Being a patriotic ‘kiwi’, I am always very pleased to write about interesting Parkinson’s research originating from the homeland. And recently the results of an interesting clinical study that was designed and conducted in New Zealand have been published.
The clinical study was focused on whether a diet manipulation could influence motor and non-motor symptoms/features of Parkinson’s.
Specifically, the researchers were looking at the low-fat versus ketogenic diets.
In today’s post, we will discuss what is meant by a ketogenic diet, we will assess the results of the study, and consider what they might mean for the Parkinson’s community.
The All Blacks. Source: Newshub
Aotearoa (also known as New Zealand) is a remarkable little country (and yes, I know I’m slightly biased).
It flies under the radar for most folks who are not interested in rugby, amazing scenery, great quality of life, or hobbits, but historically this tiny South Pacific nation of 4.6 million people has punched well above its weight on many important matters.
For example, on the 19th September 1893, the governor, Lord Glasgow, signed a new Electoral Act into law. And as a result of that simple act, New Zealand became the first self-governing country in the world in which all women (over the age of 21) had the right to vote in parliamentary election (Australia followed in 1902, the US in 1920, & the Britain in 1928). That achievement, it should be said, was the result of years of dogged effort by suffrage campaigners, led by Kate Sheppard who is today acknowledged with her portrait on the $10 note:
The NZ $10 note. Source: Whaleoil
A New Zealander made the first trans-global radio transmission on the 18th October 1924. Invalided during WWI, Frank Bell revived his childhood interest in wireless communication, and after being the first kiwi to have two-way radio contact with Australia and North America, he achieved something far more impressive. From the family sheep station in ‘Shag Valley’ (East Otago – bottom of the South Island), he sent a Morse code transmission (“Greetings from New Zealand, signed Bell Z4AA”) which was received and replied to by amateur operator Cecil Goyder at Mill Hill School (London).
Frank and his older sister Brenda. Source: NZhistory
New Zealand was also where jet boats was first invented by Sir Bill (William Hamilton). His first jet boat was a 3.6 meter (12 foot) plywood hull with a 100 E Ford engine, and the jet a centrifugal type pump. This craft was tested on the Irishman Creek dam, before it ran successfully upriver in 1953. And from there it kind of went viral. In 1960, three Hamilton jet boats (the Kiwi, Wee Red and Dock), became the first and only boats to travel all the way up through the Grand Canyon.
Sir Hamilton and his first jet boat (1958). Source: ipenz
And the list doesn’t stop there. We could go on with other great firsts:
- Sir Ed (Hillary) – first to summit Everest (to be fair, it was a team effort)
- Sir Ernest (Rutherford) – first to split the atom
- Sir Peter (Blake) – first to sail around the world in less than 75 days (again, a bit of a team effort)
- Sir John (Walker) – first to run the mile in under 3:50 (now a member of the Parkinson’s community)
- Georgina Beyer – first openly transsexual mayor, and then the world’s first openly transsexual Member of Parliament
- AJ Hackett & Henry van Asch – set up the first commercial bungy jump on the Kawarau Bridge, near Queenstown
- Helen Clark, Dame Siliva Cartwright & Sian Elias – first country to have women in the top three senior public roles (Prime Minister, the Governor General, & the Chief Justice, respectively)
- Rocket Lab – first private company in the Southern Hemisphere to reach space (in 2009)
And I guess we better stop there (if only out for fear of making larger nations feel somewhat inadequate), but you get the idea – small nation, doing lots of great stuff.
There is also a very proactive Parkinson’s community – with groups like Parkinson’s New Zealand organising and running support groups across the country, and helping to fund some of the great local Parkinson’s research.
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?
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.
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.
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.
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?
My piece was called the Dilemma of Success, and it explored a hypothetical situation that we may very well face in the not-so-distant future.
Optimistic as I am about the future of Parkinson’s research, I think this is a very serious issue – one which the Parkinson’s community needs to discuss and start planning for. I am re-posting it here today as I am keen for some thoughts/discussion on this matter.
Lord Robert Baden-Powell. Source: Utahscouts
My scout master looked around the horse shoe, making eye contact with each of us, before asking a simple question:
“When did Noah build the ark?”
My fellow scouts and I looked at each other. Some of us were wondering if the guy had completely lost the plot and somehow thought that it was Sunday morning and he was doing the sermon. Others seriously looked like they were trying to calculate an exact date.
He waited a moment for one of us to offer up some idiotic attempt at an answer, before he solemnly said:
“Before the rain”
It’s one of those childhood moments that didn’t make sense at the time, but comes back to haunt you whenever you can foresee certain troubles coming over the hill towards you.
The dilemma of success
It will be nice to have this problem, but it will still be a problem.
And we need to plan for it
The great ice hockey player Wayne Gretzky once said “A good hockey player plays where the puck is. A great hockey player plays where the puck is going to be” (the original quote actually came from his father, Walter).
At the start of each year, it is a useful practise to layout what is planned for the next 12 months. This can help us better anticipate where ‘the puck’ will be, and allow us to prepare for things further ahead.
2017 was an incredible year for Parkinson’s research, and there is a lot already in place to suggest that 2018 is going to be just as good (if not better).
In this post, we will lay out what we can expect over the next 12 months with regards to the Parkinson’s-related clinical trials research of new therapies.
