Dr. Benjamin Rix Brooks, of the Carolinas HealthCare System’s Neuromuscular/ALS-MDA Center at Carolinas HealthCare System Neurosciences Institute.

Dr Brooks will be presenting the results of a single-center, randomized, double-blind, placebo-controlled clnical trial which was conducted to evaluate the safety, tolerability and clinical endpoint responsiveness of a drug called Ibudilast (or MN-166) in subjects with the neurodegenerative condition, Amyotrophic Lateral Sclerosis (or ALS – also known as motor neuron disease; Click here to read a previous SoPD post about ALS and Click here to learn more about this clinical trial).

What is Ibudilast?

Ibudilast is a phosphodiesterase inhibitor.

What is a phosphodiesterase inhibitor?

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UDCA 2.0 = TUDCA?

Ursodeoxycholic acid (UDCA) has been proposed as a drug that could be repurposed for Parkinson’s. As a medication, it is called ‘Ursodiol‘ and it is used to treat gallstones.

But there are absorption issues with UDCA: The passage of UDCA through the wall of the small intestine is slow and incomplete (Source).

There may be a solution, however, called Tauroursodeoxycholic acid (TUDCA). Think of it as UDCA-2.0. It is more easily absorbed by the gut. And there is also good evidence to suggest that it has the same beneficial neuroprotective properties as UDCA.

In today’s post we will discuss what exactly UDCA and TUDCA are, review the Parkinson’s research for both, and discuss why one of these drugs should be tested in the clinic for PD.

Gallstones – ouch! Source: Healthline

Let me introduce you to your gallbladder:

It is one of the less appreciated organs; a pear-shaped, hollow organ located just under your liver and on the right side of your body. Its primary function is to store and concentrate your bile. Bile is a yellow-brown digestive enzyme – made and released by the liver – which helps with the digestion of fats in your small intestine (the duodenum).

Source: Mayoclinic

Now, let me introduce you to your gallstones:

Gallstones are hardened deposits that can form in your gallbladder. About 80% of gallstones are made of cholesterol. The remaining 20% of gallstones are made of calcium salts and bilirubin. Bilirubin is the yellow pigment in bile. When the body produces too much Bilirubin or cholesterol, gallstones can develop.

About 10-20% of the population have gallstones (Source), but the vast majority experience no symptoms and need no treatment.

Interesting intro, but what does any of this have to do with Parkinson’s?

One of the treatments for gallstones is called UDCA. And this compound is being considered for “repurposing” as a treatment for Parkinson’s.

What is UDCA?

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The aggregating antics of (some) anaesthetics

This is one of those posts that I am reluctant to write because there is the very real possibility of it being taken out of context and causing someone to panic. But several readers have asked me to address a new piece of research that was published this week which has them concerned.

Anaesthetics are very useful agents in medicine, but they have long been known to have biological effects beyond simply numbing/sedating individuals. Some of those effects are beneficial, while others….mmm, not so beneficial. And the new research published this week leans towards the latter: Certain anaesthetics apparently induce mutant protein aggregation in neurons and cause stress responses in those brain cells.

In today’s post, we will discuss what anaesthetics are, how (we think) they work, and what the results of this new research actually mean.

William Morton’s first public demonstration. Source: Pinterest

On Friday 16th October 1846, history was made.

On that date, an American dentist named William T. G. Morton (1819-1868) made the first public demonstration of the use of inhaled ether as a surgical anaesthetic.

William Morton. Source: Wikipedia

At this demonstration Dr. John Collins Warren painlessly removed a tumor from the neck of a Mr. Edward Gilbert Abbott. After finishing the operation and Abbott had regained consciousness, Warren asked Abbott how he felt.

John Collins Warren. Source: General-anaesthesia

Abbott replied, “Feels as if my neck’s been scratched.”

Warren then turned to the medical audience and said:

“Gentlemen, this is no Humbug”

This was an obvious shot at an unsuccessful demonstration of nitrous oxide as a anaesthesia the year before (by Horace Wells in the same theatre), which ended with the audience shouting “Humbug!” after they heard the patient groaning with pain during the procedure.

The important thing to appreciate here is the magnitude of Morton’s achievement within in the history of medicine.

Before 16th October 1846, surgical procedures were not very pleasant affairs.

After 16th October 1846,… well, to be honest, they are still not very pleasant affairs, but at least the patient can skip most of the painful parts of an operation.

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

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Is there NOP hope for Parkinson’s?

Please do not misread the title of this post!

Compounds targeting the Nociceptin receptor (or NOP) could provide the Parkinson’s community with novel treatment options in the not-too-distant future.

In pre-clinical models of Parkinson’s, compounds designed to block NOP have demonstrated neuroprotective properties, while drugs that stimulate NOP appear to be beneficial in reducing L-dopa induced dyskinesias. 

