We have previously discussed the importance of the right foods for people with Parkinson’s on this blog – Click here for a good example.
Recently, new data from researchers in Sweden points towards the benefits of a specific component of fish in particular.
It is a protein called β-parvalbumin, which has some very interesting properties.
In today’s post, we discuss what beta-parvalbumin is, review the new research findings, and consider how this new information could be applied to Parkinson’s.
A very old jaw bone. Source: Phys
In 2003, researchers found 34 bone fragments belonging to a single individual in a cave near Tianyuan, close to Beijing (China).
But it was not the beginning of a potential murder investigation.
This was the start of something far more interesting.
Naming the individual “Tianyuan man”, the researchers have subsequently found that “many present-day Asians and Native Americans” are genetically related to this individual. His bones represented one of the oldest set of modern human remains ever found in the eastern Eurasia region.
Tianyuan caves. Source: Sciencemag
But beyond the enormous family tree, when researchers further explored specific details about his jaw bone (or lower mandible as it is called) they found something else that was very interesting about Tianyuan man:
Title: Stable isotope dietary analysis of the Tianyuan 1 early modern human.
Authors: Hu Y, Shang H, Tong H, Nehlich O, Liu W, Zhao C, Yu J, Wang C, Trinkaus E, Richards MP.
Journal: Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):10971-4.
PMID: 19581579 (This research article is OPEN ACCESS if you would like to read it)
In this study, the investigators analysed the carbon and nitrogen isotopes found within bone collagen samples taken from the jaw bone of Tianyuan man. In humans, the carbon and nitrogen isotope values indicate the sources of dietary protein over many years of life.
The researchers found that a substantial portion of Tianyuan man’s diet 40,000 years ago came from freshwater fish.
Interesting preamble, but what does this have to do with Parkinson’s?
An Advanced Glycation Endproduct (or AGE) is a protein or lipid that has become glycated.
Glycation is a haphazard process that impairs the normal functioning of molecules. It occurs as a result of exposure to high amounts of sugar. These AGEs are present at above average levels in people with diabetes and various ageing-related disorders, including neurodegenerative conditions. AGEs have been shown to trigger signalling pathways within cells that are associated with both oxidative stress and inflammation, but also cell death.
RAGE (or receptor of AGEs) is a molecule in a cell membrane that becomes activated when it interacts with various AGEs. And this interaction mediates AGE-associated toxicity issues. Recently researchers found that that neurons carrying the Parkinson’s associated LRRK2 G2019S genetic variant are more sensitive to AGEs than neurons without the genetic variant.
In today’s post we will look at what AGE and RAGE are, review the new LRRK2 research, and discuss how blocking RAGE could represent a future therapeutic approach for treating Parkinson’s.
The wonder of ageing. Source: Club-cleo
NOTE: Be warned, the reading of this post may get a bit confusing. We are going to be discussing ageing (as in the body getting old) as well as AGEing (the haphazard process processing of glycation). For better clarification, lower caps ‘age’ will refer to getting old, while capitalised ‘AGE’ will deal with that glycation process. I hope this helps.
Ageing means different things to different people.
For some people ageing means more years to add to your life and less activity. For others it means more medication and less hair. More wrinkles and less independence; more arthritis and less dignity; More candles, and less respect from that unruly younger generation; More… what’s that word I’m thinking of? (forgetfulness)… and what were we actually talking about?
Wisdom is supposed to come with age, but as the comedian/entertainer George Carlin once said “Age is a hell of a price to pay for wisdom”. I have to say though, that if I had ever met Mr Carlin, I would have suggested to him that I’m feeling rather ripped off!
George Carlin. Source: Thethornycroftdiatribe
Whether we like it or not, from the moment you are born, ageing is an inevitable part of our life. But this has not stopped some adventurous scientific souls from trying to understand the process, and even try to alter it in an attempt to help humans live longer.
Regardless of whether you agree with the idea of humans living longer than their specified use-by-date, some of this ageing-related research could have tremendous benefits for neurodegenerative conditions, like Parkinson’s.
What do we know about the biology of ageing?
“Repurposing” in medicine refers to taking drugs that are already approved for the treatment of one condition and testing them to see if they are safe and effective in treating other diseases. Given that these clinically available drugs have already been shown to be safe in humans, repurposing represents a method of rapidly acquiring new potential therapeutics for a particular condition.
