Is Parkinson’s research going viral?

# # # # With the world emerging from the recent/ongoing COVID pandemic, there has been a resurgence of interest in the role of viruses in the pathogenesis of chronic diseases like Parkinson’s. With scientists around the world watching to see if there is an increase in Parkinsonism following the recent pandemic, other researchers have taken a look at large datasets to assess if there are any associations between previous viral infections and subsequent diagnosis of a neurodegenerative condition. In today’s post, we will review two recent research publications that provide evidence supporting such associations. # # # #

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In January of this year, there was an interesting report published in the journal Science.

This is the report in question:

Title: Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis.
Authors: Bjornevik K, Cortese M, Healy BC, Kuhle J, Mina MJ, Leng Y, Elledge SJ, Niebuhr DW, Scher AI, Munger KL, Ascherio A.
Journal: Science. 2022 Jan 21;375(6578):296-301.
PMID: 35025605                (this report is OPEN ACCESS if you would like to read it)

In this paper, the researchers used data from more than 10 million US military recruits who had medical evaluations every two years over a 20-year period. Of these individuals, 955 were diagnosed with multiple sclerosis.

Interesting… Remind me: What is multiple sclerosis?

Multiple sclerosis (or MS) is a chronic neuroimmunologic condition in which the immune system starts to attack the insulating protective covering (or myelin) on the branches (or axons) of neurons.

Source: Medlineplus

As that myelin is lost, signaling between neurons becomes weaker and disrupted, and a range of symptoms start to show themselves. Symptoms can include double vision, blindness in one eye, muscle weakness and trouble with sensation or coordination.

Got it. So what did the researchers find about these soldiers diagnosed with multiple sclerosis?

The investigators were interested in investigating potential causal factors of the multiple sclerosis. Specifically, they were curious about Epstein-Barr virus.

What is Epstein-Barr virus?

The Epstein–Barr virus (EBV; previously known as Human gammaherpesvirus 4) is one of nine known human herpesvirus. It is a double-stranded DNA virus and it is one of the most common viruses in humans. In fact, most people get infected with EBV at some point in their lives.

Source: Microbenotes

After you get an EBV infection, the virus becomes latent (or inactive) and just hangs around in the B lymphocytes (a type of white blood cell) in your body. In some cases, the virus may reactivate.

There is currently no vaccine to protect against EBV infection.

Ok. Why were the researchers interested in EBV in multiple sclerosis?

Previous research had suggested a strong association between EBV infections and multiple sclerosis (Click here for a good review on this topic).

And in this new study, the researchers analysed blood samples from 801 of the soldiers who developed multiple sclerosis. They compared those samples from more than 1,500 matched controls (people who did not have multiple sclerosis). Of the 801 multiple sclerosis cases, the researchers found that only one person tested negative for EBV. And they calculated that people infected with EBV were 32 times more likely to develop multiple sclerosis as uninfected people.

The investigators also looked at other viral infections and found no other association with multiple sclerosis. And interestingly, they also reported that levels of neurofilament light chain (this is considered a biomarker of neuronal degeneration) in blood only increased after EBV infection in the group of soldiers diagnosed with multiple sclerosis.

Wow! So EBV infection causes multiple sclerosis?

Well, the scientists suggested that “EBV as the leading cause of multiple sclerosis“.

But whether it is a trigger or a driver of the pathology still needs to be determined.

What does that mean?

Well, a trigger is the event that kicks off a starts a condition, whereas a driver is a factor that encourages an outcome after it has been initiated by a trigger.

Given the wide spread incidence of EBV infections (remember I said above that “most people get infected with EBV at some point in their lives“), an EBV infection in itself is not unlikely to be sufficient to trigger multiple sclerosis. 

So it may be that EBV and other factors act synergistically in driving multiple sclerosis.

This all needs to be further investigated, but it is the strongest data yet suggesting a viral role in multiple sclerosis, and it raises the possibility that a vaccine against EBV could provide some protection against developing multiple sclerosis.

Very interesting. Has any similar association between viral infections and Parkinson’s ever been reported?

Funny you ask that. This month, this report was made available:

Title: Virus exposure and neurodegenerative disease risk across national biobanks.
Authors: Levine KS, Leonard HL, Blauwendraat C, Iwaki H, Johnson N, Bandres-Ciga S, Ferrucci L, Faghri F, Singleton AB, Nalls MA.
Journal: Neuron. 2023 Apr 5;111(7):1086-1093.e2.
PMID: 36669485                    (this report is OPEN ACCESS if you would like to read it)

Using two independent datasets, the researchers who produced this report wanted to examine if there are any possible links between viral exposures and subsequent risk of developing a neurodegenerative disease.

First, they used the FinnGen database (a nationwide Finnish biobank involving samples from 300,000 individuals) for the discovery part of the analysis, and then they employed data from the UK Biobank to determine if replication of the discovery results was possible.

They filtered the data for any medical codes or mentions for viral infections prior to a diagnosis of a neurodegenerative condition.

