viral illnesses

Massive health-record review links viral illnesses to brain disease

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Study ties common viruses such as flu to Alzheimer’s and other conditions — but the analysis has limitations, researchers warn

Coloured scanning electron micrograph (SEM) of influenza (flu) viruses (blue) budding from a burst epithelial cell.
In this false-colour scanning electron microscope image, influenza virus particles (blue) stand ready to release from a burst epithelial cell (red).

An analysis of about 450,000 electronic health records has found a link between infections with influenza and other common viruses and an elevated risk of having a neurodegenerative condition such as Alzheimer’s or Parkinson’s disease later in life. But researchers caution that the data show only a possible connection, and that it’s still unclear how or whether the infections trigger disease onset.

The analysis, published in Neuron on 19 January1, found at least 22 links between viral infections and neurodegenerative diseases. Some of the viral exposures were associated with an increased risk of brain disease up to 15 years after infection.

“It’s startling how widespread these associations seem to be, both for the number of viruses and number of neurodegenerative diseases involved,” says Matthew Miller, a viral immunologist at McMaster University in Hamilton, Canada.

Mining health records

This isn’t the first time viruses have been linked to neurodegenerative disease. Infection with a type of herpes virus has been associated with the development of Alzheimer’s2, for instance. And a landmark study published in Science3 last year found the strongest evidence yet that Epstein–Barr virus is tied to multiple sclerosis. But many of these past studies examined only a single virus and a specific brain disease.The quest to prevent MS — and understand other post-viral diseases

To understand whether viruses are linked to brain diseases more broadly, Kristin Levine, a biomedical data scientist at the US National Institutes of Health’s Center for Alzheimer’s Related Dementias in Bethesda, Maryland, and her colleagues analysed hundreds of thousands of medical records to look for instances in which a person had both a viral infection and a brain disease on file.

First, the team examined records from about 35,000 people with brain diseases and about 310,000 people without, sourced from FinnGen, a large Finnish database that includes health information. The team found 45 significant links between infections and brain diseases, and then tested those against more than 100,000 records from another database, the UK Biobank. After this analysis, they were left with 22 significant pairings.

One of the strongest associations was between viral encephalitis, a rare inflammation of the brain that can be caused by multiple types of virus, and Alzheimer’s. People with encephalitis were about 31 times more likely to develop Alzheimer’s later in life than were people who did not have encephalitis. Most other associations were more modest: people who had a bout of flu that led to pneumonia were four times more likely to develop Alzheimer’s than were people who didn’t develop the flu with pneumonia. There were no pairings that suggested a protective link between viral infection and brain disease.

“I’m very excited they’re expanding this research broader than what other studies have looked at,” says Kristen Funk, a neuroimmunologist at the University of North Carolina, Charlotte, who studies the link between herpesviruses and Alzheimer’s.

Data shortcomings

Kjetil Bjornevik, an epidemiologist at the Harvard T.H. Chan School of Public Health in Boston, Massachusetts, and an author of the Epstein–Barr paper in Science, applauds Levine and her colleagues for bringing more attention to the role of viral infections in brain diseases. But he warns that their approach of using medical records “could be problematic” because they analysed only infections that were severe enough to warrant a trip to a health practitioner. Taking milder infections into account might weaken the associations, he says.Are infections seeding some cases of Alzheimer’s disease?

The data are also sourced almost exclusively from people of European ancestry, which means that the findings might not be applicable to the larger global population, Funk says. Furthermore, she adds, outside Europe, “certain viruses are more prevalent”, such as Zika or West Nile virus, so the analysis might have missed links between those pathogens and brain disease. Levine acknowledges the limitations of the analysis; the team worked with the data that were available, she says.

These limitations also underscore the difficulty of untangling whether a viral infection leads to neurodegenerative disease, or whether the disease makes a person more susceptible to infection, Bjornevik says. To make it even more tricky, the authors found that the more time that elapsed between the infection and the diagnosis of brain disease, the weaker the link was. The body is known to begin changing years before symptoms of brain disease develop and a diagnosis is made4, so it’s tough to determine which is causing which, he adds. Another plausible theory is that these viral infections might be accelerating molecular changes in the body that were already ongoing, says Cornelia van Duijn, a genetic epidemiologist at the University of Oxford, UK.Could long COVID be linked to herpes viruses? Early data offer a hint

If future studies add more weight to the connection between viral infection and brain disease, it could offer health officials a tangible way to delay the onset of neurodegenerative disease. Vaccines exist for many of these viruses, van Dujin says. Because multiple types of dementia are diagnosed late in life — close to the average life expectancy — if clinicians could postpone disease onset by even a couple of years, that could mean that many people might never develop the disease, she adds.

“It’s not very clear that the infections are causing brain disease,” she says. But viral infections aren’t pleasant, and if there’s any link to brain disease, “I think we owe it to people to prevent them.”

Could a Viral Illness Increase Chances of Developing Alzheimer’s or Other Neurodegenerative Disease?