The antidepressant, Trazodone, has recently been proposed for repurposing to neurodegenerative conditions, such as Parkinson’s.
In today’s post we will look at what Trazodone is, why it is being considered for repurposing, and we will review the results of a new primate study that suggests it may not be ideal for the task.
Opinions. Everyone has them. Source: Creativereview
I am regularly asked by readers to give an opinion on specific drugs and supplements.
And I usually cut and paste in my standard response: I can not answer these sorts of questions as I am just a research scientist not a clinician; and even if I was a clinician, it would be unethical for me to comment as I have no idea of your medical history.
In many of these cases, there simply isn’t much proof that the drug/supplement has any effect in Parkinson’s, so it is hard to provide any kind of “opinion”. But even if there was proof, I don’t like to give opinions.
Eleven out of every ten opinions are usually wrong (except in the head of the beholder) so why would my opinion be any better? And each individual is so different, why would one particular drug/supplement work the same for everyone?
In offering an answer to “my opinion” questions, I prefer to stick to the “Just the facts, ma’am” approach and I focus solely on the research evidence that we have available (Useless pub quiz fact: this catchphrase “Just the facts, ma’am” is often credited to Detective Joe Friday from the TV series Dragnet, and yet he never actually said it during any episode! – Source).
Detective Joe Friday. Source: Wikipedia
Now, having said all of that, there is one drug in particularly that is a regular topic of inquiry (literally, not a week goes by without someone asking about): an antidepressant called Trazodone.
What is Trazodone?
In your brain there are different types of cells.
Firstly there are the neurons (the prima donnas that we believe do most of the communication of information). Next there are the microglia cells, which act as the first and main line of active immune defence in the brain. There are also oligodendrocyte, that wrap protective sheets around the branches of the neurons and help them to pass signals.
And then there are astrocytes.
These are the ‘helper cells’ which maintain a comfortable environment for the neurons and aid them in their task. Recently, researchers in California reported an curious observation in the Parkinsonian brain: some astrocytes have entered an altered ‘zombie’-like state. And this might not be such a good thing.
In today’s post, we’ll review the research and discuss what it could mean – if independently replicated – for the Parkinson’s community.
Zombies. Source: wallpapersbrowse
I don’t understand the current fascination with zombies.
There are books, movies, television shows, video games. All dealing with the popular idea of dead bodies wandering the Earth terrifying people. But why the fascination? Why does this idea have such appeal to a wide portion of the populous?
I just don’t get it.
Even more of a mystery, however, is where the modern idea of the ‘zombie’ actually came from originally.
You see, no one really knows.
Huh? What do you mean?
Some people believe that the word ‘zombie’ is derived from West African languages – ndzumbi means ‘corpse’ in the Mitsogo language of Gabon, and nzambi means the ‘spirit of a dead person’ in the Kongo language. But how did a word from the African continent become embedded in our psyche?
Others associate the idea of a zombie with Haitian slaves in the 1700s who believed that dying would let them return back to lan guinée (African Guinea) in a kind of afterlife. But apparently that freedom did not apply to situations of suicide. Rather, those who took their own life would be condemned to walk the Hispaniola plantations for eternity as an undead slave. Perhaps this was the starting point for the ‘zombie’.
More recently the word ‘zonbi’ (not a typo) appeared in the Louisiana Creole and the Haitian Creole and represented a person who is killed and was then brought to life without speech or free will.
Delightful stuff for the start of a post on Parkinson’s research, huh?
But we’re going somewhere with this.
On Saturday 7th January, 2018, one of the world’s largest pharmaceutical companies – Pfizer – announced that it was abandoning research efforts focused on finding new drugs for Alzheimer’s and Parkinson’s.
Naturally, the Parkinson’s and Alzheimer’s communities reacted with disappointment to the news, viewing it as a demoralising tragedy. And there was genuine concern that other pharmaceutical companies would follow suit in the wake of this decision.
Those fears, however, are unfounded.
In today’s post we will look at some of the reasons underlying Pfizer’s decision, why our approach to failure is wrong, why Pfizer will definitely be back, and what the Parkinson’s community can do about it all.
