Biological Evidence for Anxiety in Long COVID

Megan Brooks

March 08, 2022

Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

Investigators have found biochemical evidence of brain injury in patients hospitalized with acute COVID-19 and in those with long COVID. 

Combined blood biomarker evidence of neuronal damage activation of glial cells, indicating brain inflammation, correlated with symptoms of anxiety in long COVID patients.

This study shows that "some patients with long COVID have evidence of brain damage or brain inflammation, which gives validity to the symptoms that these patients present with," Igor Koralnik, MD, head of the Neuro COVID-19 Clinic at Northwestern Memorial Hospital, Chicago, Illinois, said during a media briefing.

The study was published online March 7 in Neurology: Neuroimmunology & Neuroinflammation.

Ongoing Inflammation

Although patients hospitalized with COVID-19 often present with encephalopathy, patients with mild initial COVID-19 who don't require hospitalization can also develop neurologic symptoms as part of post-acute sequelae of severe acute respiratory coronavirus type 2 (SARS-CoV-2) infection (neuro-PASC).

Symptoms of neuro-PASC include cognitive difficulties, headaches, dizziness, disorders of smell and taste and neuropsychiatric complaints such as new-onset anxiety and depression.

The lingering nature of these complaints suggests that ongoing brain inflammation and/or direct damage to the central nervous system may persist long after acute infection with the virus resolves.

However, the precise pathogenic mechanisms remain unclear.

The investigators looked for biochemical evidence of brain injury in 64 patients, including acutely infected, hospitalized patients with COVID-19 encephalopathy (CE), neuro-PASC patients suffering chronic neurologic symptoms up to 13 months after either severe acute disease requiring hospitalization or mild initial infection, and healthy controls.

They found that the acutely infected hospitalized encephalopathic COVID-19 patients had "highly elevated" levels of plasma neurofilament light chain (pNfL) and plasma glial fibrillary acidic protein (pGFAP), indicating direct damage to nerve cells and increased inflammation within the brain.

Plasma SARS-CoV-2 nucleocapsid antigen (pN Ag) was also more frequently detected in the CE patients than in all neuro-PASC groups.

The neuro-PASC patients — both those who had been hospitalized and those who were never hospitalized — did not have the same elevation of the two blood markers at the time of sampling (3 months or more after their acute infection with COVID).

However, the subgroup of neuro-PASC patients who also suffered from anxiety or depression, had higher neuroglial scores, which were strongly correlated with increased anxiety levels.

The correlation between anxiety and neuroglial scores remained after controlling for potential confounding factors and was observed in both qualitative and quantitative measures of anxiety, "which suggests there is a true relationship," Barbara Hanson, PhD, who co-authored the study and analyzed the data in the Northwestern Medicine Neuro COVID-19 research lab, said in a news release.

Validating, Important Research

"When it comes to the neuropsychiatric symptoms of COVID-19, many patients probably feel that their symptoms are dismissed, so finding empirical evidence that shows that there is likely to be a biological basis of these kinds of symptoms, I think is very validating and important for these patients," Hanson told the briefing.

Limitations of the study include the limited sample size and patients without post-COVID neurologic symptoms were not represented in the study. The researchers say future studies should include this patient population to determine whether SARS-CoV-2 infection affects the levels of plasma biomarkers in the absence of neurologic sequelae.

This research is important, considering the scope of the problem, Hanson told the briefing.

It's estimated that about one third of all patients with COVID-19 develop neurologic symptoms following the acute illness, she explained.

With more than 48 million documented COVID infections since the start of the pandemic in the United States, it is likely that more than 15 million people have been or are currently suffering neurologic sequelae in the United States alone.

This would make neuro-PASC the third most prevalent neurologic disorder in the United States behind only tension and migraine headaches and ahead of stroke, Alzheimer's disease and other dementias, spinal cord and traumatic brain injuries, and idiopathic epilepsy.

"That's pretty striking," Hanson said.

The study had no targeted funding. The investigators have disclosed no relevant financial relationships.

Neurol Neuroimmunol NeuroInflammation. Published online March 7, 2022. Full text

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