R3 Seminar Recap: Impact of Long COVID on neurocognitive function

Researchers Jacqueline Becker, PhD; Jennifer Frontera, MD; and Michael VanElzakker, PhD, were joined by RECOVER Patient Representatives Mike Zissis and Liza Fisher, who shared their experiences with these cognitive symptoms. Given that neurocognitive symptoms (such as trouble thinking clearly, remembering things, and concentrating) are among the most commonly reported and debilitating effects of Long COVID, RECOVER continues to prioritize studies in this area. 

Researchers use different ways to measure neurocognitive symptoms

Dr. Jacqueline Becker (Icahn School of Medicine, Mount Sinai) explained that neurocognitive symptoms in Long COVID can affect multiple areas of brain function, including attention, memory, processing speed, and executive function (the ability to plan and stay on task). She defined neurocognition as “how the brain processes information” and shared, “It’s what allows us to think, learn, remember, make decisions, and function in everyday life.”

Importantly, she noted that researchers understand these symptoms in 2 ways:

• Objective cognitive tests measure what the brain can do under controlled conditions, such as memory exercises or timed problem-solving tasks.
• Patient-reported measures capture how people feel cognitively in their everyday lives—how much effort thinking takes, how often they lose their train of thought, or how much their symptoms interfere with work and daily activities.

These 2 measures often don’t match. A patient can struggle significantly in daily life while still performing within a normal range on a standard cognitive test. This disconnect is one of the most important challenges researchers are working to address in future research studies.

Current findings and gaps inform RECOVER’s next steps

Dr. Becker shared that findings from the first phase of RECOVER’s adult observational study confirmed that a significant share of Long COVID patients experience measurable cognitive impairment. Long COVID patients may experience a decline in executive function and memory. A more recent study found that some patients continue to have problems with executive functioning and memory even years after having COVID-19. 

RECOVER’s next phase of the adult observational study (Cycle 2) is designed to answer more specific questions, focusing on 3 types of dysfunction within the body: neurocognitive, cardiopulmonary (heart and lung), and autonomic (the system that controls automatic body functions like breathing and heart rate). Dr. Becker also outlined 4 priorities in the next phase of the study:

• Collect cognitive data alongside biosamples from adult participants to better understand how SARS-CoV-2 (the virus that causes Long COVID) causes cognitive symptoms.
• Track cognitive symptoms over time and link them to biomarkers (signs of disease that can be observed and measured) in blood.
• Define the types of cognitive symptoms (phenotypes) and explore the relationship between patient-reported brain fog and an objective decline.
• Explore the relationship between cognitive symptoms and symptoms in the heart, lungs, and autonomic nervous system.

“One of the most important roles of observational research like RECOVER is that all of this can help us identify patterns and uncover mechanisms so that we know what to treat and in whom,” shared Dr. Becker. Researchers are applying what they've learned about Long COVID to inform treatment targets in upcoming RECOVER-TLC (Treating Long COVID) clinical trials.

RECOVER-TLC will test low-dose naltrexone, glucagon-like protein-1 (GLP-1) receptor agonists, and stellate ganglion nerve block (SGB) as possible treatments for Long COVID, which Dr. Becker notes “all [look] at cognition as a secondary outcome.” REVERSE-LC, another RECOVER-TLC trial, will test the drug baricitinib. Dr. Becker shares that “the primary outcome [of this trial] is specifically neurocognitive function and physical impairment.”

Researchers find physical evidence of cognitive decline in people with Long COVID

Dr. Jennifer Frontera (NYU Langone Health) shared her team’s research, which found that people with Long COVID were significantly more likely to be diagnosed with mild cognitive impairment (MCI) over a 4-year period than people who had COVID-19 and fully recovered or never had COVID-19 at all. This held true even among people who were never hospitalized. 

