Tagged: Influenza

The myth of Spring babies

baby-spring

In large datasets, strange anomalies can appear that may tell us something new about a condition, such as the curious association between melanoma and Parkinson’s disease.

These anomalies can also appear in small datasets, such as the idea that spring babies are more at risk of developing Parkinson’s disease. But the smaller dataset results may be a bit misleading.

In today’s post, we will look at what evidence there is supporting the idea that people born in the spring are more vulnerable to Parkinson’s disease.


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Spring lambs. Source: Wenatcheemumblog

When is your birthday?

More specifically, which month were you born in? Please feel free to leave your answer in the comments section below this post.

Why do I ask?

In 1987, an interesting research report was published in a scientific research book:

Miura

Title: Season of birth in parkinsonism.
Authors: Miura, T., Shimura, M., and Kimura, T.
Book: Miura T. (ed) Seasonality of birth:Progress in biometeorology, 1987.p157-162. Hague, Netherlands.
PMID: N/A

In the report, the researchers outlined a study that they had conducted on the inhabitants of an asylum for the aged in Tokyo (Japan). They had found not only a very high rate of Parkinsonism (6.5% of the inhabitants), but also that the majority of those individuals affected by the Parkinsonism were born in the first half of the year (regardless of which year they were actually born).

Sounds crazy right? (excuse the pun)

And that was probably what everyone who read the report thought….

…except that one year later this independent group in the UK published a very similar result:

Continue reading

Flu jabs and Parkinson’s disease

o-FLU-JAB-facebook

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.


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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).

Why?

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.

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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.

influenzaha-na

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).

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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.

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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:

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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.

Coincidental?

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’.

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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.

Economo

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.

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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:

Oliver-Sacks-1933-2015-1

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_con_robert_de_niro_en_1990

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:

Richard_Smeyne

Source: Researchgate

Nice guy.

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:

PNAS

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:

JNS

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:

PLOS

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:

Flu

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?

Good question.

And yes they have:

flu1
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:

occupation
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.
PMID: 22753266

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.

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Source: RSPB

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

Hepatitis – Parkinson’s goes viral?

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Last week a new piece of Parkinson’s disease research has been widely discussed in the media.

It involves Hepatitis – the viral version of it at least.

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


Fig2_v1c

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

A definitive diagnosis of Parkinson’s disease can only be made at the postmortem stage with an examination of the brain. Until that moment, all cases of Parkinson’s disease are ‘suspected’.

Critical to that postmortem diagnosis is the presence of circular shaped, dense clusters of proteins, called Lewy bodies (see the image above for a good example).

What causes Lewy bodies? We don’t know, but many people have theories.

This is Friedrich Heinrich Lewy (1885-1950).

DrLewy

Friedrich Lewy. Source: Lewy Body Society

As you can probably guess, Friedrich was the first to discover the ‘Lewy body’. His finding came by examining the brains of 85 people who died with Parkinson’s disease between 1908 – 1923.

In 1931, Friedrich Lewy read a paper at the International Congress of Neurology in Bern. During that talk he noted the similarities between the circular inclusions (called ‘negri bodies’) in the brains of people who suffered from rabies and his own Lewy bodies (observed in Parkinson’s disease).

rabies

A Negri body in a cell affected by rabies (arrow). Source: Nethealthbook

Given the similarities, Lewy proposed a viral cause for Parkinson’s disease.

Now, the idea that Parkinson’s disease could have a viral component has existed for a long time – even before Lewy made his conclusion. As we have previous mentioned, theories of viral causes for Parkinson’s have been circulating ever since the 1918 flu pandemic (Click here to read our post on this topic).

vonecomo-parkinson

An example of post-encephalitic Parkinsonism. Source: Baillement

About the same time as the influenza virus was causing havoc around the world, another condition began to appear called ‘encephalitis lethargica‘ (also known as post-encephalitic Parkinsonism). This disease left many of the victims in a statue-like condition, both motionless and speechless – similar to Parkinson’s disease. Initially, it was assumed that the influenza virus was the causal factor, but more recent research has left us not so sure anymore.

