The National Institute of Health has awarded a $3.75 million research grant to a multidisciplinary team of USF Health researchers to study Long COVID and its potential link to serious neurological impacts that can ultimately lead to dementia and Alzheimer’s disease – as well as to explore possible interventions to prevent that.
The grant, awarded in September, funds a five-year investigation with the potential for broad impact, given COVID-19 has burdened an estimated 30 million Americans with neurologic symptoms, according to Subhra Mohapatra, PhD, professor of Molecular Medicine at the USF Health Morsani College of Medicine and research career scientist at the James A Haley Veterans Hospital, the team’s lead researcher.
“These include dementias and a drop in global cognitive performance,” Dr. Mohapatra said. “However, the exact mechanisms for these disorders are unknown, and how to prevent progression to Alzheimer’s disease remains an open question.”
Dr. Subhra Mohapatra
That is the mystery to be examined by a diverse team that includes, in addition to Dr. Subhra Mohapatra, Dr. Paula Bickford, a multi-principal investigator and professor of Neurosurgery and Brain Repair; Dr. Shyam Mohapatra, a multi-principal investigator and a professor and director of MCOM’s Division of Translational Medicine; and co-investigators Drs. Laura Blair, Bala Chandran, and Arunava Roy from the Department of Molecular Medicine; and Dr. Eleni Markoutsa of the Department of Internal Medicine.
Four years ago, as the COVID-19 pandemic swept across the globe, Dr. Subhra Mohapatra and her fellow researchers set out simply to understand how the virus could be prevented and how infected individuals could be treated effectively. But that initial mission soon led to a startling discovery: a link between the condition known as “Long COVID” – when symptoms of COVID persist, rather than resolving after the initial infection, and can include fatigue, dizziness, disturbances in sleep, “brain fog,” and eventual neurological problems.
In a series of studies, they found that Long COVID produces a marker for Alzheimer’s disease called tau – an accumulation of neurotoxic molecules that create aggregates known as tauopathy. This accumulation leads to memory loss and loss of cognition, the hallmarks of Alzheimer’s. Autopsies of individuals suffering from these symptoms revealed evidence that the virus made its way into the brain through inflammation to cause neurological issues.
It should be noted, Dr. Mohapatra said, that the duration of Long COVID varies – with many improving significantly over time, while others experiencing symptoms far longer.
The team aims to understand the cellular and molecular mechanisms behind COVID-induced tauopathy and identify potential drug targets to prevent or slow its progression.
“Neuro-COVID spanning weeks to months past the time of recovery from COVID-19 illness has afflicted millions of Americans, particularly the aged indviduals ” Dr. Bickford, an expert in the field Aging and brain repair, explained. “Though the magnitude of the problem is still being defined, the public health impact is profound due to the number of individuals of all ages who have been or will be infected. There is a great lack of knowledge of the basic neuropathology and how to treat or prevent these conditions.”
In fact, the team’s approach has been based on finding ways to disrupt the progression. “Can we find a drug that can halt this progression and prevent people from developing this?” said Dr. Shyam Mohapatra, a nanomedicine expert in the team. “We are making progress in that regard. We have preliminary data and are working to test a hypothesis that we can intervene by reducing certain signature proteins we have discovered. These can help in terms of interfering in the process and preventing the disease.”
The danger, Dr. Subhra Mohapatra said, is that Long COVID could lead to a wave of early onset Alzheimer’s disease in 10 years. The elderly and those with pre-existing medical conditions are at greatest risk for Long COVID and its related neurological issues.
“We found that with an increase in age, there was a greater accumulation of these neurotoxic tau molecules,” Dr. Mohapatra said. “And we also observed that with age, there is more neuro-inflammation in the brain that includes a classic molecular pathway that is a signature of Alzheimer’s.”
The significance of the team’s work – and the magnitude of the research award – cannot be overstated, said Charles J. Lockwood, MD, MHCM, executive vice president of USF Health and dean of the Morsani College of Medicine.
“This NIH RO1 award has the potential to significantly impact our understanding of the long-term adverse effects of COVID, provide new insights into the triggers of dementia and eventually help the patients we serve,” he said. “At USF Health, we believe that highly interdisciplinary research can help us tackle complex, real-world challenges, such as this project on Long COVID, which, sadly, will be with us for the foreseeable future. These programs which foster critical thinking, innovation, and collaboration, are vital for addressing the pressing issues of our time."
The team has come a long way since 2020, when it simply set out to learn more about COVID-19 and possible treatments. Dr. Subhra Mohapatra joined USF Health in 2007 from Moffitt Cancer Center, working first on cancer research, later on viral infections and then on neurodegenerative disease, with a special focus on traumatic brain injuries. When the team began researching COVID, she was instantly drawn to possible effects on the brain.
“The first question we asked was whether COVID was affecting the brain directly,” she said. “We published a paper early on examining how COVID can enter the brain, what are the pathways it can take – and lo and behold realized that we could see molecular evidence. Our model suggested that it can cause neuroinflammation – that was very important, because any neurodegenerative disease begins with this inflammation.”
Four years later, they are truly taking their research to an even higher level – fueled by a landmark grant that underscores the vital importance of their work.