Charlie Munger (left) and Warren Buffett. Source: Youtube
Many readers will be familiar with the name Warren Buffett.
The charming, folksy “Oracle of Omaha” is one of the wealthiest men in the world. And he is well known for his witticisms about investing, business and life in general.
Warren Buffett. Source: Quickmeme
He regularly provides great one liners like:
“We look for three things [in good business leaders]: intelligence, energy, and integrity. If they don’t have the latter, then you should hope they don’t have the first two either. If someone doesn’t have integrity, then you want them to be dumb and lazy”
“Work for an organisation of people you admire, because it will turn you on. I always worry about people who say, ‘I’m going to do this for ten years; and if I really don’t like it very much, then I’ll do something else….’ That’s a little like saving up sex for your old age. Not a very good idea”
“Choosing your heroes is very important. Associate well, marry up and hope you find someone who doesn’t mind marrying down. It was a huge help to me”
Mr Buffett is wise and a very likeable chap.
Few people, however, are familiar with his business partner, Charlie Munger. And Charlie is my favourite of the pair.
Nuclear receptor related 1 protein (or NURR1) is a protein that is critical to the development and survival of dopamine neurons – the cells in the brain that are affected in Parkinson’s disease.
Given the importance of this protein for the survival of these cells, a lot of research has been conducted on finding activators of NURR1.
In today’s post we will look at this research, discuss the results, and consider issues with regards to using these activators in Parkinson’s disease.
Comet Hale–Bopp. Source: Physics.smu.edu
Back in 1997, 10 days after Comet Hale–Bopp passed perihelion (April 1, 1997 – no joke; perihelion being the the point in the orbit of a comet when it is nearest to the sun) and just two days before golfer Tiger Woods won his first Masters Tournament, some researchers in Stockholm (Sweden) published the results of a study that would have a major impact on our understanding of how to keep dopamine neurons alive.
Dopamine neurons are one group of cells in the brain that are severely affected by Parkinson’s disease. By the time a person begins to exhibit the movement symptoms of the condition, they will have lost 40-60% of the dopamine neurons in a region called the substantia nigra. In the image below, there are two sections of brain – cut on a horizontal plane through the midbrain at the level of the substantia nigra – one displaying a normal compliment of dopamine neurons and the other from a person who passed away with Parkinson’s demonstrating a reduction in this cell population.
The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinson’s disease brain (right). Source:Memorangapp
The researchers in Sweden had made an amazing discovery – they had identified a single gene that was critical to the survival of dopamine neurons. When they artificially mutated the section of DNA where this gene lives – an action which resulted in no protein for this gene being produced – they generated genetically engineered mice with no dopamine neurons:
Title: Dopamine neuron agenesis in Nurr1-deficient mice
Authors: Zetterström RH, Solomin L, Jansson L, Hoffer BJ, Olson L, Perlmann T.
Journal: Science. 1997 Apr 11;276(5310):248-50.
The researchers who conducted this study found that the mice with no NURR1 protein exhibited very little movement and did not survive long after birth. And this result was very quickly replicated by other research groups (Click here and here to see examples)
So what was this amazing gene called?
We have previously discussed the powerful antioxidant Resveratrol, and reviewed the research suggesting that it could be beneficial in the context of Parkinson’s disease (Click here to read that post).
I have subsequently been asked by several readers to provide a critique of the Parkinson’s-associated research focused on Resveratrol’s twin sister, Pterostilbene (pronounced ‘Terra-still-bean’).
But quite frankly, I can’t.
Why? Because there is NO peer-reviewed scientific research on Pterostilbene in models of Parkinson’s disease.
In today’s post we will look at what Pterostilbene is, what is known about it, and why we should seriously consider doing some research on this compound (and its cousin Piceatannol) in the context of Parkinson’s disease.
Blue berries are the best natural source of Pterostilbene. Source: Pennington
So this is likely to be the shortest post in SoPD history.
Because there is nothing to talk about.
There is simply no Parkinson’s-related research on the topic of today’s post: Pterostilbene. And that is actually a crying shame, because it is a very interesting compound.
What is Pterostilbene?
Like Resveratrol, Pterostilbene is a stilbenoid.
Stilbenoids are a large class of compounds that share the basic chemical structure of C6-C2-C6:
Resveratrol is a good example of a stilbenoid. Source: Wikipedia
Stilbenoids are phytoalexins (think: plant antibiotics) produced naturally by numerous plants. They are small compounds that become active when the plant is under attack by pathogens, such as bacteria or fungi. Thus, their function is generally considered to part of an anti-microbial/anti-bacterial plant defence system for plants.
The most well-known stilbenoid is resveratrol which grabbed the attention of the research community in a 1997 study when it was found to inhibit tumour growth in particular animal models of cancer:
In October 2015, researchers from Georgetown University announced the results of a small clinical trial that got the Parkinson’s community very excited. The study involved a cancer drug called Nilotinib, and the results were rather spectacular.
What happened next, however, was a bizarre sequence of disagreements over exactly what should happen next and who should be taking the drug forward. This caused delays to subsequent clinical trials and confusion for the entire Parkinson’s community who were so keenly awaiting fresh news about the drug.
Earlier this year, Georgetown University announced their own follow up phase II clinical trial and this week a second phase II clinical trial funded by a group led by the Michael J Fox foundation was initiated.