Since then there, however, has been additional bits of evidence suggesting a viral role in Parkinson’s disease. Such as this report:

H1N1

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

The researchers in this study found that when they injected the highly infectious 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 associated protein Alpha Synuclein. Importantly, they witnessed the loss of dopamine neurons in the midbrain of the mice 60 days after resolution of the infection – that cell loss resembling what is observed in the brains of people with Parkinson’s disease.

The Parkinson’s associated protein alpha synuclein has also recently demonstrated anti-viral properties:

Beckham

Title: Alpha-Synuclein Expression Restricts RNA Viral Infections in the Brain.
Authors: Beatman EL, Massey A, Shives KD, Burrack KS, Chamanian M, Morrison TE, Beckham JD.
Journal: J Virol. 2015 Dec 30;90(6):2767-82. doi: 10.1128/JVI.02949-15.
PMID: 26719256               (This article is OPEN ACCESS if you would like to read it)

David Beckham (not the football player) and his research colleagues introduced West nile virus to brain cells grown in cell culture and they observed an increase in alpha synuclein production. They also found that the brains of people with West nile infections had increased levels of alpha synuclein.

The researchers then injected West Nile virus into both normal mice and genetically engineered mice (which produced no alpha synuclein) and they found that the genetically engineered mice which produced no alpha synuclein died quicker than the normal mice. They reported that there was an almost 10x increase in viral production in the genetically engineered mice. This suggested to them that alpha synuclein may be playing a role in protecting cells from viral infections.

Interesting, but what about this new data involving Hepatitis?

Yes, indeed. Let’s move on.

Wait a minute, what is Hepatitis exactly?

The name Hepatitis comes from the Greek: Hepat – liver; and itis – inflammation, burning sensation. Thus – as the label suggests – Hepatitis is inflammation of liver tissue.

Progress-of-Liver-Damage

Hepatitis and the liver. Source: HealthandLovepage

It can be caused by infectious agents (such as viruses, bacteria, and parasites), metabolic changes (induced by drugs and alcohol), or autoimmune/genetic causes (involving a genetic predisposition).

The most common cause of hepatitis is viral.

There are five main types of viral hepatitis (labelled A, B, C, D, and E). Hepatitis A and E are mainly spread by contaminated food and water. Both hepatitis B and hepatitis C are commonly spread through infected blood (though Hepatitis B is mainly sexually transmitted). Curiously, Hepatitis D can only infect people already infected with hepatitis B.

Hepatitis A, B, and D are preventable via the use of immunisation. A vaccine for hepatitis E has been developed and is licensed in China, but is not yet available elsewhere

Hepatitis C, however, is different.

There is currently no vaccine for it, mainly because the virus is highly variable between strains and the virus mutates very quickly, making an effective vaccine a difficult task. A number of vaccines under development (Click here for more on this).

What is known about Hepatitis C and the brain?

Quite a bit.

Similar to HIV (which we discussed in a previous post), the hepatitis C virus (HCV) enters the brain via infected blood-derived macrophage cells. In the brain, it is hosted by microglial cells, which results in altered functioning of those microglial cells. This causes problems for neuronal cells – including dopamine neurons. For example, people infected with HCV have reduced dopamine transmission, based on brain imaging studies (Click here and here for more on this result).

Have there been connections between hepatitis C virus and Parkinson’s disease before?

Yes.

Dopatitle

 

Title: Hepatitis C virus infection: a risk factor for Parkinson’s disease.
Authors: Wu WY, Kang KH, Chen SL, Chiu SY, Yen AM, Fann JC, Su CW, Liu HC, Lee CZ, Fu WM, Chen HH, Liou HH.
Journal: J Viral Hepat. 2015 Oct;22(10):784-91.
PMID: 25608223

The researchers in this study used data collected from a community-based screening program in north Taiwan which involved 62,276 people. The World Health Organisation (WHO) estimates that the prevalence of hepatitis C viral infection worldwide is approximately 2.2–3%, representing 130–170 million people. Taiwan is a high risk area for hepatitis, with antibodies for hepatitis viruses in Taiwan present in 4.4% in the general population (Source).