1. Our approach to failure
Matthew Syed. Source: Amazon
In the first chapter of his book, Syed makes comparisons between the way the aviation industry and the medical profession approach failure, pointing out the processes that follow situations when a disasters occur. In the aviation industry, when any event occurs there is a major investigative process that starts with the recovery of the black boxes. The aviation industry uses this system of investigation to learn from every single incident. It makes the information available to all and this helps with re-thinking everything from cockpit ergonomics and design to air traffic controller procedures. Even the airline companies are keen to be seen to be involved in this process of investigation. Failure, while unfortunate, is not shameful or stigmatising, but rather embraced and enlightening.
In addition, Syed points out that when an airline pilot sits down in his/her cockpit, their neck is also on the line if something goes wrong. Thus, it is in their best interest that the flight should be successful. And this is another reason why the aviation industry takes the reporting of failure so seriously. Everyone benefits from learning from previous situations. And all of this comes together with the observation that 2017 was the safest year on record for flying (based on deaths/flights – Source).
Here at the SoPD, we regularly talk about the ‘bad boy’ of Parkinson’s disease – a protein called Alpha Synuclein.
Twenty years ago this year, genetic variations were identified in the alpha synuclein gene that increase one’s risk of developing Parkinson’s. In addition, alpha synuclein protein was found to be present in the Lewy bodies that are found in the brains of people with Parkinson’s. Subsequently, alpha synuclein has been widely considered to be the villain in this neurodegenerative condition and it has received a lot of attention from the Parkinson’s research community.
But it is not the only protein that may be playing a role in Parkinson’s.
Today’s post is all about TAU.
I recently informed my wife that I was thinking of converting to Taoism.
She met this declaration with more of a smile than a look of shock. And I was expecting the latter, as shifting from apatheism to any form of religious belief is a bit of a leap you will appreciate.
When asked to explain myself, I suggested to her that I wanted to explore the mindfulness of what was being proposed by Lao Tzu (the supposed author of the Tao Te Ching – the founding document of Taoism).
This answer also drew a smile from her (no doubt she was thinking that Simon has done a bit of homework to make himself sound like he knows what he was talking about).
But I am genuinely curious about Taoism.
Most religions teach a philosophy and dogma which in effect defines a person. Taoism – which dates from the 4th century BCE – flips this concept on its head. It starts by teaching a single idea: The Tao (or “the way”) is indefinable. And then it follows up by suggesting that each person should discover the Tao on their own terms. Given that most people would prefer more concrete definitions in their own lives, I can appreciate that a lot of folks won’t go in for this approach.
Personally speaking, I quite like the idea that the Tao is the only principle and everything else is a just manifestation of it.
According to Taoism, salvation comes from just one source: Following the Tao.
Oh and don’t worry, I’m not going to force any more philosophical mumbo jumbo on you – Taoism is just an idea I am exploring as part of a terribly clichéd middle-life crisis I’m working my way through (my wife’s actual response to all of this was “why can’t you just be normal and go buy a motor bike or something?”).
My reason for sharing this, however, is that this introduction provides a convenient segway to what we are actually going to talk about in this post.
You see, some Parkinson’s researchers are thinking that salvation from neurodegenerative conditions like Parkinson’s will come from just one source: Following the TAU.
What is TAU?
Last year – two years after actor Robin Williams died – his wife Susan Schneider Williams wrote an essay entitled The terrorist inside my husband’s head, published in the journal Neurology.
It is a heartfelt/heartbreaking insight into the actor’s final years. It also highlights the plight of many who are diagnosed with Parkinson’s disease, but experience an array of additional symptoms that leave them feeling that something else is actually wrong.
Today’s post is all about Dementia with Lewy bodies (or DLB). In particular, we will review the latest refinements and recommendations of the Dementia with Lewy Bodies Consortium, regarding the clinical and pathologic diagnosis of DLB.
Robin Williams. Source: Quotesgram
On the 28th May of 2014, the actor Robin Williams was diagnosed with Parkinson’s disease.
At the time, he had a slight tremor in his left hand, a slow shuffling gait and mask-like face – some of the classical features of Parkinson’s disease.
According to his wife, the diagnosis gave the symptoms Robin had been experiencing a name. And this brought her a sense of relief and comfort. Now they could do something about the problem. Better to know what you are dealing with rather than be left unsure and asking questions.