In todays post we will look at what Nilotinib is, how it apparently works for Parkinson’s disease, what is planned with the new trial, and how it differs from the ongoing Georgetown Phase II trial.
The FDA. Source: Vaporb2b
This week the U.S. Food and Drug Administration (FDA) has given approval for a multi-centre, double-blind, randomised, placebo-controlled Phase IIa clinical trial to be conducted, testing the safety and tolerability of Nilotinib (Tasigna) in Parkinson’s disease.
This is exciting and welcomed news.
What is Nilotinib?
Nilotinib (pronounced ‘nil-ot-in-ib’ and also known by its brand name Tasigna) is a small-molecule tyrosine kinase inhibitor, that has been approved for the treatment of imatinib-resistant chronic myelogenous leukemia (CML).
What does any that mean?
Basically, it is the drug that is used to treat a type of blood cancer (leukemia) when the other drugs have failed. It was approved for treating this cancer by the FDA in 2007.
A new research report looking at the use of cholesterol-reducing drugs and the risk of developing Parkinson’s disease has just been published in the scientific journal Movement disorders.
The results of that study have led to some pretty startling headlines in the media, which have subsequently led to some pretty startled people who are currently taking the medication called statins.
In todays post, we will look at what statins are, what the study found, and discuss what it means for our understanding of Parkinson’s disease.
Cholesterol forming plaques (yellow) in the lining of arteries. Source: Healthguru
Cholesterol gets a lot of bad press.
Whether it’s high and low, the perfect balance of cholesterol in our blood seems to be critical to our overall health and sense of wellbeing. At least that is what we are constantly being told this by media and medical professionals alike.
But ask yourself this: Why? What exactly is cholesterol?
Good question. What is cholesterol?
Cholesterol (from the Greek ‘chole‘- bile and ‘stereos‘ – solid) is a waxy substance that is circulating our bodies. It is generated by the liver, but it is also found in many foods that we eat (for example, meats and egg yolks).
The chemical structure of Cholesterol. Source: Wikipedia
Cholesterol falls into one of three major classes of lipids – those three classes of lipids being Triglycerides, Phospholipids and Steroids (cholesterol is a steroid). Lipids are major components of the cell membranes and thus very important. Given that the name ‘lipids’ comes from the Greek lipos meaning fat, people often think of lipids simply as fats, but fats more accurately fall into just one class of lipids (Triglycerides).
Like many fats though, cholesterol dose not dissolve in water. As a result, it is transported within the blood system encased in a protein structure called a lipoprotein.
The structure of a lipoprotein; the purple C inside represents cholesterol. Source: Wikipedia
Lipoproteins have a very simple classification system based on their density:
- very low density lipoprotein (VLDL)
- low density lipoprotein (LDL)
- intermediate density lipoprotein (IDL)
- high density lipoprotein (HDL).
Now understand that all of these different types of lipoproteins contain cholesterol, but they are carrying it to different locations and this is why some of these are referred to as good and bad.
The first three types of lipoproteins carry newly synthesised cholesterol from the liver to various parts of the body, and thus too much of this activity would be bad as it results in an over supply of cholesterol clogging up different areas, such as the arteries.
LDLs, in particular, carry a lot of cholesterol (with approximately 50% of their contents being cholesterol, compared to only 20-30% in the other lipoproteins), and this is why LDLs are often referred to as ‘bad cholesterol’. High levels of LDLs can result in atherosclerosis (or the build-up of fatty material inside your arteries).
Progressive and painless, atherosclerosis develops as cholesterol silently and slowly accumulates in the wall of the artery, in clumps that are called plaques. White blood cells stream in to digest the LDL cholesterol, but over many years the toxic mess of cholesterol and cells becomes an ever enlarging plaque. If the plaque ever ruptures, it could cause clotting which would lead to a heart attack or stroke.
So yeah, some lipoproteins can be considered bad.
HDLs, on the other hand, collects cholesterol and other lipids from cells around the body and take them back to the liver. And this is why HDLs are sometimes referred to as “good cholesterol” because higher concentrations of HDLs are associated with lower rates of atherosclerosis progression (and hopefully regression).
But why is cholesterol important?
While cholesterol is usually associated with what is floating around in your bloodstream, it is also present (and very necessary) in every cell in your body. It helps to produce cell membranes, hormones, vitamin D, and the bile acids that help you digest fat.
It is particularly important for your brain, which contains approximately 25 percent of the cholesterol in your body. Numerous neurodegenerative conditions are associated with cholesterol disfunction (such as Alzheimer’s disease and Huntington’s disease – Click here for more on this). In addition, low levels of cholesterol is associated with violent behaviour (Click here to read more about this).
Are there any associations between cholesterol and Parkinson’s disease?
The associations between cholesterol and Parkinson’s disease is a topic of much debate. While there have been numerous studies investigating cholesterol levels in blood in people with Parkinson’s disease, the results have not been consistent (Click here for a good review on this topic).
Rather than looking at cholesterol directly, a lot of researchers have chosen to focus on the medication that is used to treat high levels of cholesterol – a class of drugs called statins.
Title: Prospective study of statin use and risk of Parkinson disease.
Authors: Gao X, Simon KC, Schwarzschild MA, Ascherio A.