The researchers found that the significant association between hepatitis C viral infections and Parkinson’s disease – that is to say, a previous infection of hepatitis C increased the risk of developing Parkinson’s disease (by 40%). The researchers then looked at what the hepatitis C and B viral infections do to dopamine neurons growing in cell culture. They found that hepatitis C virus induced 60% dopaminergic cell death, while hepatitis B had no effect.

This study was followed up a few months later, by a second study suggesting an association between Hepatitis C virus and Parkinson’s disease:

Hep title

Title: Hepatitis C virus infection as a risk factor for Parkinson disease: A nationwide cohort study.
Authors: Tsai HH, Liou HH, Muo CH, Lee CZ, Yen RF, Kao CH.
Journal: Neurology. 2016 Mar 1;86(9):840-6.
PMID: 26701382

The researchers in this study wanted to investigate whether hepatitis C could be a risk factor for Parkinson’s disease. They did this by analyzing data from 2000-2010 drawn again from the Taiwan National Health Insurance Research Database.

The database included 49,967 people with either hepatitis B, hepatitis C or both, in addition to 199,868 people without hepatitis. During the 12 year period, 270 participants who had a history of hepatitis developed Parkinson’s disease (120 still had hepatitis C). This compared with 1,060 participants who were free of hepatitis, but went on to develop Parkinson’s disease.

When the researchers controlled for potentially confounding factors (such as age, sex, etc), the researchers found participants with hepatitis C had a 30% greater risk of developing Parkinson’s disease than the controls.

So if this has been demonstrated, why is this new study last week so important?

Good question.

The answer is very simple: This study is not based on statistics from Taiwan – this new study has found the same result from a new population.

HEP TITLE

Title: Viral hepatitis and Parkinson disease: A national record-linkage study.
Authors: Pakpoor J, Noyce A, Goldacre R, Selkihova M, Mullin S, Schrag A, Lees A, Goldacre M.
Journal: Neurology. 2017 Mar 29. [Epub ahead of print]
PMID: 28356465

These researchers used the English National Hospital Episode Statistics database and linked it to mortality data collected from 1999 till 2011. They too have found a strong association between hepatitis C and Parkinson’s disease (standardized rate ratio 1.51, 95% CI 1.18–1.9).

Curiously (and different from the previous studies), the researchers in this study also found a strong association for hepatitis B and Parkinson’s disease (standardized rate ratio 1.76, 95% CI 1.28–2.37). And these associations appear to be specific to Hepatitis B and C, as the investigators did not find any association between autoimmune hepatitis, chronic hepatitis, or HIV.

One important caveat with this new study, however, is that the authors could not
control for lifestyle factors (such as smoking or alcohol consumption). In addition, their system of linking medical records may underestimate the numbers of patients with
Parkinson’s disease as it would not take into account people with Parkinson’s disease who do not seek medical advice or those who are misdiagnosed (given a wrong diagnosis – it does happen!).

Regardless of these cautionary notes, the results still add to the accumulating evidence of an association between the virus that causes Hepatitis and the neurodegenerative condition of Parkinson’s disease.

But what about those people with Parkinson’s disease who have never had Hepatitis?

Yeah, this is a good question.

But there is a rather uncomfortable answer to it.

Here’s the rub: “Approximately 70%–80% of people with acute Hepatitis C do not have any symptoms” (Source: Centre for Disease Control). That is to say, the majority of people infected with the Hepatitis C virus will not be aware that they are infected. Some of those people who are infected may think that they have a case of the flu (HCV symptoms include fever, fatigue, loss of appetite,…), while others will simply not display any symptoms at all.

So many people with Parkinson’s disease may have had HCV, but never been aware of it.

And this is the really difficult part of researching the causal elements of Parkinson’s disease.

The responsible agent may actually leave little or no sign that they were ever present. For a long time, people have suggested that Parkinson’s disease is caused by a thief in the night – some agent that comes in, causes a problem and disappears without detection.