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Summary: Study reveals a significant association between certain viral illnesses, including viral encephalitis and pneumonia-causing flu with an increased risk of developing a neurodegenerative disorder later in life. Researchers say existing vaccines against the viruses may reduce the chances of developing neurodegeneration.

Source: NIH

Some viral illnesses may increase a person’s chances of later developing Alzheimer’s disease or another neurodegenerative disorder.

Though a causal link cannot be confirmed, an NIH study in which researchers mined the medical records of hundreds of thousands of people in Finland and the United Kingdom found significant associations.

As published in Neuron, the researchers found there may be at least 22 pairings between a neurodegenerative disorder diagnosis and a previous viral infection that led to a hospital visit.

The strongest risk association was between viral encephalitis—an inflammation of the brain caused by a virus—and Alzheimer’s disease. Meanwhile, hospitalizations due to pneumonia-causing flu viruses were linked to the diagnoses of several disorders, including dementia, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS).

The study results also raised the possibility that existing vaccinations may help some people reduce the chances of experiencing these disorders.

“Neurodegenerative disorders are a collection of diseases for which there are very few effective treatments and many risk factors,” said Andrew B. Singleton, Ph.D., director, NIH Center for Alzheimer’s Related Dementias (CARD); NIH Distinguished Investigator; and a study author.

“Our results support the idea that viral infections and related inflammation in the nervous system may be common—and possibly avoidable—risk factors for these types of disorders.”

Neurodegenerative disorders damage different parts of the nervous system. Typically, this happens later in life and produces a variety of problems, including with thinking, remembering, and moving. Several previous studies have suggested that certain viruses may play a role in each of these disorders.

For example, a 1991 study of autopsied brain tissue suggested there may be link between herpes simplex virus and Alzheimer’s disease. More recently, scientists found evidence for a link between the Epstein Barr virus and multiple sclerosis by analyzing patient blood samples and medical records. The latter study sparked the CARD team to conduct this new study.

“After reading the Epstein Barr virus study we realized that for years scientists had been searching, one-by-one, for links between an individual neurodegenerative disorder and a specific virus,” said Michael Nalls, Ph.D., leader of the NIH CARD Advanced Analytics Expert Group and study senior author.

“That’s when we decided to try a different, more data science-based approach. By using medical records, we were able to systematically search for all possible links in one shot.”

Led by Kristin S. Levine, M.S. and Hampton L. Leonard, M.S., two NIH CARD data scientists, the researchers mined the medical records of 300,000 individuals stored in FinnGen, a nationwide Finnish biobank.

Specifically, they searched for individuals who had one of six neurodegenerative disorder diagnoses: Alzheimer’s disease, ALS, generalized dementia, multiple sclerosis, Parkinson’s disease, or vascular dementia; and then checked to see if a viral infection caused those individuals to make a prior visit to the hospital. Hospitalizations due to COVID-19 were not included in the study.

Initially, they found 45 significant associations between a neurodegenerative disease diagnosis and a previous viral infection. That number narrowed to 22 associations after the scientists performed a second search of UKBiobank, which contains the records of 500,000 individuals from the United Kingdom.

Of all the neurodegenerative disorders, generalized dementia had the most associations, with links to six different virus exposures. These exposures were categorized as viral encephalitis, viral warts, other viral diseases, all influenza, influenza and pneumonia, and viral pneumonia. Individuals who had viral encephalitis were at least 20 times more likely to be diagnosed with Alzheimer’s than those who did not experience that virus.

This shows a brain
The strongest risk association was between viral encephalitis—an inflammation of the brain caused by a virus—and Alzheimer’s disease. Meanwhile, hospitalizations due to pneumonia-causing flu viruses were linked to the diagnoses of several disorders, including dementia, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS).

Severe cases of influenza were linked to the widest range of risks. Influenza and pneumonia exposures were associated with all the neurodegenerative disorder diagnoses except multiple sclerosis.

“Keep in mind that the individuals we studied did not have the common cold. Their infections made them so sick that they had to go to the hospital,” said Dr. Nalls.

“Nevertheless, the fact that commonly-used vaccines reduce the risk or severity of many of the viral illnesses observed in this study raises the possibility that the risks of neurodegenerative disorders might also be mitigated.”

Further analysis of the FinnGen data suggested that the risks associated with some viruses may wear off over time. Here the researchers analyzed 16 of the 22 associations that were common between the FinnGen and the UKBioBank data.

For all 16, the risks of being diagnosed with a neurodegenerative disorder was high within one year of an infection. However, only six of those associations remained significant if the infection happened five to 15 years before the diagnosis.

Finally, it is known that about 80% of the viruses observed in this study can invade the nervous system and trigger the immune system’s inflammatory response.

“The results of this study provides researchers with several new critical pieces of the neurodegenerative disorder puzzle,” said Dr. Nalls. “In the future, we plan to use the latest data science tools to not only find more pieces but also help researchers understand how those pieces, including genes and other risk factors, fit together.”