Journal: Arch Neurol. 2012 Mar;69(3):380-4.
PMID: 22410446 (This article is OPEN ACCESS if you would like to read it)
In this study the researchers conduced a prospective study involving the medical details of 38 192 men and 90 874 women from two huge US databases: the Nurses’ Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS).
NHS study was started in 1976 when 121,700 female registered nurses (aged 30 to 55 years) completed a mailed questionnaire. They provided an overview of their medical histories and health-related behaviours. The HPFS study was established in 1986, when 51,529 male health professionals (40 to 75 years) responded to a similar questionnaire. Both the NHS and the HPFS send out follow-up questionnaires every 2 years.
By analysing all of that data, the investigators found 644 cases of Parkinson’s disease (338 women and 306 men). They noticed that the risk of Parkinson’s disease was approximately 25% lower among people currently taking statins when compared to people not using statins. And this association was significant in statin users younger than 60 years of age (P = 0.02).
What are statins?
Also known as HMG-CoA reductase inhibitors, statins are a class of drug that inhibits/blocks an enzyme called 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase.
HMG-CoA reductase is the key enzyme regulating the production of cholesterol from mevalonic acid in the liver. By blocking this process statins help lower the total amount of cholesterol available in your bloodstream.
Statins are used to treat hypercholesterolemia (also called dyslipidemia) which is high levels of cholesterol in the blood. And they are one of the most widely prescribed classes of drugs currently available, with approximately 23 percent of adults in the US report using statin medications (Source).
Now, while the study above found an interesting association between statin use and a lower risk of Parkinson’s disease, the other research published on this topic has not been very consistent. In fact, a review in 2009 found a significant associations between statin use and lower risk of Parkinson’s disease was observed in only two out of five prospective studies (Click here to see that review).
New research published this week has attempted to clear up some of that inconsistency, by starting with a huge dataset and digging deep into the numbers.
So what new research has been published?
Title: Statins may facilitate Parkinson’s disease: Insight gained from a large, national claims database
Authors: Liu GD, Sterling NW, Kong L, Lewis MM, Mailman RB, Chen H, Leslie D, Huang X
Journal: Movement Disorder, 2017 Jun;32(6):913-917.
Using the MarketScan Commercial Claims and Encounters database which catalogues the healthcare use and medical expenditures of more than 50 million employees and their family members each year, the researcher behind that study identified 30,343,035 individuals that fit their initial criteria (that being “all individuals in the database who had 1 year or more of continuous enrolment during January 1, 2008, to December 31, 2012, and were 40 years of age or older at any time during their enrolment”). From this group, the researcher found a total of 21,599 individuals who had been diagnosed with Parkinson’s disease.
In their initial analysis, the researchers found that Parkinson’s disease was positively associated with age, male gender, hypertension, coronary artery disease, and usage of cholesterol-lowering drugs (both statins and non-statins). The condition was negatively associated with hyperlipidemia (or high levels of cholesterol). This result suggests not only that people with higher levels of cholesterol have a reduced chance of developing Parkinson’s disease, but taking medication to lower cholesterol levels may actually increase ones risk of developing the condition.
One interesting finding in the data was the effect that different types of statins had on the association.
Statins can be classified into two basic groups: water soluble (or hydrophilic) and lipid soluble (or lipophilic) statins. Hydrophilic molecule have more favourable interactions with water than with oil, and vice versa for lipophilic molecules.
Hydrophilic vs lipophilic molecules. Source: Riken
Water soluble (Hydrophilic) statins include statins such as pravastatin and rosuvastatin; while all other available statins (eg. atorvastatin, cerivastatin, fluvastatin, lovastatin and simvastatin) are lipophilic.
In this new study, the researchers found that the association between statin use and increased risk of developing Parkinson’s disease was more pronounced for lipophilic statins (a statistically significant 58% increase – P < 0.0001), compared to hydrophilic statins (a non-significant 19% increase – P = 0.25). One possible explanation for this difference is that lipophilic statins (like simvastatin and atorvastatin) cross the blood-brain barrier more easily and may have more effect on the brain than hydrophilic ones.
The investigators also found that this association was most robust during the initial phase of statin treatment. That is to say, the researchers observed a 82% in risk of PD within 1 year of having started statin treatment, and only a 37% increase five years after starting statin treatment.; P < 0.0001). Given this finding, the investigators questioned whether statins may be playing a facilitatory role in the development of Parkinson’s disease – for example, statins may be “unmasking” the condition during its earliest stages.
So statins are bad then?
Can I answer this question with a diplomatic “I don’t know”?
It is difficult to really answer that question based on the results of just this one study. This is mostly because this new finding is in complete contrast to a lot of experimental research over the last few years which has shown statins to be neuroprotective in many models of Parkinson’s disease. Studies such as this one:
Title: Simvastatin inhibits the activation of p21ras and prevents the loss of dopaminergic neurons in a mouse model of Parkinson’s disease.
Authors: Ghosh A, Roy A, Matras J, Brahmachari S, Gendelman HE, Pahan K.
Journal: J Neurosci. 2009 Oct 28;29(43):13543-56.