But Mr Williams sensed that something else was wrong, and he was left unsure and asking questions. While filming the movie Night at the Museum 3, Williams experienced panic attacks and regularly forgot his lines. He kept asking the doctors “Do I have Alzheimer’s? Dementia? Am I schizophrenic?”
Williams took his own life on the 11th August 2014, and the world mourned the tragic loss of a uniquely talented performer.
When the autopsy report came back from the coroner, however, it indicated that the actor had been misdiagnosed.
He didn’t have Parkinson’s disease.
What he actually had was Dementia with Lewy bodies (or DLB).
What is Dementia with Lewy bodies?
In Silicon valley (California), everyone is always looking for the “next killer app” – the piece of software (or application) that is going to change the world. The revolutionary next step that will solve all of our problems.
The title of today’s post is a play on the words ‘killer app’, but the ‘app’ part doesn’t refer to the word application. Rather it relates to the Alzheimer’s disease-related protein Amyloid Precursor Protein (or APP). Recently new research has been published suggesting that APP is interacting with a Parkinson’s disease-related protein called Leucine-rich repeat kinase 2 (or LRRK2).
The outcome of that interaction can have negative consequences though.
In today’s post we will discuss what is known about both proteins, what the new research suggests and what it could mean for Parkinson’s disease.
Seattle. Source: Thousandwonders
In the mid 1980’s James Leverenz and Mark Sumi of the University of Washington School of Medicine (Seattle) made a curious observation.
After noting the high number of people with Alzheimer’s disease that often displayed some of the clinical features of Parkinson’s disease, they decided to examined the postmortem brains of 40 people who had passed away with pathologically confirmed Alzheimer’s disease – that is, an analysis of their brains confirmed that they had Alzheimer’s.
What the two researchers found shocked them:
Title: Parkinson’s disease in patients with Alzheimer’s disease.
Authors: Leverenz J, Sumi SM.
Journal: Arch Neurol. 1986 Jul;43(7):662-4.
Of the 40 Alzheimer’s disease brains that they looked at nearly half of them (18 cases) had either dopamine cell loss or Lewy bodies – the characteristic features of Parkinsonian brain – in a region called the substantia nigra (where the dopamine neurons are located). They next went back and reviewed the clinical records of these cases and found that rigidity, with or without tremor, had been reported in 13 of those patients. According to their analysis 11 of those patients had the pathologic changes that warranted a diagnosis of Parkinson’s disease.
And the most surprising aspect of this research report: Almost all of the follow up studies, conducted by independent investigators found exactly the same thing!
It is now generally agreed by neuropathologists (the folks who analyse sections of brain for a living) that 20% to 50% of cases of Alzheimer’s disease have the characteristic round, cellular inclusions that we call Lewy bodies which are typically associated with Parkinson disease. In fact, in one analysis of 145 Alzheimer’s brains, 88 (that is 60%!) had chemically verified Lewy bodies (Click here to read more about that study).
A lewy body (brown with a black arrow) inside a cell. Source: Cure Dementia
Oh, and if you are wondering whether this is just a one way street, the answer is “No sir, this phenomenon works both ways”: the features of the Alzheimer’s brain (such as the clustering of a protein called beta-amyloid) are also found in many cases of pathologically confirmed Parkinson’s disease (Click here and here to read more about this).
So what are you saying? Alzheimer’s and Parkinson’s disease are the same thing???
People with high socioeconomic status jobs are believed to be better off in life.
New research published last week by the Centre for Disease Control, however, suggests that this may not be the case with regards to one’s risk of developing Parkinson’s disease.
In today’s post we will review the research and discuss what it means for our understanding of Parkinson’s disease.
The impact of socioeconomic status. Source: Medicalxpress
In 2013, a group of researchers at Carnegie Mellon University found a rather astonishing but very interesting association:
Children from lower socioeconomic status have shorter telomeres as adults.
Yeah, wow, strange… sorry, but what are telomeres?
Do you remember how all of your DNA is wound up tightly into 23 pairs of chromosomes? Well, telomeres are at the very ends of each of those chromosomes. They are literally the cap on each end. The name is derived from the Greek words ‘telos‘ meaning “end”, and ‘merοs‘ meaning “part”.