In today’s post we look at exactly what NOP is and what it does, we will review some of the Parkinson’s-based research that have been conducted so far, and we will look at what is happening in the clinic with regards to NOP-based treatments.

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Source: LUMS

On the surface of every cell in your body, there are lots of small proteins that are called receptors.

They are numerous and ubiquitous.

And they function act like a ‘light switch’ – allowing for certain biological processes to be initiated or inhibited. All a receptor requires to be activated (or blocked) is a chemical messenger – called a ligand – to come along and bind to it.

An example of a receptor on a cell. Source: Droualb

Each type of receptor has a particular structure, which is specific to certain shaped ligands (the chemical messenger I mentioned above). These ligands are floating around in the extracellular space (the world outside of the cell), having been released (or secreted) by other cells.

And this process represents one of the main methods by which cells communicate with each other.

By binding to a receptor, the ligand can either activate the receptor or alternatively block it. The activator ligands are called agonists, while the blockers are antagonists.

Agonists_and_antagonists

Agonist vs antagonist. Source: Psychonautwiki

Many of the drugs we currently have available in the clinic function in this manner.

For example, with Parkinson’s medications, some people will be taking Pramipexole (‘Mirapex’ and ‘Sifrol’) or Apomorphine (‘Apokyn’) to treat their symptoms. These drugs are Dopamine agonists because they bind to the dopamine receptors, and help with dopamine-mediated functions (dopamine being one of the chemicals that is severely in the Parkinsonian brain). As you can see in the image below the blue dopamine agonists can bypass the dopamine production process (which is reduced in Parkinson’s) and bind directly to the dopamine receptors on the cells that are the intended targets of dopamine.

Source: Bocsci

There are also dopamine antagonists (such as Olanzapine or ‘Zyprexa’) which blocks dopamine receptors. These drugs are not very helpful to Parkinson’s, but dopamine antagonist are commonly prescribed for people with schizophrenia.

Are there other receptors of interest in Parkinson’s?

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Monthly Research Review – March 2018

At the end of each month the SoPD writes a post which provides an overview of some of the major pieces of Parkinson’s-related research that were made available during March 2018.

The post is divided into four parts based on the type of research (Basic biology, disease mechanism, clinical research, and other news). 

So, what happened during March 2018?

In world news:

March 25th – Qantas launches direct non-stop Boeing 787 Dreamliner flights between Perth Airport and Heathrow Airport, making it the first commercially non-stop service between Australia and the United Kingdom (17 hours on a plane – strewth!).

Boeing 787 Dreamliner. Source: Deredactie

March 14th – Prof Stephen Hawking, English theoretical physicist and cosmologist, sadly passed away at age 76. Diagnosed with in a very rare early-onset, slow-progressing form of Amyotrophic lateral sclerosis (ALS; also known as motor neurone disease or MND) in 1963 at age 21, he was gradually left him wheel chair bound. An amazing mind and a sad loss.

p03dn27d

Prof Stephen Hawking. Source: BBC

A funeral for Prof Hawking was held in Cambridge. The bell at Great St. Mary’s tolled 76 times at the start of the service. His remains will be cremated and his ashes will be interred at London’s Westminster Abbey near the remains of Isaac Newton.

King’s Parade in Cambridge was absolutely packed with mourners. Source: News.rthk

March 19th – In other sad news, ‘Sudan’, the world’s last male northern white rhinoceros died in Kenya, making the subspecies ‘functionally extinct’. Poachers had reduced the population from 2000 in the 1960s to just 15 1980s, and efforts to keep the species alive .

Sudan, the last surviving male northern white rhino. Source: PBS

March 24 – In over 800 cities internationally, people participated in student-led demonstrations against gun violence and mass shootings, calling for stronger gun control in the ‘March for our lives‘.

Source: Marchforourlives

And finally, on the 17th March, a driver in Milton Keynes (UK) got into big trouble with the law when he was pulled over and presented a police officer with an obvious fake drivers license (Source: Sky News):

Fake news Mr Trump? Clearly a fake. Everyone knows Homer lives at 742 Evergreen Terrace!

In the world of Parkinson’s research, a great deal of new research and news was reported:

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Objective measures: Getting smart about pills

There has been a lot of discussion on this site (and elsewhere on the web) regarding the need for more objective systems of measuring Parkinson’s – particularly in the setting of clinical trials.

Yes, subjective reports of patient experience are important, but they can easily be biased by ‘placebo responses’.

Thus, measures that are beyond the clinical trial participants conscious control – and focused on biological outcomes – are needed. 

In today’s post, we will consider one possible approach: Smart pills. We will discuss what they are, how they work, and how they could be applied to Parkinson’s research.