PMID: 19864567 (This study is OPEN ACCESS if you would like to read it)
In this study, the researchers found that two statins (pravastatin and simvastatin – one hydrophilic and one lipophilic, respectively) both exhibited the ability to suppress the response of helper cells in the brain (called microglial) in a neurotoxin model of Parkinson’s disease. This microglial suppression resulted in a significant neuroprotective effect on the dopamine neurons in these animals.
Another study found more Parkinson’s disease relevant effects from statin treatment:
TItle: Lovastatin ameliorates alpha-synuclein accumulation and oxidation in transgenic mouse models of alpha-synucleinopathies.
Authors: Koob AO, Ubhi K, Paulsson JF, Kelly J, Rockenstein E, Mante M, Adame A, Masliah E.
Journal: Exp Neurol. 2010 Feb;221(2):267-74.
PMID: 19944097 (This study is OPEN ACCESS if you would like to read it)
In this study, the researchers treated two different types of genetically engineered mice (both sets of mice produce very high levels of alpha synuclein – the protein closely associated with Parkinson’s disease) with a statin called lovastatin. In both groups of alpha synuclein producing mice, lovastatin treatment resulted in significant reductions in the levels of cholesterol in their blood when compared to the saline-treated control mice. The treated mice also demonstrated a significant reduction in levels of alpha synuclein clustering (or aggregation) in the brain than untreated mice, and this reduction in alpha synuclein accumulation was associated with a lessening of pathological damage in the brain.
So statins may not be all bad?
One thing many of these studies fail to do is differentiate between whether statins are causing the trouble (or benefit) directly or whether simply lowering cholesterol levels is having a negative impact. That is to say, do statins actually do something else? Other than lowering cholesterol levels, are statins having additional activities that could cause good or bad things to happen?
The recently published study we are reviewing in this post suggested that non-statin cholesterol medication is also positively associated with developing Parkinson’s disease. Thus it may be that statins are not bad, but rather the lowering of cholesterol levels that is. This raises the question of whether high levels of cholesterol are delaying the onset of Parkinson’s disease, and one can only wonder what a cholesterol-based process might be able to tell us about the development of Parkinson’s disease.
If the findings of this latest study are convincingly replicated by other groups, however, we may need to reconsider the use of statins not in our day-to-day clinical practice. At the very least, we will need to predetermine which individuals may be more susceptible to developing Parkinson’s disease following the initiation of statin treatment. It would actually be very interesting to go back to the original data set of this new study and investigate what addition medical features were shared between the people that developed Parkinson’s disease after starting statin treatment. For example, were they all glucose intolerant? One would hope that the investigators are currently doing this.
Are Statins currently being tested in the clinic for Parkinson’s disease?
(Oh boy! Tough question) Yes, they are.
There is currently a nation wide study being conducted in the UK called PD STAT.
Is this dangerous given the results of the new research study?
(Oh boy! Even tougher question!)
Again, we are asking this question based on the results of one recent study. Replication with independent databases is required before definitive conclusions can be made.
There have, however, been previous clinical studies of statins in neurodegenerative conditions and these drugs have not exhibited any negative effects (that I am aware of). In fact, a clinical trial for multiple sclerosis published in 2014 indicated some positive results for sufferers taking simvastatin:
Title: Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial.
Authors: Chataway J, Schuerer N, Alsanousi A, Chan D, MacManus D, Hunter K, Anderson V, Bangham CR, Clegg S, Nielsen C, Fox NC, Wilkie D, Nicholas JM, Calder VL, Greenwood J, Frost C, Nicholas R.
Journal: Lancet. 2014 Jun 28;383(9936):2213-21.
PMID: 24655729 (This article is OPEN ACCESS if you would like to read it)
In this double-blind clinical study (meaning that both the investigators and the subjects in the study were unaware of which treatment was being administered), 140 people with multiple sclerosis were randomly assigned to receive either the statin drug simvastatin (70 people; 40 mg per day for the first month and then 80 mg per day for the remainder of 18 months) or a placebo treatment (70 people).
Patients were seen at 1, 6, 12, and 24 months into the study, with telephone follow-up at months 3 and 18. MRI brain scans were also made at the start of the trial, and then again at 12 months and 25 months for comparative sake.
The results of the study indicate that high-dose simvastatin was well tolerated and reduced the rate of whole-brain shrinkage compared with the placebo treatment. The mean annualised shrinkage rate was significantly lower in patients in the simvastatin group. The researchers were very pleased with this result and are looking to conduct a larger phase III clinical trial.
Other studies have not demonstrated beneficial results from statin treatment, but they have also not observed a worsening of the disease conditions:
Title: A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease.
Authors:Sano M, Bell KL, Galasko D, Galvin JE, Thomas RG, van Dyck CH, Aisen PS.
Journal: Neurology. 2011 Aug 9;77(6):556-63.
PMID: 21795660 (This article is OPEN ACCESS if you would like to read it)
In this study, the investigators recruited a total of 406 individuals were mild to moderate Alzheimer’s disease, and they were randomly assigned to two groups: 204 to simvastatin (20 mg/day, for 6 weeks then 40 mg per day for the remainder of 18 months) and 202 to placebo control treatment. While Simvastatin displayed no beneficial effects on the progression of symptoms in treated individuals with mild to moderate Alzheimer’s disease (other than significantly lowering of cholesterol levels), the treatment also exhibited no effect on worsening the disease.
So what does it all mean?