Telomeres are regions of repetitive nucleotide sequences (think the As, Gs, Ts, & Cs that make up your DNA) at each end of a chromosome. Their purpose seems to involve protecting the end of each chromosome from deteriorating or fusing with neighbouring chromosomes. Researchers also use their length is a marker of ageing because every time a cell divides, the telomeres on each chromosome gradually get shorter.
Our apologies to anyone who is squeamish about needles, but this is generally how most people get their seasonal flu vaccination.
Why are we talking about flu vaccines?
Because new research, published last week, suggests everyone should be going out and getting them in the hope of reducing our risk of Parkinson’s disease.
In today’s post we will review the research, exactly what a flu vaccine is, and how it relates to Parkinson’s disease.
Electron micro photograph of Influenza viruses. Source: Neuro-hemin
Long time readers of the SoPD blog will know that I have a particular fascination with theories regarding a viral or microbial role in the development of Parkinson’s disease (the ‘idiopathic’ – or arising spontaneously – variety at least).
Numerous reasons. For example:
- The targeted nature of the condition (why are only selective groups of cells are lost in the brain during the early stages of the condition?)
- The unexplained protein aggregation (eg. Lewy bodies; could they be a cellular defensive mechanism against viruses/microbes – Click here to read more on this idea)
- The asymmetry of the onset (why do tremors start on only one side of the body in most cases?)
And we have previously discussed research here on the website regarding possible associations between Parkinson’s disease and and various types of viruses (including Hepatitis C, Herpes Simplex, and Influenza).
Today we re-visit influenza as new research has been published on this topic.
What is influenza?
Influenza is a single-stranded, RNA virus of the orthomyxovirus family of viruses.
A schematic of the influenza virus. Source: CDC
It is the virus that causes ‘the flu’ – (runny nose, sore throat, coughing, and fatigue) – with the symptom arising two days after exposure and lasting for about a week. In humans, there are three types of influenza viruses, called Type A, Type B, and Type C. Type A are the most virulent in humans. The influenza virus behind both of the outbreaks in the 1918 pandemic was a Type A.
Schematic of Influenza virus. Source: Bcm
As the image above indicates, the influenza virus has a rounded shape, with “HA” (hemagglutinin) and “NA” (neuraminidases) proteins on the outer surface of the virus. The HA protein allows the virus to stick to the outer membrane of a cell. The virus can then infect the host cell and start the process of reproduction – making more copies of itself. The NA protein is required for the virus to exit the host cell and go on to infect other cells. Different influenza viruses have different combinations of hemagglutinin and neuraminidase proteins, hence the numbering. For example, the Type A virus that caused the outbreaks in the 1918 pandemic was called H1N1.
Inside the influenza virus, there are there are eight pieces (segments) of RNA, hence the fact that influenza is an RNA virus. Some viruses have DNA while others have RNA. The 8 segments of RNA provide the information that is required for making new copies of the virus. Each of these segments provides the instructions for making one or more proteins of the virus (eg. segment 4 contains the instructions to make the HA protein).
The 8 segments of RNA in influenza. Source: URMC
The Influenza virus is one of the most changeable viruses we are aware of, which makes it such a tricky beast to deal with. Influenza uses two techniques to change over time. They are called shift and drift.
Shifting is an sudden change in the virus, which produces a completely new combination of the HA and NA proteins. Virus shift can take place when a person or animal is infected with two different subtypes of influenza. When new viral particles are generated inside the cell, there is a mix of both subtypes of virus which gives rise to an all new type of virus.
An example of viral shift. Source: Bcm
Drifting is the process of random genetic mutation. Gradual, continuous, spontaneous changes that occur when the virus makes small “mistakes” during the replication of its RNA. These mistakes can results in a slight difference in the HA or NA proteins, and although those changes are small, they can be significant enough that the human immune system will no longer recognise and attack the virus. This is why you can repeatedly get the flu and why flu vaccines must be administered each year to combat new forms of circulating influenza virus.
What is a flu jab exactly?
Seasonal flu vaccination is a treatment that is given each year to minimise the risk of being infected by an influenza virus.
The ‘seasonal’ part of the label refers to the fact that the flu vaccine changes each year. Most flu vaccines target three strains of the viruses (and are thus called ‘Trivalent flu vaccines’) which are selected each year based on data collected by various health organisations around the world.