Perhaps Hepatitis is that thief.

But hang on a second, 60–70% of HCV infected people will go on to develop chronic liver disease (Source). Do people with Parkinson’s disease have liver issue?

Umm, well actually, in some cases: yes.

There have been studies of liver function in Parkinson’s disease where abnormalities have been found (Click here for more on this). And dopamine cell dysfunction has been seen in people with cirrhosis issues (Click here for more on this). In fact, the prevalence of Parkinsonism in people with cirrhosis has been estimated to be as high as 20% (and Click here for more on that).

So what are we saying? Hepatitis causes Parkinson’s disease???

No, we are not saying that.

Proving causality is the hardest task in science.

In addition, there have been a few studies in the past that have looked at viral infections as the cause of Parkinson’s disease that found strong associations with other viruses. For example this study:

Title: Infections as a risk factor for Parkinson’s disease: a case-control study.
Authors: Vlajinac H, Dzoljic E, Maksimovic J, Marinkovic J, Sipetic S, Kostic V.
Journal: Int J Neurosci. 2013 May;123(5):329-32.
PMID: 23270425

In this study, the researchers found that Parkinson’s Disease was also significantly associated to mumps, scarlet fever, influenza, and whooping cough as well as herpes simplex 1 infections. They found no association between Parkinson’s disease and Tuberculosis, measles or chickenpox though.

This result raises the tantalizing possibility that other viruses may also be involved with the onset of Parkinson’s disease (it should be added though that this study was based on only 110 people with Parkinson’s (compared with 220 controls) in one particular geographical location (Belgrade, Serbia)).

So different viruses may cause Parkinson’s disease?

We are not saying that either, but we would like to see more research on this topic.

And the situation may actually be more complicated than we think.

Recently, it has been reported that previous infection with flaviviruses (such as dengue) actually enhances the effect of Zika virus infect (Click here to read more on this). That is to say, a prior infection by one particular virus may exacerbate the infection of another virus. It could be that a previous infection by one virus increases that chance that a later infection by another virus – a particular combination of viral infections – may result in Parkinsonian symptoms (we are simply speculating here). 

Add to this complicated situation, the sheer number of unknown viruses. It is estimated that there are a minimum of 320,000 mammalian viruses still awaiting discovery (Click here for the source of this statistic), thus it is possible that additional unknown viruses may be involved with disease initiation for conditions like Parkinson’s disease.

A gang of unknown thieves in the night perhaps?

So what does it all mean?

Summing up: last week a new study was published that supported previous results that Hepatitis C viral infections could increase the risk of developing Parkinson’s disease. The results are important because they replicate previous findings from a different population of people.

The findings do not immediately mean that people with Hepatitis C are going to develop Parkinson’s disease, but it does suggest that they may be more vulnerable. The findings also suggest that more research is needed on the role of viral/infectious agents in the development of Parkinson’s disease.

We would certainly like to see more research in this area.


The banner for today’s post was sourced from Youtube

Viruses and Parkinson’s – a hit and run story?

SupportGroup

I was recently presenting a talk at a Parkinson’s support group meeting. Afterwards I sat with some of the attendees and we chatted over tea and cookies. At one point the lady sitting beside me tapped me on the arm and said:

“The other day we were discussing some of the commonalities that we [people with Parkinson’s] share. I wonder if they would be of interest to you?”

“Absolutely”‘ I replied, “Let’s hear them”

“Well, firstly, most of us have little or any sense of smell” she said

And I nodded, “this is a common feature amongst people with Parkinson’s disease” (Click here for more on this)

“Ok. Number two, we all have trouble doing ‘number twos'”

I nodded again, and explained that constipation and gastrointestinal problems are also common features of Parkinson’s disease. (Click here for more on this)

“Interesting”, she said, before aiding: “Thirdly, none of us have ever had chickenpox”

I confess I looked at her a long time.

I was speechless.

I had never heard of anything like that.