Research investigating cholesterol and its association with Parkinson’s disease has been going on for a long time. This week a research report involving a huge database was published which indicated that using cholesterol reducing medication could significantly increase one’s risk of developing Parkinson’s disease.
These results do not mean that someone being administered statins is automatically going to develop Parkinson’s disease, but – if the results are replicated – it may need to be something that physicians should consider before prescribing this class of drug.
Whether ongoing clinical trials of statins and Parkinson’s disease should be reconsidered is a subject for debate well above my pay grade (and only if the current results are replicated independently). It could be that statin treatment (or lowering of cholesterol) may have an ‘unmasking’ effect in some individuals, but does this mean that any beneficial effects in other individuals should be discounted? If preclinical data is correct, for example, statins may reduce alpha synuclein clustering in some people which could be beneficial in Parkinson’s.
As we have said above, further research is required in this area before definitive conclusions can be made. This is particularly important given the inconsistencies of the previous research results in the statin and Parkinson’s disease field of investigation.
EDITORIAL NOTE: The information provided by the SoPD website is for information and educational purposes only. Under no circumstances should it ever be considered medical or actionable advice. It is provided by research scientists, not medical practitioners. Any actions taken – based on what has been read on the website – are the sole responsibility of the reader. Any actions being contemplated by readers should firstly be discussed with a qualified healthcare professional who is aware of your medical history. While some of the information discussed in this post may cause concern, please speak with your medical physician before attempting any change in an existing treatment regime.
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Please excuse our use of UK slang in the title of this post, but a group of Australian researchers have recently discovered something really interesting about Parkinson’s disease.
And being a patriotic kiwi, it takes something REALLY interesting for me to even acknowledge that other South Pacific nation. This new finding, however, could be big.
In today’s post, we will review new research dealing with a protein called SOD1, and discuss what it could mean for the Parkinson’s community.
The number of dark pigmented dopamine cells in the substantia nigra are reduced in the Parkinson’s disease brain (right). Source: Adaptd from Memorangapp
Every Parkinson’s-associated website and every Parkinson’s disease researchers will tell you exactly the same thing when describing the two cardinal features in the brain of a person who died with Parkinson’s disease:
- The loss of certain types of cells (such as the dopamine producing cells of the substantia nigra region of the brain – see the image above)
- The clustering (or aggregation) of a protein called Alpha synuclein in tightly packed, circular deposits, called Lewy bodies (see image below).
A Lewy body inside a cell. Source: Adapted from Neuropathology-web
The clustered alpha synuclein protein, however, is not limited to just the Lewy bodies. In the affected areas of the brain, aggregated alpha synuclein can be seen in the branches of cells – see the image below where alpha synuclein has been stained brown on a section of brain from a person with Parkinson’s disease.
Examples of Lewy neurites (indicated by arrows). Source: Wikimedia
Now, one of the problems with our understanding of Parkinson’s disease is disparity between the widespread presence of clustered alpha synuclein and very selective pattern of cell loss. Alpha synuclein aggregation can be seen distributed widely around the affected areas of the brain, but the cell loss will be limited to specific populations of cells.
If the disease is killing a particular population of cells, why is alpha synuclein clustering so wide spread?
So why is there a difference?
We don’t know.
It could be that the cells that die have a lower threshold for alpha synuclein toxicity (we discussed this is a previous post – click here?).
But this question regarding the difference between these two features has left many researchers wondering if there may be some other protein or agent that is actually killing off the cells and then disappearing quickly, leaving poor old alpha synuclein looking rather guilty.
Poor little Mr “A Synuclein” got the blame, but his older brother actually did it! Source: Youtube
And this is a very serious discussion point.
This year of 2017 represents the 200th anniversary of James Parkinson’s first description of Parkinson’s disease, but it also represents the 20th anniversary since the association between alpha synuclein and PD was first established. We have produced almost 7,000 research reports on the topic of alpha synuclein and PD during that time, and we currently have ongoing clinical trials targetting alpha synuclein.
But what if our basic premise – that alpha synuclein is the bad guy – is actually wrong?
Is there any evidence to suggest this?
We are just speculating here, but yes there is.
For example, in a study of 904 brains, alpha synuclein deposits were observed in 11.3% of the brains (or 106 cases), but of those cases only 32 had been diagnosed with a neurodegenerative disorder (Click here to read more on this). The remaining 74 cases had demonstrated none of the clinical features of Parkinson’s disease.
So what else could be causing the cell death?
Well, this week some scientists from sunny Sydney (Australia) reported a protein that could fit the bill.
Sydney. Source: Vagabond
The interesting part of their finding is that the protein is also associated with another neurodegenerative condition: Amyotrophic lateral sclerosis.
Remind me again, what is Amyotrophic lateral sclerosis?
Parkinson’s disease and Amyotrophic lateral sclerosis (ALS) are the second and third most common adult-onset neurodegenerative conditions (respectively) after Alzheimer’s disease. We recently discussed ALS in a previous post (Click here to read that post).
ALS, also known as Lou Gehrig’s disease and motor neuron disease, is a neurodegenerative condition in which the neurons that control voluntary muscle movement die. The condition affects 2 people in every 100,000 each year, and those individuals have an average survival time of two to four years.
You may have heard of ALS due to it’s association with the internet ‘Ice bucket challenge‘ craze that went viral in 2014-15.