The three chosen viruses for a particular year are traditionally injected into and grown in hens’ eggs, then harvested and purified before the viral particles are chemically deactivated. The three dead viruses are then pooled together and packaged as a vaccine. As you can see in the image below, the process of vaccine production is laborious and takes a full year:
The process of vaccine production. Source: Linkedin
By injecting people with the dead viruses from three different strains of the influenza virus, however, the immune system has the chance to build up a defence against those viruses without the risk of the individual becoming infected (the dead viruses in the vaccine can not infect cells).
Flu vaccines cause the immune system to produce antibodies which are used by the immune system to help defend the body against future attacks from viruses. These antibodies generally take about two weeks to develop in the body after vaccination.
As we have said most injected flu vaccines protect against three types of flu virus. Generally each of the three viruses is taken from the following strains:
- Influenza A (H1N1) – the strain of flu that caused the swine flu pandemic in 2009.
- Influenza A (H3N2) – a strain of flu that mainly affects the elderly and people at risk with long term health conditions. In 2016/17 the vaccine contains an A/Hong Kong/4801/2014 H3N2-like virus.
- Influenza B – a strain of flu that particularly affects children. In 2016/17 the vaccine contains B/Brisbane/60/2008-like virus.
How effective are the vaccines?
Well, it really depends on which strains of influenza are going to affect the most people each year, and this can vary greatly. Overall, however, research from the Centers for Disease Control and Prevention (or CDC) suggests that the seasonal flu vaccine reduces the chance of getting sick by approximately 50% (Source). Not bad when you think about it.
Ok, so are there actually any connections between influenza and Parkinson’s disease?
This question is up for debate.
There are certainly some tentative associations between influenza and Parkinson’s disease. Early on, those connections were coincidental, but more recently research is suggesting that there could be a closer relationship.
Between January 1918 and December 1920 there were two outbreaks of an influenza virus during an event that became known as the 1918 flu pandemic. Approximately 500 million people across the globe were infected by the H1N1 influenza virus, and this resulted in 50 to 100 million deaths (basically 3-5% of the world’s population). Given that is occurred during World War 1, censors limited the media coverage of the pandemic in many countries in order to maintain morale. The Spanish media were not censored, however, and this is why the 1918 pandemic is often referred to as the ‘Spanish flu’.
1918 Spanish flu. Source: Chronicle
At the same time that H1N1 was causing havoc, a Romanian born neurologist named Constantin von Economo reported a number of unusual symptoms which were referred to as encephalitis lethargica (EL). This disease left victims in a statue-like condition, speechless and motionless.
Constantin von Economo. Source: Wikipedia
By 1926, EL had spread around the world, with nearly five million people being affected. Many of those who survived never returned to their pre-existing state of health. They were left frozen in an immobile state.
An individual with encephalitis lethargica. Source: Baillement
Historically, it was believed that EL was caused by the influenza virus from the 1918 Spanish influenza pandemic. This was largely due to a temporal association (things happening at approximately the same time) and the finding of influenza antigens in some of the suffers of EL (Click here to read more about this).
And then there were also the observations of Dr Oliver Sacks:
Amazing guy! Dr Oliver Sacks. Source: Pensologosou
During the late 1960s, while employed as a neurologist at Beth Abraham Hospital’s chronic-care facility in New York, Dr Sacks began working with a group of survivors of EL, who had been left immobile by the condition. He treated these individuals with L-dopa (the standard treatment for Parkinson’s disease now, but it was still experimental at the time) and he observed them become miraculously reanimated. The sufferers went from being completely motionless to suddenly active and mobile. Unfortunately the beneficial effects were very short lived.
You may be familiar with Dr Sack’s book about his experience of treating these patients. It is called ‘Awakenings’ and it was turned into a film starring actors Robin Williams and Robert De Niro.
Robin Williams and Robert De Niro in Awakenings. Source: Pinterest
More recent, postmortem analysis of the brains of EL patients found an absence of influenza RNA – click here for more on this), which has led many researchers to simply reject the association between influenza and EL. The evidence supporting this rejection, however, has also been questioned (click here to read more on this), leaving the question of an association between influenza and EL still open for debate.
I think it’s fair to say that we genuinely do not know what caused EL. Whether it was influenza or not is still be undecided.
Ok, so that was the coincidental evidence. Has there been a more direct connection between influenza and Parkinson’s disease?