Massive health-record review links viral illnesses to brain disease

Posted by

0


Study ties common viruses such as flu to Alzheimer’s and other conditions — but the analysis has limitations, researchers warn.

Coloured scanning electron micrograph (SEM) of influenza (flu) viruses (blue) budding from a burst epithelial cell.
In this false-colour scanning electron microscope image, influenza virus particles (blue) stand ready to release from a burst epithelial cell (red).

An analysis of about 450,000 electronic health records has found a link between infections with influenza and other common viruses and an elevated risk of having a neurodegenerative condition such as Alzheimer’s or Parkinson’s disease later in life. But researchers caution that the data show only a possible connection, and that it’s still unclear how or whether the infections trigger disease onset.

The analysis, published in Neuron on 19 January1, found at least 22 links between viral infections and neurodegenerative diseases. Some of the viral exposures were associated with an increased risk of brain disease up to 15 years after infection.

“It’s startling how widespread these associations seem to be, both for the number of viruses and number of neurodegenerative diseases involved,” says Matthew Miller, a viral immunologist at McMaster University in Hamilton, Canada.

Mining health records

This isn’t the first time viruses have been linked to neurodegenerative disease. Infection with a type of herpes virus has been associated with the development of Alzheimer’s2, for instance. And a landmark study published in Science3 last year found the strongest evidence yet that Epstein–Barr virus is tied to multiple sclerosis. But many of these past studies examined only a single virus and a specific brain disease.The quest to prevent MS — and understand other post-viral diseases

To understand whether viruses are linked to brain diseases more broadly, Kristin Levine, a biomedical data scientist at the US National Institutes of Health’s Center for Alzheimer’s Related Dementias in Bethesda, Maryland, and her colleagues analysed hundreds of thousands of medical records to look for instances in which a person had both a viral infection and a brain disease on file.

First, the team examined records from about 35,000 people with brain diseases and about 310,000 people without, sourced from FinnGen, a large Finnish database that includes health information. The team found 45 significant links between infections and brain diseases, and then tested those against more than 100,000 records from another database, the UK Biobank. After this analysis, they were left with 22 significant pairings.

One of the strongest associations was between viral encephalitis, a rare inflammation of the brain that can be caused by multiple types of virus, and Alzheimer’s. People with encephalitis were about 31 times more likely to develop Alzheimer’s later in life than were people who did not have encephalitis. Most other associations were more modest: people who had a bout of flu that led to pneumonia were four times more likely to develop Alzheimer’s than were people who didn’t develop the flu with pneumonia. There were no pairings that suggested a protective link between viral infection and brain disease.

“I’m very excited they’re expanding this research broader than what other studies have looked at,” says Kristen Funk, a neuroimmunologist at the University of North Carolina, Charlotte, who studies the link between herpesviruses and Alzheimer’s.

Data shortcomings

Kjetil Bjornevik, an epidemiologist at the Harvard T.H. Chan School of Public Health in Boston, Massachusetts, and an author of the Epstein–Barr paper in Science, applauds Levine and her colleagues for bringing more attention to the role of viral infections in brain diseases. But he warns that their approach of using medical records “could be problematic” because they analysed only infections that were severe enough to warrant a trip to a health practitioner. Taking milder infections into account might weaken the associations, he says.Are infections seeding some cases of Alzheimer’s disease?

The data are also sourced almost exclusively from people of European ancestry, which means that the findings might not be applicable to the larger global population, Funk says. Furthermore, she adds, outside Europe, “certain viruses are more prevalent”, such as Zika or West Nile virus, so the analysis might have missed links between those pathogens and brain disease. Levine acknowledges the limitations of the analysis; the team worked with the data that were available, she says.

These limitations also underscore the difficulty of untangling whether a viral infection leads to neurodegenerative disease, or whether the disease makes a person more susceptible to infection, Bjornevik says. To make it even more tricky, the authors found that the more time that elapsed between the infection and the diagnosis of brain disease, the weaker the link was. The body is known to begin changing years before symptoms of brain disease develop and a diagnosis is made4, so it’s tough to determine which is causing which, he adds. Another plausible theory is that these viral infections might be accelerating molecular changes in the body that were already ongoing, says Cornelia van Duijn, a genetic epidemiologist at the University of Oxford, UK.Could long COVID be linked to herpes viruses? Early data offer a hint

If future studies add more weight to the connection between viral infection and brain disease, it could offer health officials a tangible way to delay the onset of neurodegenerative disease. Vaccines exist for many of these viruses, van Dujin says. Because multiple types of dementia are diagnosed late in life — close to the average life expectancy — if clinicians could postpone disease onset by even a couple of years, that could mean that many people might never develop the disease, she adds.

“It’s not very clear that the infections are causing brain disease,” she says. But viral infections aren’t pleasant, and if there’s any link to brain disease, “I think we owe it to people to prevent them.”