Friday, June 02, 2017

Nature Comms: Revisiting The Influenza-Parkinson's Link

Credit NIAID


Last week the journal Nature published a brief communications with the daunting title of 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 that raises (again) the theory that certain types of influenza infections may increase a person's chances of developing neurological disorders like Parkinson's disease (PD). 
While the full text of this report isn't much easier to digest that the title, behind the avalanche of scientific jargon you'll a truly fascinating exploration of one of medicine's biggest mysteries.
But in order to appreciate the report, some background is needed.  Given the complexity of the backstory, you may want to get yourself a fresh cup of coffee. This could take a while.

First, from the title, is 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which is thankfully abbreviated as MPTP This compound figures prominently in the 1996 book, "The Case of the Frozen Addicts” by James William Langston, who was one of the first doctors drawn into a medical mystery that baffled doctors for weeks. 
If you haven't read it, or are unaware of the story, briefly:
In 1982, over the course of a couple of weeks, six people in the San Francisco area were found to have developed severe `Parkinson's-like' symptoms literally overnight; they were stiff, unable to talk, stared without blinking, and had no control over their bodies. 
At first some doctors thought it was a psychiatric condition, but after comparing notes, several attending doctors discovered all 6 had recently shot up with heroin.  
Only it wasn't `heroin'. Chemical analysis on some of the recovered powder showed it was a synthetic drug - intended to be MMPP - which provides an opioid-like euphoria, but due to a manufacturing error also included MPTP - which turns out can cross the blood brain barrier where it is metabolized into a toxin (MPP+) that kills dopamine-producing neurons.
The result was instant, profound, chemically induced Parkinson's disease (PD).
These six `frozen addicts' were treated with levodopa, and for a time regained a good portion of their abilities, but within a year or two its side effects (including personality changes and psychosis) proved too much, and they eventually slipped back into their  Parkisonian state.  
Attempts to transplant fetal dopamine neurons into some of their brains in the late 1980s yielded limited success. 
Out of this drug fueled tragedy, however, came a couple of big advances. 
  • First, with little evidence of Parkinson's being hereditary, we finally had a potential environmental trigger for the syndrome. If not MPTP, perhaps a similar molecule.
  • And second, since Parkinson's has only been found to occur in humans, the lack of an animal model had greatly impeded research. Now, using MPTP, researchers could induce `Parkinson's' in lab animals, and that in turn opened up new avenues of research in recent years.
It is worth noting that the symptoms of these six patients are strikingly similar to those experienced by several million people following the 1918 pandemic, when - for nearly a decade - we saw an epidemic of Encephalitis lethargica leading some researchers to question whether or not it might be a part of some long-term sequelae of the virus.
While the influenza-Encephalitis lethargica link remains unproven, during the middle of the last decade we began to see ominous signs of neurological complications in people infected with the H5N1 bird flu virus.

In 2009, in Study: H5N1 Infection And Brain Damage, we looked at a story by Maggie Fox – who was then writing for Reuters – on a PNAS study that found the H5N1 virus was neurotropic (able to infect & damage nerve cells) . . . at least in mice. 

Bird flu causes Alzheimer's-like brain damage, study says
Tests on mice infected with H5N1 virus show lasting damage to nerve cells, including the brain

Maggie Fox
Aug. 10, 2009 

Survivors of bird flu, and perhaps other influenza viruses, may not be out of the woods once the fever and cough are gone: Animal studies suggest the virus may damage the brain and cause Alzheimer's and Parkinson's disease.

The tests on mice show that the H5N1 virus can get into the brain, causing damage that resembles Parkinson's and Alzheimer's in humans, the researchers wrote in the Proceedings of the National Academy of Sciences.

“Our results suggest that a pandemic H5N1 pathogen, or other neurotropic influenza virus, could initiate central nervous system disorders of protein aggregation including Parkinson's and Alzheimer's diseases,” Richard Smeyne of St. Jude Children's Research Hospital in Memphis, Tenn., and colleagues wrote.
(Continue . . . )

Dr. Richard Smeyne, mentioned in the above article, is the corresponding author on today's report, and has been researching the link between influenza and neurological disorders for years. Dr. Smeyne is interviewed again in an article published on the  St. Jude Children’s Research Hospital website, again from 2009 (now a dead link).

Avian influenza strain primes brain for Parkinson’s disease

At least one strain of the H5N1 avian influenza virus leaves survivors at significantly increased risk for Parkinson’s disease and possibly other neurological problems later in life, according to new research from St. Jude Children’s Research Hospital.
This avian flu strain does not directly cause Parkinson’s disease, but it does make you more susceptible,” said Richard Smeyne, Ph.D., associate member in St. Jude Developmental Neurobiology. Smeyne is the paper’s senior author.

Since then we've seen additional evidence of neurological involvement with H5N1 infection (see CJ ID & MM: Case Study Of A Neurotropic H5N1 Infection - Canada), a complication that has been particularly associated with clade  viruses.
But it isn't necessarily just bird flu.
In 2011 a study by Boise State biology professor Troy Rohn  appeared in PLOS ONE , which unexpectedly found immunohistochemical evidence of prior influenza A infection in the post-mortem brain tissues of 12 Parkinson’s patients they tested.