This is Dr Richard J Smeyne:
He is a research faculty member in the Department of Developmental Neurobiology at St. Jude Children’s Research Hospital (Memphis, Tennessee).
He has had a strong interest in what role viruses like influenza could be playing in the development of Parkinson’s disease, and his research group has published several interesting research reports on this topic, including:
Title: Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration.
Author: Jang H, Boltz D, Sturm-Ramirez K, Shepherd KR, Jiao Y, Webster R, Smeyne RJ.
Journal: Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):14063-8.
PMID: 19667183 (This article is OPEN ACCESS if you would like to read it)
Dr Smeyne and his colleagues found in this study that when they injected the highly infectious A/Vietnam/1203/04 (H5N1) influenza virus into mice, the virus progressed from the periphery (outside the brain) into the brain itself, where it induced Parkinson’s disease-like symptoms.
The virus also caused a significant increase in the accumulation of the Parkinson’s disease-associated protein Alpha Synuclein. In addition, they witnessed the loss of dopamine neurons in the midbrain of the mice at 60 days after the infection – that cell loss resembling what is observed in the brains of people with Parkinson’s disease.
Naturally this got the researchers rather excited!
In a follow up study on H5N1, however, these same researchers found that the Parkinson’s disease-like symptoms that they observed were actually only temporary:
Title: Inflammatory effects of highly pathogenic H5N1 influenza virus infection in the CNS of mice.
Authors: Jang H, Boltz D, McClaren J, Pani AK, Smeyne M, Korff A, Webster R, Smeyne RJ.
Journal: Journal for Neuroscience, 2012 Feb 1;32(5):1545-59.
PMID: 22302798 (This article is OPEN ACCESS if you would like to read it)
Dr Smeyne and colleagues repeated the 2009 study and had a closer look at what was happening to the dopamine neurons that were disappearing at 60 days post infection with the virus. When they looked at mice at 90 days post infection, they found that the number of dopamine neurons had returned to their normal number. This pattern was also observed in a region of the brain called the striatum, where the dopamine neurons release their dopamine. The levels of dopamine dropped soon after infection, but rose back to normal by 90 days post infection.
How does that work?
The results suggest that rather than developing new dopamine neurons in some kind of miraculous regenerative process, the dopamine neurons that were infected by the virus simply stopped producing dopamine while they dealt with the viral infection. Once the crisis was over, the dopamine neurons went back to life as normal. And because the researcher use chemicals in the production of dopamine to identify the dopamine neurons, they mistakenly thought that the cells had died when they couldn’t see those chemicals.
One interesting observation from the study was that H5N1 infection in mice induced a long-lasting inflammatory response in brain. The resident helper cells, called microglia, became activated by the infection, but remained active long after the dopamine neurons returned to normal service. The investigators speculated as to whether this activation may be a contributing factor in the development of neurodegenerative disorders.
And this is an interesting idea.
In a follow up study, they investigated this further by looking another influenza viruse that doesn’t actually infect cells in the brain:
Title: Induction of microglia activation after infection with the non-neurotropic A/CA/04/2009 H1N1 influenza virus.
Author: Sadasivan S, Zanin M, O’Brien K, Schultz-Cherry S, Smeyne RJ.
Journal: PLoS One. 2015 Apr 10;10(4):e0124047.
PMID: 25861024 (This article is OPEN ACCESS if you would like to read it)
In this study, a different type of influenza (H1N1) was tested, and while it did not infect the brain, it did cause the microglia cells to flare up and become activated. And again, this activation was sustained for a long period after the infection (at least 90 days).
This is a really interesting finding and relates to the idea of a “double hit” theory of Parkinson’s disease, in which the virus doesn’t necessarily cause Parkinson’s disease but may play a supplemental or distractionary role, grabbing the attention of the immune system while some other toxic agent is also attacking the body. Or perhaps simply weakening the immune system by forcing it to fight on multiple fronts. Alone the two would not cause as much damage, but in combination they could deal a terrible blow.
So what was the flu vaccine research published last week?