Source: Chicagotribune

In order to encourage a growing discussion regarding objective measures of Parkinson’s (and to follow up on previous rants – Click here and here for examples), I have decided to regularly (once a month) highlight new technologies that could provide the sort of unbiased methods of data collection that are required for assessing whether a treatment is having an impact on Parkinson’s.

Today, we will look at smart pills.

What is a smart pill?

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Making. It. Personal.

This is one of those post (read: rants) where I want to put an idea out into the ether for someone to chew on. It starts with a very simple question:

Why is ‘the drug’ the focus of a clinical trial?

If our goal is to find beneficial therapies for people with Parkinson’s, then the way we currently clinically test drugs is utterly nonsensical.

And if we do not change our “we’ve always done it this way” mindset, then we are simply going to repeat the mistakes of the past. Others are changing, so why aren’t we?

In today’s post, we will consider one possible alternative approach.

I hope you know who Grace Hopper is – if not, click here. Source: Mentalfloss

Why is ‘the drug‘ the focus of a clinical trial?

The way we clinically test drugs makes absolutely no sense when you actually stop and think about it.

Other medical disciplines (such as oncology) have woken up to this fact, and it is time for the field of Parkinson’s research to do this same.

Let me explain:

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Something is interesting in the state of Denmark

 

 

Gaucher disease is a genetic disorder caused by the reduced activity of an enzyme, glucocerebrosidase. This enzyme is produced by a region of DNA (or a gene) called GBA – the same GBA gene associated with a particular form of Parkinson’s.

Recently, a Danish company has been testing a new drug that could benefit people with Gaucher disease.

It is only natural to ask the question: Could this drug also benefit GBA-associated Parkinson’s?

In today’s post, we will discuss what Gaucher disease is, how this experimental drug works, and why it would be interesting to test it in Parkinson’s.

Will Shakespeare. Source: Ppolskieradio

The title of this post is a play on words from one of the many famous lines of William Shakespeare’s play, Hamlet.

The original line – delivered by Marcellus (a Danish army sentinel) after the ghost of the dead king appears – reads: If the authorities knew about the problems and chose not to prevent them, then clearly something is rotten in the state of Denmark.

(Act 1, Scene 4)

The title of this post, however, is: Something is interesting in the state of Denmark

This slight change was made because certain Danish authorities know about the problem and they are trying to prevent it. The ‘authorities’ in this situation are some research scientists at a biotech company in Denmark, called Orphazyme.

And the problem is Parkinson’s?

No, the problem is Gaucher disease.

Huh? What is Gaucher disease?

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“What’s the evolutionary advantage of Parkinson’s?”

Each year King’s College London holds the Edmond J. Safra Memorial Lecture. It is a public event – exploring cutting-edge research on Parkinson’s – held in honour of the late philanthropist and financier, Mr Edmond J Safra, .

I was lucky enough to attend this year’s event (entitled A vision of tomorrow: How can technology improve diagnosis and treatment for Parkinson’s patients?). It highlighted the fantastic research being carried out by Professor Marios Politis and his team.

During the Q&A session of the event though, a question was asked from the audience regarding what the evolutionary advantage of Parkinson’s might be. The question drew a polite chuckle from the audience.

But the question wasn’t actually as silly as some might think.

In today’s post we look at some evidence suggesting an evolutionary advantage involving Parkinson’s.

King’s College London Chapel. Source: Schoolapply

Despite the impressive name, King’s College London is not one of the grand old universities of England.

Named after its patron King George IV (1762-1830), the university was only founded in 1829 (compare this with 1096 for Oxford and 1209 for Cambridge; even silly little universities like Harvard date back further – 1636). The university is spread over five separate campuses, geographically spread across London. But if you ever get the chance to visit the main Strand campus, ask for the chapel and take a moment to have a look – it is very impressive (the image above really doesn’t do it justice).

As I mentioned in the intro, each year King’s College London holds the Edmond J. Safra Memorial Lecture. It is an event that is open to the public and it involves a discussion regarding innovative new research on Parkinson’s. The evening is held in honour of the late Mr Edmond J Safra.

Edmond J. Safra. Source: Edmondjsafrafoundation

This year, Professor Marios Politis and members of his research group were presenting lectures on “How can technology improve diagnosis and treatment for Parkinson’s”. The lectures were very interesting, but the reason I am writing about it here is because during the question and answer session at the end of the lectures, the following question was asked:

“What’s the evolutionary advantage of Parkinson’s?”

Given the debilitating features of the condition, the audience was naturally amused by the question. And there was most likely several people present who would have thought the idea of any evolutionary advantage to Parkinson’s a ridiculous concept.

But it’s not.

And there is actually research to suggest that something evolutionary could be happening with Parkinson’s.

?!?!? What do you mean?

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