They found 45 viral exposures that were significantly associated with an increased risk of a neurodegenerative condition in their FinnGen/discovery data set, and they were able to replicate 22 of those associations in the independent UK biobank dataset.

Interesting. What were the 22 associations?

Well, first, they were able to replicate the EBV/multiple sclerosis association that we discussed above – providing further support for that connection.

Next, they reported that 24 of 406 viral encephalitis cases went on to develop Alzheimer’s. 24/406 may not sound like much (it’s only 5.9%), but this is much higher than the general rate of Alzheimer’s in a comparator data set (less than 3%).

In addition, the investigators reported that ‘influenza’ and ‘pneumonia’ were significantly associated with five of the six neurodegenerative condition’s in both datasets:

• Alzheimer’s
• ALS
• Dementia
• Vascular dementia
• Parkinson’s

It should be noted that these were suggested to be severe cases of influenza and pneumonia.

Parkinson’s?

Yes, influenza and pneumonia had an an odds ratio with Parkinson’s of 1.72 in the FinnGen data set.

What is an odds ratio?

Odds ratios are measures of association, rather than risk or causation. An odds ratio of 1.0 indicates that the odds of a situation are exactly the same between group – in other words there is no association. An odds ratio of less than 1.0 (for example, 0.75) means that there is a negative association (a ~25% reduced risk of something occurring).

So an odds ration of 1.72 suggests an increased risk of something happening?

Yes, in the FinnGen data set, influenza and pneumonia infections had an an odds ratio of 1.72 with Parkinson’s, indicating an increased risk of PD after these infections. And interestingly, this was a very similar result to that found in a recent study (using Danish data), which found an association between influenza and Parkinson’s with an odds ratio of 1.73 (up to 10 years after virus exposure).

So influenza is causing Parkinson’s?

We can’t conclude that, but as we discussed above perhaps this virus is having a ‘trigger’ or ‘driver’ role, which puts people at greater risk of developing the condition. We have previously discussed the relationship between influenza and Parkinson’s (Click here to read that post).

Interestingly, no viruses in the study were associated with a protective effect.

A protective effect? Why would viruses have a protective effect?!?

Viruses are deeply misunderstood entities.

They are very simple in their basic function, but they have been stigmatised by their name (which comes from the Latin vīrus meaning “poison, venom” – Source) and obviously their association with disease.

Although there are approximately two hundred different kinds of viruses that are known to infect us, cause pathology, and in some cases kill us, there are many viruses that can in fact be mutualistic (meaning that they have beneficial effects on host fitness).

Que???

The same way the squeaky hinge gets the oil, we only really notice the viruses that cause trouble (think Ebola, HIV, SARS-CoV-2, etc).

But there are in fact many viruses that are good guys, and in some cases necessary.

Beyond the major role that viruses have played in the evolution of life on Earth (for example, ancient retroviruses helped with the establishment of placental mammals – click here and here to read more about this), there are many viruses which have beneficial functions in biology. The most frequently cited example here is the polydnaviruses associated with braconid and ichneumonid parasitoid wasps.

The what associated with the which and the where?!?

Braconid and ichneumonid parasitoid wasps are types of parasitic wasps whose life cycle requires support from viruses called polydnaviruses.

Source: Australian.museum

Polydnaviruses are integrated within the wasp’s chromosomal DNA, and they are produced and released when female braconid and ichneumonid parasitoid wasps lay their eggs within a host. The viruses provide immunosuppression in the host allowing the egg to grow:

Source: Mdpi

GB virus C is another example. It is an asymptomatic blood-borne virus that has been shown to slow the progression of HIV to AIDS (Click here to read more about this).

There is also evidence that the hepatitis A virus can protect against hepatitis C (Click here to read more).

Sorry, that was a bit of a detour.

But I thought it was interesting that none of the viral infections in the study were associated with a protective effect.

So what does it all mean?

Neurodegeneration is a curious thing. To feel pain on our skin requires nerve cells to register that pain. And these nerve cells are extremely sensitive and very efficient at transmitting this information to our brain. The cells ‘feel’ the pain. And yet, when nerve cells in our brains die, we feel nothing and only become aware of their absence due to the loss of a particular function over time.

What causes the loss of those brain cells is still a mystery in the case of most of the neurodegenerative conditions. Environmental factors, like viruses, are believed to play a role in some of these ailments. Epstein–Barr virus has certainly been associated with multiple sclerosis – although the exact mechanics of this relationship still need to be worked out. And influenza has been associated with Parkinson’s, but it is a weaker association than the EBV and multiple sclerosis relationship. Could it be that unknown (yet to be characterised) viral agents are influencing neurodegenerative conditions? Perhaps. Silent assassins passing in the night without our notice.

If strong associations are found between particular viruses and neurodegeneration, then there is of course the possibility of developing vaccines which could possibly reduce the risk of being diagnosed with one of the associated conditions (such as Parkinson’s or Alzheimer’s). More research (such as a comprehensive VirScan study – click here to read more about this) is required to determine the role (if any) of viruses in Parkinson’s.

 

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