The Ice bucket challenge. Source: Forbes
What is the protein associated with ALS?
In 1993, scientists discovered that mutations in the gene called SOD1 were associated with familial forms of ALS (Click here to read more about this). We now know that mutations in the SOD1 gene are associated with around 20% of familial cases of ALS and 5% of sporadic ALS.
The SOD1 gene produces an enzyme called Cu-Zn superoxide dismutase.
This enzyme is a very powerful antioxidant that protects the body from damage caused by toxic free radical generated in the mitochondria.
SOD1 protein structure. Source: Wikipedia
One important note here regarding ALS: the genetic mutations in the SOD1 gene do not cause ALS by affecting SOD1’s antioxidant properties (Click here to read more about this). Rather, researchers believe that the cell death seen in SOD1-associated forms of ALS is the consequences of some kind of toxic effect caused by the mutant protein.
So what did the Aussie researchers find about SOD1 in Parkinson’s disease?
This week, the Aussie researchers published this research report:
Title: Amyotrophic lateral sclerosis-like superoxide dismutase 1 proteinopathy is associated withneuronal loss in Parkinson’s disease brain.
Authors: Trist BG, Davies KM, Cottam V, Genoud S, Ortega R, Roudeau S, Carmona A, De Silva K, Wasinger V, Lewis SJG, Sachdev P, Smith B, Troakes C, Vance C, Shaw C, Al-Sarraj S, Ball HJ, Halliday GM, Hare DJ, Double KL.
Journal: Acta Neuropathol. 2017 May 19. doi: 10.1007/s00401-017-1726-6.
Given that oxidative stress is a major feature of Parkinson’s disease, the Aussie researchers wanted to investigate the role of the anti-oxidant enzyme, SOD1 in this condition. And what they found surprised them.
Heck, it surprised us!
Two areas affected by Parkinson’s disease – the substantia nigra (where the dopamine neurons reside; SNc in the image below) and the locus coeruleus (an area in the brain stem that is involved with physiological responses to stress; LC in the image below) – exhibited little or no SOD1 protein in the control brains.
But in the Parkinsonian brains, there was a great deal of SOD1 protein (see image below).
SO1 staining in PD brain and Control brains. Source: Springer
In the image above, you can see yellowish-brown stained patches in both the PD and control images. This a chemical called neuromelanin and it can be used to identify the dopamine-producing cells in the SNc and LC. The grey staining in the PD images (top) are cells that contain SOD1. Note the lack of SOD1 (grey staining) in the control images (bottom).
Approximately 90% of Lewy bodies in the Parkinson’s affected brains contained SOD1 protein. The investigators did report that the levels of SOD1 protein varied between Lewy bodies. But the clustered (or ‘aggregated’) SOD1 protein was not just present with alpha synuclein, often it was found by itself in the degenerating regions.
The researchers occasional saw SOD1 aggregation in regions of age-matched control brains, and they concluded that a very low level of SOD1 must be inherent to the normal ageing process.
But the density of SOD1 clustering was (on average) 8x higher in the SNc and 4x higher in the LC in the Parkinsonian brain compared to age-matched controls. In addition, the SOD1 clustering was significantly greater in these regions than all of the non-degenerating regions of the same Parkinson’s disease brains.
The investigators concluded that these data suggest an association between SOD1 aggregation and neuronal loss in Parkinson’s disease. Importantly, the presence of SOD1 aggregations “closely reflected the regional pattern of neuronal loss”.
They also demonstrated that the SOD1 protein in the Parkinsonian brain was not folded correctly, a similar characteristic to alpha synuclein. A protein must fold properly to be able to do it’s assigned jobs. By not folding into the correct configuration, the SOD1 protein could not do it’s various functions – and the investigators observed a 66% reduction in SOD1 specific activity in the SNc of the Parkinson’s disease brains.
Interestingly, when the researchers looked at the SNc and LC of brains from people with ALS, they identified SOD1 aggregates matching the SOD1 clusters they had seen in these regions of the Parkinson’s disease brain.
Is this the first time SOD1 has been associated with Parkinson’s disease?
No, but it is the first major analysis of postmortem Parkinsonian brains. SOD1 protein in Lewy bodies has been reported before:
Title: Cu/Zn superoxide dismutase-like immunoreactivity is present in Lewy bodies from Parkinson disease: a light and electron microscopic immunocytochemical study
Authors: Nishiyama K, Murayama S, Shimizu J, Ohya Y, Kwak S, Asayama K, Kanazawa I.
Journal: Acta Neuropathol. 1995;89(6):471-4.
The investigators behind this study reported SOD1 protein was present in Lewy bodies, in the substantia nigra and locus coeruleus of brains from five people with Parkinson’s disease. Interestingly, they showed that SOD1 is present in the periphery of the Lewy body, similar to alpha synuclein. Both of these protein are present on the outside of the Lewy body, as opposed to another Parkinson’s associated protein, Ubiquitin, which is mainly present in the centre (or the core) of Lewy bodies (see image below).
A more recent study also demonstrated SOD1 protein in the Parkinsonian brain, including direct interaction between SOD1 and alpha synuclein:
Title: α-synuclein interacts with SOD1 and promotes its oligomerization
Authors: Helferich AM, Ruf WP, Grozdanov V, Freischmidt A, Feiler MS, Zondler L, Ludolph AC, McLean PJ, Weishaupt JH, Danzer KM.
