Global Research Spanning 30+ Countries to Examine COVID’s Impact on the Brain
By Paul Nicolaus
March 30, 2021 | While it isn’t clear just yet how the coronavirus could impact cognition over the long haul, a global group of researchers is looking to learn more.
The Alzheimer’s Association and scientists located in over 30 countries are creating a consortium to follow and analyze COVID-19 patients, searching for any lingering effects on the brain. The World Health Organization is providing technical guidance.
A January paper announcing the new international research endeavor (DOI: 10.1002/alz.12255), surveys a century’s worth of data on major viral infections, such as the 1918 flu, to give a sense of their lasting effects on the brain, including issues like memory impairment and sleep disruption.
They also provide an overview of what is currently known about the connection between COVID-19 and cognition. Abnormal brain imaging has emerged as a main feature of this illness, they pointed out, and studies have suggested that COVID-19 is linked to brain dysfunction such as the loss of smell and taste and so-called brain fog.
In some, “SARS‐CoV‐2 infection triggers a massive release of cytokines, chemokines, and other inflammation signals,” the co-authors noted. This leads to blood-brain barrier dysfunction, which can promote neuroinflammation and brain cell death—factors known to play a role in the risk and progression of Alzheimer’s disease (AD).
While forecasts are continually evolving during the current pandemic, the co-authors estimated that roughly 1 in every 200 people worldwide will have been infected by the time it eventually winds down. While most of those individuals will survive, the public health impact could be felt far beyond the current crisis.
Historical data from previous pandemics caused by neurotropic respiratory viruses, along with emerging data and observations from medical professionals, “strongly supports” an expectation of increased motor impairment, cognitive decline, affective disorders, and psychotic disorders, they added.
So does COVID-19 raise a person’s later life risk for conditions such as Parkinson’s disease, AD, or other forms of dementia?
“We don’t know,” said Heather Snyder, vice president of medical and scientific relations at the Alzheimer’s Association. “That is still a big question.” But this and other related questions are being raised now as a way of getting ahead.
The Alzheimer’s Association has been working with a team at UT Health San Antonio since the spring to bring researchers together from around the world, explained Snyder, a co-author of the paper.
One of the main underlying goals is to develop common ways of collecting data that will make it possible to track changes in the brain and the downstream impact on memory, thinking, reasoning, function, and behavior.
One of the key symptoms related to COVID-19 is the loss of taste and smell, Snyder said, which is thought to occur because of the virus’s impact on the brain. There are still plenty of unknowns at this stage, though, and it’s not entirely clear when and how the virus is getting into the brain.
But there is a growing body of literature suggesting that people with COVID-19 experience an immune response and may experience a breakdown of the blood-brain barrier that normally protects the brain from outside harm. And those biologies play a role in AD and other forms of dementia.
According to Snyder, previous studies have linked other pandemics to memory impairment, like Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). That historical component, along with recent reports of brain fog and “long-haulers,” has sparked a desire to better understand the impact of COVID-19 on the brain.
Study of Studies
Although the international endeavor has been referred to as a study, Snyder said it’s actually more like a consortium or a study of studies. The research consists of three main groups, she explained. The first consists of individuals that have been hospitalized with confirmed cases of COVID-19. Researchers will be following up with them at 6, 9, and 18 months—and possibly beyond.
The second group is made up of ongoing cohort studies. Many of the sites and many of the study teams already had participants enrolled in studies that were collecting information related to cognition. They’ve added in some additional measures as they continue to engage those participants, Snyder said.
The third group, meanwhile, involves community recruitment. Some of the sites engage people in the community, enroll them, gather information about when they had COVID-19, and then follow them over time.
For the community and hospital-based cohorts, the individuals involved are age 50 and over. For the cohort studies, it depends on the individual criteria that were already in place. Some of the study teams will collect brain images using magnetic resonance imaging (MRI). Some will collect blood samples from participants; standard protocols have been proposed that would store those samples in a way that would enable follow-on analysis and follow-on studies. Some teams may also conduct more detailed imaging or collect other types of fluids.
The research will analyze the viral infection’s short- and long-term effects on the central nervous system and differences across countries regarding the viral impact of COVID-19.
The goal is to understand the long-term implications that could impact the brain, cognition, and function—including the underlying biology that could contribute to AD and other brain disorders.
Several sources of information and various clinical surveys of diverse populations predict serious cognitive decline in a large fraction of those who recover from COVID-19, explained Hermona Soreq, professor of molecular neuroscience at the Hebrew University of Jerusalem. But while the clinical and psychological observations are clear, the cellular and molecular origins are still being debated, according to Soreq, who is not currently affiliated with the research endeavor.