Again, from Dr Smeyne’s research group, this report looked whether the combination of an influenza virus infection plus a toxic agent gave a worse outcome than just the toxic agent by itself. An interesting idea for a study, but then the investigators threw in another component: what effect would a influenza vaccine have in such an experiment. And the results are interesting:
Title: Synergistic effects of influenza and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can be eliminated by the use of influenza therapeutics: experimental evidence for the multi-hit hypothesis
Authors: Sadasivan S, Sharp B, Schultz-Cherry S, & Smeyne RJ
Journal: npj Parkinson’s Disease 3, 18
PMID: N/A (This article is OPEN ACCESS if you would like to read it)
What the researchers found was that H1N1-infected mice that were treated with a neurotoxin (called MPTP – a toxin that specifically kills dopamine neurons) exhibit a 20% greater loss of dopamine neurons than mice that were treated with MPTP alone.
And this increase in dopamine neuron loss was completely eliminated by giving the mice the influenza vaccination. The researchers concluded that the results demonstrate that multiple insults (such as a viral infection and a toxin) can enhance the impact, and may even be significant in allowing an individual to cross a particular threshold for developing a disease.
It’s an intriguing idea.
Have epidemiologists (population data researchers) ever investigated a connection between Parkinson’s disease and influenza?
And yes they have:
Title: Parkinson’s disease or Parkinson symptoms following seasonal influenza.
Authors: Toovey S, Jick SS, Meier CR.
Journal: Influenza Other Respir Viruses. 2011 Sep;5(5):328-33.
PMID: 21668692 (This article is OPEN ACCESS if you would like to read it)
In this first study, the researcher used the UK‐based General Practice Research Database to perform a case–control analysis (that means they compare an affected population with an unaffected ‘control’ population. They identified individual cases who had developed an ‘incident diagnosis’ of Parkinson’s disease or Parkinson’s like symptoms between 1994 and March 2007. For each of those case files identified, they matched them with at least four age matched control case files for comparative sake.
Their analysis found that the risk of developing Parkinson’s disease was not associated with previous influenza infections. BUT, they did find that Influenza was associated with Parkinson’s‐like symptoms such as tremor, particularly in the month after an infection. One can’t help but wonder if the dopamine neurons stopped producing dopamine during that period while they dealt with the viral infection.
But of course, I’m only speculating here… and it’s not like there was a second study suggesting that there is actually an association between Parkinson’s disease and influenza.
A year after that first study, a second study was published:
Journal: Association of Parkinson’s disease with infections and occupational exposure to possible vectors.
Authors: Harris MA, Tsui JK, Marion SA, Shen H, Teschke K.
Journal: Movement Disorder. 2012 Aug;27(9):1111-7.
This second study reported that there is actually an association between Parkinson’s disease and influenza.
This investigation was also a case-control study, but it was based in British Columbia, Canada. The researchers recruited 403 individuals detected by their use of antiparkinsonian medications and matched them with 405 control subjects selected from the universal health insurance plan. Severe influenza was associated with Parkinson’s disease at an odds ratio of 2.01 (1 being no difference) and the range of the odds was 1.16-3.48. That’s pretty significant.
Interestingly, the effect is reduced when the reports of infection were restricted to those occurring within 10 years before diagnosis. This observation would suggest that early life infections may have more impact than previously thought.
Curiously, the researchers also found that exposure to certain animals (cats odds ration of 2.06; range 1.09-3.92) and cattle (2.23; range 1.22-4.09) was also associated with developing Parkinson’s disease.
Time to get rid of the pet cow.
Do any other neurodegenerative condition have associations with influenza?
In the limited literature search that we conducted, we only found reports dealing with influenza and Alzheimer’s disease.
Large studies suggest that Alzheimer’s is not associated with influenza (click here to read more on this). Interestingly, the Alzheimer’s associated protein beta amyloid has been shown to inhibit influenza A viruses (Click here to read that report), which may partly explain the lack of any association.
Influenza does have a mild association, however, with depression (Click here to see that report).
So what does it all mean?
A viral theory for Parkinson’s disease has existed since the great epidemic of 1918. Recent evidence points towards several viruses potentially having some involvement in the development of this neurodegenerative condition. And recent evidence suggests that influenza in particular could be particularly influential.
In 1938, Jonas Salk and Thomas Francis developed the first vaccine against flu viruses. It could be interesting for epidemiologists to go back and see if regular flu vaccination usage (if such data exists) reduces the risk of developing Parkinson’s disease.
But until such data is published, however, perhaps it would be wise to go and get a flu vaccine shot.
The banner for today’s post was sourced from the HuntingtonPost