In science, we are always looking for the presence of possible causal agents – not their absence. I was so intrigued that I took her contact details and told her that I would go away and do some homework on the matter.

I’d like to share my findings here as part of a larger discussion on viruses and Parkinson’s disease.


Given the random and indiscriminate way in which Parkinson’s disease attacks people, scientists have looked for a virus that may be causing the condition.

283615-virus

Throughout our lives, our immune system is constantly under attack from viruses. They are small infectious agent that thrive by replicating themselves inside the living cells of other organisms. Technically speaking they are not alive as they lack most of the machinery which characterizes ‘life’ (most importantly the components that is necessary for reproduction). We currently know of approx. 3000 viruses, but we can only guess at the total number of viruses (it may be in the millions!).

There are several different ways that Parkinson’s disease could theoretically be caused in some way by a virus:

1. There may be a specific virus that we are unaware of that infects the body at some point in one’s life causing the slow progressive disease. This could be consider the ‘lightning bolt’ theory – a single unlucky event with terrible consequences. Such a theory has weight as it would explain why some clusters of Parkinson’s disease is sometimes observed. People often use the example of Michael J Fox and his TV work colleagues in this theory.

 

leadership-fox-m-img_2

Actor Michael J Fox and three other people who worked on the Canadian TV show ‘Leo & me’ went on to develop Parkinson’s disease. Image source: Michael J Fox Foundation

2. A virus attacking the body coincides with a secondary event (e.g. a bacterial infection) that may result in the slow progressive events that result in Parkinson’s disease. The secondary event may be a genetic mutation or exposure to an environmental toxin. The virus attack in itself may not be enough in itself.

The two theories outlined above are just theories. We do not know if Parkinson’s disease is caused by a viral infection.

There is, however, some lines of evidence supporting the idea:

Influenza and Parkinson’s disease

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, 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’.

Influenza is the virus that causes ‘the flu’. Most commonly in a mild form (runny nose, sore throat, coughing, and fatigue), the symptom will arise two days after exposure and last for about a week. 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. It was called H1N1.

NOTE: The “H” (hemagglutinin) and the “N” (neuraminidases) are both proteins that are found on the outer surface of the virus. Different viruses have different hemagglutinin and neuraminidase proteins, hence the numbering.

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 many of the victims in a statue-like condition, both motionless and speechless. You may be familiar with the Oliver Sacks book ‘Awakenings’ which was turned into a film starring Robin Williams and Robert De Niro – the patients in that book were victims of EL.

robin_williams_con_robert_de_niro_en_1990

Robin Williams and Robert De Niro in Awakenings

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 and the finding of influenza antigens in some of the suffers of EL. More recent evidence rejects this hypothesis (e.g. an absence of viral RNA recovered from the brains of postencephalitic PD patients – click here for more on this). We genuinely don’t know what caused EL.

But there has recently been some evidence suggesting a link between Parkinson’s disease and influenza:

Jang-title

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

The researchers in this study found that when they injected the highly infectious H5N1 influenza virus into mice, the virus progressed from the periphery into the brain, where it induced Parkinson’s disease-like symptoms. The virus also caused a significant increase in the aggregation of the protein Alpha Synuclein. Importantly, they witnessed the loss of dopamine neurons in the midbrain of the mice 60 days after resolution of the infection.

This study supports the theory we discussed above (theory 1.) of a virus possibly causing Parkinson’s disease. These same researchers have also looked at other influenza viruses and found additional results:

Sadasivan-title

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

In this second study, however, the different type of influenza (H1N1) did not infect the brain, but did cause the immune system to flare up. This is an interesting example of the second theory we discussed above (theory 2.), the double hit theory of Parkinson’s disease, in which the virus doesn’t necessarily cause Parkinson’s disease but plays a supportive role to some other toxic agent in attacking the body.

In a follow up study to their 2009 report on H5N1, these same researchers found that the Parkinson’s disease-like symptoms that they observed were actually only temporary:

Jang-title2

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 third study may give further support to the double hit theory (theory 2.), but also indicates how complicated a viral component to Parkinson’s disease can be.