Some studies indicate that the post-COVID-19 cognitive decline stems from a malfunctioning of the blood-brain barrier, she told Bio-IT World. Others point to direct infection and destruction of neurons in the brain. Still others suggest that over-active immune cells are the root cause.
Beyond that, different studies have been conducted in different countries and age groups as well as different disease symptom severity levels, which only adds to the confusion.
To address this, dozens of experts from various countries have come together to evaluate the risk, she added, in the hopes of finding new ways to reduce the impact of cognitive damage in the post-pandemic infection community.
To date, scientists from roughly 30 countries have come together.
Researchers are hoping to enroll about 1,000 participants at each site, for a total of roughly 30,000, explained Gabriel A. de Erausquin, lead author of the paper and distinguished professor of neurology at the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases at UT Health San Antonio.
Lining up that many participants will be more difficult in some countries than others, however. Cuba and Haiti, for instance, are much smaller countries with, at least for the time being, smaller numbers of COVID-19 cases.
The effort will depend on funding as well. “We don’t have a uniform management, if you will, or a uniform funding source,” he told Bio-IT World. “Rather, each country, or small groups of countries, are seeking funding available to them locally.”
In Europe, for example, Sweden, the Netherlands, Denmark, Germany, England, and Wales are all participating and are all seeking their own funding (except for one component of work that is a collaboration between the UK and the US). In South America, Peru, Bolivia, Argentina, Chile, and Brazil are involved in the coordination effort, but of those countries, only Argentina has secured independent funding.
The effort extends to other parts of the world as well. Australia is involved, for example. So are China, India, and Thailand. They all have different components that are funded locally, or they are in the process of seeking funding, he added.
International Aspect Brings Benefits, Challenges
Little is known about the determinants or risk factors for the complications that may impact the brain following COVID-19, said de Erausquin. We know relatively little about the habits or the genes that may either reduce risk or protect altogether, for example, and the same goes for whether individuals will slowly recover or worsen over time.
The only way to address these types of unknowns is to compile a large enough and heterogeneous enough sample to include plenty of genetic variation and differences regarding aspects like environment.
Within the US, there are several institutions involved in addition to the University of Texas Health San Antonio, including the University of Washington in Seattle, Boston University, Albert Einstein College of Medicine in New York City, and the University of Pittsburgh.
“And we are in very active discussions with the National Institutes of Health,” de Erausquin added, “particularly the National Institute on Aging, to try to find a way to support this effort moving forward.”
But even in a country as diverse as the US, research participation by minority groups is limited and difficult to achieve, he explained. To address these larger questions about the role of genetic variation and possibly the role of different types of vaccines and virus strains, he believes the type of international effort that has been initiated is crucial.
There are plenty of challenges, though, that come along with this type of large-scale international collaboration. Scientific, funding, and coordination issues will all need to be addressed, de Erausquin noted.
“You have to find tools, for instance, that will either be the same across cultures, languages, and settings, or at least will be comparable in a way that the data you extract are not biased by any of those features or practices,” he said.
Identifying a source of funding or several sources of funding for each of the scientists involved is another major hurdle. In that sense, the Alzheimer’s Association has been a welcome source of support early on. The organization has provided initial funding for coordination efforts that will enable the independent research groups to be in a position to seek funding for their specific data collection and recruitment efforts. And then, of course, there’s the challenge of merely holding a meeting when stakeholders live in different parts of the world and, in some cases, radically different time zones.
Soreq agreed that this effort’s international aspect is important considering the diverse patient populations studied and the various medical procedures involved. And she, too, believes the collaborative effort faces some significant challenges since the predicted duration of the observed damage and the underlying mechanisms that drive this post-disease cognitive decline aren’t yet known.
In Search of Preventative and Treatment Strategies
Still, those involved see the potential upside involved in this large-scale endeavor. “The goal would be to either find a way to prevent or a way to reverse these types of complications moving forward,” said de Erausquin.
To get there, the first step is to have a clear understanding of the questions that need to be answered, like what are the critical risk factors? And what are the critical protective factors that determine which people will experience complications? When there is a better understanding, he said it may be possible to leverage inherited or environmental protections to reduce risk or correct a problem that’s already underway.
It is anticipated that the first round of data stemming from the new research initiative will be made available in 2022.
Paul Nicolaus is a freelance writer specializing in science, nature, and health. Learn more at www.nicolauswriting.com.