Journal: Mol Neurodegener. 2015 Dec 8;10:66.
PMID: 26643113 (This article is OPEN ACCESS if you would like to read it)
These researchers found that alpha synuclein and SOD1 interact directly, and they noted that Parkinson’s disease related mutations in alpha synuclein (A30P, A53T) and ALS associated mutation in SOD1 (G85R, G93A) modify the binding of the two proteins to each other. They also reported that alpha synuclein accelerates SOD1 aggregation in cell culture. This same group of researchers published another research report last year in which they noted that aggregated alpha synuclein increases SOD1 clustering in a mouse model of ALS (Click here for more on this).
Are there any genetic mutations in the SOD1 gene that are associated with Parkinson’s disease?
Two studies have addressed this question:
Title: Sequence of the superoxide dismutase 1 (SOD 1) gene in familial Parkinson’s disease.
Authors: Bandmann O, Davis MB, Marsden CD, Harding AE.
Journal: J Neurol Neurosurg Psychiatry. 1995 Jul;59(1):90-1.
PMID: 7608718 (This article is OPEN ACCESS if you would like to read it)
And then in 2001, a second analysis:
Title: Genetic polymorphisms of superoxide dismutase in Parkinson’s disease.
Authors: Farin FM, Hitosis Y, Hallagan SE, Kushleika J, Woods JS, Janssen PS, Smith-Weller T, Franklin GM, Swanson PD, Checkoway H.
Journal: Mov Disord. 2001 Jul;16(4):705-7.
Both studies found no genetic variations in the SOD1 gene that were more frequent in the Parkinson’s affected community than the general population. So, no, there are no SOD1 genetic mutations that are associated with Parkinson’s disease.
Are there any treatments targeting SOD1 that could be tested in Parkinson’s disease?
Great question. Yes there are. And they have already been tested in models of PD:
Title: The hypoxia imaging agent CuII(atsm) is neuroprotective and improves motor and cognitive functions in multiple animal models of Parkinson’s disease.
Authors: Hung LW, Villemagne VL, Cheng L, Sherratt NA, Ayton S, White AR, Crouch PJ, Lim S, Leong SL, Wilkins S, George J, Roberts BR, Pham CL, Liu X, Chiu FC, Shackleford DM, Powell AK, Masters CL, Bush AI, O’Keefe G, Culvenor JG, Cappai R, Cherny RA, Donnelly PS, Hill AF, Finkelstein DI, Barnham KJ.
Title: J Exp Med. 2012 Apr 9;209(4):837-54.
PMID: 22473957 (This article is OPEN ACCESS if you would like to read it)
CuII(atsm) is a drug that is currently under clinical investigation as a brain imaging agent for detecting hypoxia (damage caused by lack of oxygen – Click here to read more about this).
The researchers conducting this study, however, were interested in this compound for other reasons: CuII(atsm) is also a highly effective scavenger of a chemical called ONOO, which can be very toxic. CuII(atsm) not only inhibits this toxicity, but it also blocks the clustering of alpha synuclein. And given that CuII(atsm) is capable of crossing the blood–brain barrier, these investigators wanted to assess the drug for its ability to rescue model of Parkinson’s disease.
And guess what? It did!
And not just in one model of Parkinson’s disease, but FOUR!
The investigators even waited three days after giving the neurotoxins to the mice before giving the CuII(atsm) drug, and it still demonstrated neuroprotection. It also improved the behavioural features of these models of Parkinson’s disease.
Is CuII(atsm) being tested for anything else in Clinical trials?
Yes, there is a clinical trial ongoing for ALS in Australia.
The Phase I study, being run by Collaborative Medicinal Development Pty Limited, is a dose escalating study of Cu(II)ATSM to determine if this drug is safe for use in ALS (Click here for more on this study).
Cu(II)ATSM is an orally administered drug that inhibits the activity of misfolded SOD1 protein. It has been shown to paradoxically increase mutant SOD1 protein in a mouse model of ALS, but it also provides neuroprotection and improves the outcome for these mice (Click here to read more on this).
If this trial is successful, it would be interesting to test this drug on a cohort of people with Parkinson’s disease. Determining which subgroup of the Parkinson’s affected community would most benefit from this treatment is still to be determined. There is some evidence published last year that suggests people with genetic mutations in the Parkinson’s associated gene PARK2 could benefit from the approach (Click here to read more on this). More research, however, is needed in this area.
So what does it all mean?
Right, so summing up, a group of Australian researchers have reported that the ALS associated protein SOD1 is closely associated with the cell death that we observe in the brains of people with Parkinson’s disease.
They suggest that this could highlight a common mechanisms of toxic SOD1 aggregation in both Parkinson’s disease and ALS. Individuals within the Parkinson’s affected community do not appear to have any genetic mutations in the SOD1 gene, which makes this finding is very interesting.
What remains to be determined is whether SOD1 aggregation is a “primary pathological event”, or if it is secondary to some other disease causing agent. We are also waiting to see if a clinical trial targeting SOD1 in ALS is successful. If it is, there may be good reasons for targeting SOD1 as a novel treatment for Parkinson’s disease.
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