The type of MCI seen most often was Alzheimer’s type dementia, meaning it involved memory problems similar to those seen in early Alzheimer’s disease. Blood tests confirmed that a biomarker strongly associated with Alzheimer’s disease (pTau217) was significantly elevated in people with Long COVID. Elevated pTau217 levels were even found in some patients who did not report brain fog. This suggests that cognitive changes may be happening before people are aware of them.

Dr. Frontera also reported changes in brain magnetic resonance imaging (MRI) scans, including reduced blood flow to the brain and enlargement of the choroid plexus (a structure involved in clearing waste products from the brain). Both changes were associated with worse cognitive test scores and higher levels of pTau217. She emphasized that RECOVER’s tissue pathology (autopsy) study, which collected brain samples from people with Long COVID who died, can help confirm these findings. 

Research shows link between brain inflammation and cognitive dysfunction

Dr. Michael VanElzakker (Harvard Medical School, Massachusetts General Hospital) offered insights into why cognitive problems may occur. His research focuses on neuroinflammation—the activation of the brain’s immune cells (called glia). In some cases of Long COVID, glia cells become activated and stay that way. This chronic (long-term) inflammation can disrupt the brain’s normal signaling and make cognitive tasks harder.

Using a specialized brain scanner that combines Positron Emission Tomography (PET) and MRI, Dr. VanElzakker’s team found elevated signs of neuroinflammation across multiple brain regions in people with Long COVID compared to people without Long COVID. They then had patients perform a focus task inside the scanner that required blocking out distractions to identify a correct answer. Researchers found that in the group with Long COVID, their brains had to work considerably harder to complete the task—even when they got the answer right. The areas that showed the most inflammation were the same areas that required the most effort during the task.

Patient Representatives share personal stories of cognitive challenges 

RECOVER Patient Representatives Liza Fisher and Mike Zissis both shared the cognitive impacts they’ve experienced living with Long COVID. 

Ms. Fisher had COVID-19 in June 2020 and was admitted to the intensive care unit 5 weeks later. She went on to spend months in a rehabilitation hospital, where she struggled with speech and neuromuscular function and scored poorly on standard cognitive screening tests. Years later, Ms. Fisher still lives with attention and focus difficulties. She also experiences cognitive post-exertional malaise, meaning that mental effort, not just physical activity, can trigger extreme fatigue and flu-like symptoms. 

She shared that cognitive symptoms in Long COVID fluctuate, which makes them hard to capture with a single test on a single day. Furthermore, she emphasized that the experience for many people with Long COVID goes far beyond brain fog. It is a real, measurable deficit that affects every aspect of daily life.

Mr. Zissis had COVID-19 in January 2021 and knew almost immediately that something was affecting his brain. He soon lost the ability to multitask and began experiencing severe short-term memory loss—symptoms that have only partially improved years later. Today, Mr. Zissis lives with what he described as ADHD-like symptoms such as inattention, difficulty focusing, and easy distractibility. He urged clinicians to trust patients even when tests fall short and to use precise terms like “cognitive impairment” instead of the term “brain fog” to more accurately reflect the severity of cognitive symptoms. He noted the important partnership between patients and researchers to drive progress in understanding, diagnosing, and treating Long COVID. “Research can’t do anything without us, and we can’t do anything without research,” said Mr. Zissis.

Uncovering more answers about Long COVID

RECOVER’s adult observational study will continue to address critical questions about Long COVID, placing special emphasis on neurocognitive symptoms, cardiopulmonary symptoms (symptoms that affect the heart and lungs), and the similarities between Long COVID and other infection-associated chronic conditions. 

Subscribe to the RECOVER Report to stay up to date on the next phase of RECOVER research. 

Another important avenue to find answers about Long COVID, Dr. Becker shared, is through ancillary studies. Ancillary studies are independent research projects that allow researchers to request to use the data and biosamples collected by the initiative. These studies can help address questions that are not included in the study plans for RECOVER. Learn about RECOVER ancillary studies, including how to apply.

To find recordings and transcripts from previous R3 Seminars, visit the R3 Seminar Series webpage or the RECOVER YouTube channel.