Immunolocalization of Influenza A Virus and Markers of Inflammation in the Human Parkinson's Disease Brain

Troy T. Rohn*, Lindsey W. Catlin

And in 2012, in Revisiting The Influenza-Parkinson’s Link, we looked at another study, conducted by the University of British Columbia, that found a linkage between a past history of severe bouts of influenza and the likelihood of developing Parkinson’s disease later in life.
According to their research, a severe bout of influenza doubled a person’s chances of developing the neurological condition (Severe flu increases risk of Parkinson's: UBC research).
Although seasonal flu (H1N1) - unlike H5N1 - isn't technically neurotropic, the body's immune response can trigger brain inflammation.

That became an issue early in the 2009 pandemic,  when the CDC’s MMWR (July 23rd issue) reported on 4 pediatric patients with the novel H1N1 virus who presented with neurological symptoms including unexplained seizures and altered mental status.
Neurologic Complications Associated with Novel Influenza A (H1N1) Virus Infection in Children --- Dallas, Texas, May 2009
. . .  On May 28, 2009, the Dallas County Department of Health and Human Services (DCHHS) notified CDC of four children with neurologic complications associated with novel influenza A (H1N1) virus infection admitted to hospitals in Dallas County, Texas, during May 18--28.
A few months later, in Japan: Influenza Related Encephalopathy, we looked at a report in the Yomiuri Shimbun on 132 flu patients with neurological complications during the opening four months of the pandemic. In 2010's, Study: Pediatric Neurological Complications With H1N1, we looked at even more reports of influenza-related encephalopathy. 
All of which would seem to make an influenza-Parkinson's link at least plausible.
The `Multiple Hit Hypothesis' also mentioned in the title of today's Nature report comes from a 2006 paper (Progressive dopamine neuron loss in Parkinson's disease: the multiple hit hypothesis), that proposes that multiple insults over a period of time - likely from a variety of sources - may eventually accrue into PD.
Today's study advances that theory further, suggesting that multiple bouts of influenza, along with other environmental exposures, might increase the odds of developing PD.
The good news (at least, if you are a mouse), is that the timely use of vaccines (before infection) and antivirals (during infection) appears to attenuate the risk.

As you might guess by now, today's report isn't exactly `light reading', although I'm certain many of my readers will persevere. A considerably  less challenging summary is provided courtesy of the Thomas Jefferson University Hospital website, in the following press release.

Infection with Seasonal Flu May Increase Risk of Developing Parkinson's Disease


PHILADELPHIA — Most cases of Parkinson’s have no known cause, and researchers continue to debate and study possible factors that may contribute to the disease. Research reported  in the journal npj Parkinson’s Disease suggests that a certain strain of influenza virus predisposes mice to developing pathologies that mimic those seen in Parkinson’s disease.

“This study has provided more evidence to support the idea that environmental factors, including influenza may be involved in Parkinson’s disease,” says Richard J. Smeyne, PhD, Professor of Neuroscience in the Sidney Kimmel Medical College at Thomas Jefferson University and Director of the Jefferson Parkinson’s Disease Center in the Vickie and Jack Farber Institute for Neuroscience. “Here we demonstrate that even mice who fully recover from the H1N1 influenza virus responsible for the previous pandemic (also called ‘swine flu’) are later more susceptible to chemical toxins known to trigger Parkinson’s in the lab.”

Previously, Dr. Smeyne and his collaborator Dr. Stacey Schultz-Cherry in the Department of Infectious Disease at St. Jude Children’s Research Hospital in Memphis, TN, showed that a deadly H5N1 strain of influenza (so-called Bird Flu) that has a high mortality rate (60 percent of those infected died from the disease) was able to infect nerve cells, travel to the brain, and cause inflammation that, the researchers showed, would later result in Parkinson’s-like symptoms in mice. Inflammation in the brain that does not resolve appropriately, such as after traumatic injury to head, has also been linked to Parkinson’s.

Building on that work, the current paper looked at a less lethal strain, the H1N1 “swine flu,” that does not infect neurons, but which, the researchers showed, still caused inflammation in the brain via inflammatory chemicals or cytokines released by immune cells involved in fighting the infection.

Using a model of Parkinson’s disease in which the toxin MPTP, made famous in book “The Case of the Frozen Addicts”, induces Parkinson’s-like symptoms in humans and mice, Dr. Smeyne showed that mice infected with H1N1, even long after the initial infection, had more severe Parkinson’s symptoms than those who had not been infected with the flu. Importantly, when mice were vaccinated against the H1N1, or were given antiviral medications such as Tamiflu at the time of flu infection, the increased sensitivity to MPTP was eliminated.
“The H1N1 virus that we studied belongs to the family of Type A influenzas, which we are exposed to on a yearly basis,” says Dr. Smeyne. “Although the work presented here has yet to be replicated in humans, we believe it provides good reason to investigate this relationship further in light of the simple and potentially powerful impact that seasonal flu vaccination could have on long-term brain health.”
        (Continue . . . )

While we don't yet have a smoking gun, we do have a promising avenue of research.  One that - in no small part - is made possible today because of a bad batch of synthetic `heroin' cooked up in a makeshift lab 35 years ago.

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