And influenza is not the only virus to be associated with Parkinson’s disease.

Hepatitis C and Parkinson’s disease

Hepatitis C is a contagious liver disease, which is caused by the hepatitis C virus (HCV). The virus has been found in the brains of infected people, and it has also been shown to kill dopamine neurons in cell culture. Only in the last few months, however, has a more direct association with Parkinson’s disease been proposed:

HepC-Title

Title: Hepatitis C virus infection as a risk factor for Parkinson disease: A nationwide cohort study.
Authors: Tsai HH, Liou HH, Muo CH, Lee CZ, Yen RF, Kao CH.
Journal: Neurology, 2015 Dec 23. Published early online.
PMID: 26701382

The researchers in this study wanted to investigate whether hepatitis C could be a risk factor for Parkinson’s disease. They did this by analyzing data from 2000-2010 drawn from the Taiwan National Health Insurance Research Database.

The database included 49,967 people with either hepatitis B, hepatitis C or both, in addition to 199,868 people without hepatitis. During the 12 year period, 270 participants who had a history of hepatitis developed Parkinson’s disease (120 still had hepatitis C). This compared with 1,060 participants who were free of hepatitis, but went on to develop Parkinson’s disease.

When the researchers controlled for potentially confounding factors (such as age, sex, etc), the researchers found participants with hepatitis C had a 30% greater risk of developing Parkinson’s disease than the controls.

Summary

It is tempting to consider a viral theory for Parkinson’s disease, especially as the condition seems to strike indiscriminately from out of the blue. Maybe a virus works in cahoots with another factor (unable to do the job alone). The evidence of this, however, has not been apparent to allow for a definitive conclusion.


Finally, regarding my homework… 

Never having Chickenpox could mean two different things – never being exposed to it OR being exposed to it and not getting infected (missing a particular protein required for infection). The first would suggest that exposure to the virus would given some kind of resistance to Parkinson’s disease. The latter would suggest that a protein which makes you vulnerable to Chickenpox gives you resistance to Parkinson’s disease.

As to the scientific literature, there have been two studies published regarding Chickenpox and Parkinson’s disease. The first:

Semchuk-title

Title: Parkinson’s disease: a test of the multifactorial etiologic hypothesis.
Authors: Semchuk KM, Love EJ, Lee RG.
Journal: Neurology, 1993 Jun;43(6):1173-80.
PMID: 8170564

In this study, the researchers collected life-time information (family history, occupational and medical records, etc) from 130 people with Parkinson’s disease. When the looked at all of the variables, they noted that a family history of Parkinson’s had the strongest association with Parkinson’s disease. This was followed by head trauma and occupational herbicide use. The subjects with Parkinson’s disease did not differ from control subjects with regards to:

  • exposure to smoking or ionizing radiation
  • family history of essential tremor
  • work-related contact with aluminum, carbon monoxide, cyanide, manganese, mercury, or mineral oils
  • history of arteriosclerosis, chicken pox, encephalitis, hypertension, hypotension, measles, mumps, rubella, or Spanish flu.

They proposed that the results supported the idea of a multifaceted cause of Parkinson’s disease, “probably involving genetic, environmental, trauma, and possibly other factors”.

And the second published study was:

Title: Infections as a risk factor for Parkinson’s disease: a case-control study.
Authors: Vlajinac H, Dzoljic E, Maksimovic J, Marinkovic J, Sipetic S, Kostic V.
Journal: Int J Neurosci. 2013 May;123(5):329-32. doi: 10.3109/00207454.2012.760560. Epub 2013 Feb 4.
PMID: 23270425

In this study the researchers found that Parkinson’s Disease was significantly associated to mumps, scarlet fever, influenza, whooping cough and herpes simplex infections. But they found no association between Parkinson’s disease and Tuberculosis, measles or chickenpox

So it would appear that chickenpox is not associated with Parkinson’s disease. And at a subsequent Parkinson’s support group meeting I asked the audience for a raise of hands as to who has had chickenpox and there was a sea of hands.

Back to the drawing board I guess.