In prolonged COVID, blood markers are linked to neuropsychiatric symptoms

Summary: Researchers have identified elevated levels of a biomarker in the blood that persist for months in long-term COVID patients experiencing neuropsychiatric symptoms.

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In a new prolonged COVID study published on March 13, 2022, in the annals of neurologyUC San Francisco researchers identified biomarkers present at elevated levels that can persist for many months in the blood of study participants who had prolonged COVID with neuropsychiatric symptoms.

The results hold promise for developing laboratory tests to measure long-term COVID risks and for evaluating new therapies to address a form of COVID that has sometimes been viewed as a subjective syndrome that is difficult to describe and measure.

“For much of the first year of the pandemic, many people with prolonged COVID were told that what they were experiencing wasn’t even valid,” said Michael Peluso, MD, an assistant professor of medicine at UCSF and the study’s first author.

“Now, we are beginning to identify objective biological measures that correlate with what people are telling us about their prolonged COVID symptoms.”

Prolonged COVID is characterized by ongoing or new symptoms, such as fatigue, shortness of breath, cognitive difficulties, heart rhythm abnormalities, sleep disturbances, and muscle and joint pain, which can persist for months after acute SARS-virus infection. CoV2.

Researchers estimate that between 10% and 30% of people infected with the SARS-CoV-2 virus experience prolonged COVID symptoms (although it appears to be less likely among vaccinated people). As many as 23 million people in the United States may already have suffered from chronic health problems caused by infection, according to a recent report from the US Government Accountability Office.

Prolonged COVID can even affect people who initially experienced only mild illness and perhaps even those who were asymptomatic despite testing positive for infection.

Viral proteins remain in brain cells

To conduct the study, doctors surveyed 46 previously infected patients about 32 prolonged physical symptoms of COVID, as well as mental health symptoms such as memory loss, irritability, agitation, depression, anxiety, post-traumatic stress, and specific sensory losses.

In addition, the lab researchers analyzed blood plasma samples from 12 never-infected control subjects without neuropsychiatric symptoms for comparison.

All study participants were patients in the San Francisco-based COVID-19 Long-Term Impact of Infection with the Novel Coronavirus (LIINC) study, and were enrolled from March 2020 to February 2021, after testing positive for infection.

The original intent of the study was to follow patients over time to track natural immunity following COVID infection, but when it became clear that patients at return visits continued to experience symptoms many weeks after infection, understanding these prolonged symptoms of COVID became a primary focus of the study.

The new findings are based on a single time point, but patients continue to be monitored for changes in symptoms and potential immunological and other biomarkers.

Unaware of the patient’s identity and symptom status, the team used a technique based on blood plasma samples, developed by corresponding author Edward Goetzl, MD, an emeritus professor of medicine at UCSF, to measure viral and neuron-derived patient.

The researchers first isolated protein-filled sacs, called exosomes, released into the blood by all types of cells, then selected only those exosomes derived from neurons and supporting cells known as astrocytes. Goetzl sees this approach as a proxy measure that reflects the disruption that occurs in brain cells after SARS-CoV-2 infection.

The analysis detected much higher average levels of two SARS-CoV-2 viral proteins they measured, the nucleocapsid protein and the spike protein, in blood plasma samples collected between six and 12 weeks after diagnosis from patients infected with the virus. COVID who had neuropsychiatric symptoms compared. to samples from those who had COVID for a long time, but did not have neuropsychiatric symptoms.

Levels of these proteins from neuronal exosomes in long-COVID patients without neuropsychiatric disease remained higher than levels in non-long-COVID patients.

Goetzl said that SARS-CoV-2, like several other viruses, targets structures called mitochondria within the cells it invades. The virus most likely interferes with normal mitochondrial tasks, she said, including providing the cell with a usable form of energy and contributing to the immune system’s ability to respond to infection.

Prolonged COVID is characterized by ongoing or new symptoms, such as fatigue, shortness of breath, cognitive difficulties, heart rhythm abnormalities, sleep disturbances, and muscle and joint pain, which can persist for months after acute SARS-virus infection. CoV2. The image is in the public domain

The researchers measured significant differences in the levels of several mitochondrial proteins between long-COVID patients with and without neuropsychiatric symptoms, pointing to alterations in mitochondrial function within neurons, according to Goetzl.

“I think most scientists who have considered this would say that virus particles are very unlikely to remain infectious at this stage, but these viral proteins that are in the cell can still do bad things,” Goetzl said. . He is optimistic about developing small-molecule drugs that can enter infected cells and destroy specific viral proteins.

Towards diagnosis and treatment

See also

This shows a stressed woman looking at her laptop.

Many researchers attribute chronic symptoms in long-term COVID primarily to prolonged or impaired immune responses, Peluso said. The initial acute infection could trigger long-term maladaptive changes in the immune system.

The continued presence of viral proteins within the body could cause chronic inflammatory responses. The presence of certain viral molecules could also trigger autoimmune responses in which the immune system attacks the body’s own tissues.

“By identifying biomarkers like these, we will be able to more accurately diagnose prolonged COVID and identify effective treatments through well-designed clinical trials,” Peluso said. “With this study, we have taken an important step toward that goal.”

About this long research story on COVID and mental health

Author: Jeffrey Norris
Font: UCSF
Contact: Jeffrey Norris – UCSF
Image: The image is in the public domain.

original research: Open access.
“SARS-CoV-2 and mitochondrial proteins in nerve-derived COVID-19 exosomes” by Michael J. Peluso et al. annals of neurology


SARS-CoV-2 and mitochondrial proteins in exosomes derived from the nerves of COVID-19


As SARS-CoV-2 is known to invade neural cell mitochondria, a plasma system was used to quantify central nervous system proteins in living humans to investigate the neuropathogenic mechanisms of prolonged COVID-19.


SARS-CoV-2 proteins and mitochondrial proteins (MPs) in neuron-derived extracellular vesicles enriched plasma (NDEV) and astrocyte-derived EVs (ADEV) were quantified in resolved acute COVID-19 without post-acute sequelae of SARS- CoV-2 (PASC), PASC without neuropsychiatric manifestations (NP), PASC with NP and healthy controls.


Mean NDEV and ADEV levels of SARS-CoV-2 S1 and nucleocapsid (N) proteins were higher in all PASC subgroups than controls, but only N levels were higher in PASC than controls. no NP. CD81-normalized NDEV exosome marker Mean levels of respiratory chain MP complex I subunit 6 and complex III subunit 10, and neuroprotective MPs Humanin and mitochondrial 12S rRNA-c open reading frame (MOTS -c) were significantly reduced in PASC with NP but not in PASC without NP relative to controls. NDEV levels of MP voltage-dependent anion-selective channel 1 protein (VDAC1) and N-methyl-D-aspartate receptor 1 (NMDAR1) were reduced in PASC without and with NP, while those of the Calcium channel MPs mitochondrial calcium uniporter (MCU), sodium/calcium exchanger (NCLX), and leucine zipper EF hand-containing transmembrane protein 1 (LETM1) were reduced only in PASC with NPs. ADEV levels of MCU and NCLX only increased in PASC without and with NP.


Abnormal NDEV and ADEV levels of SARS-CoV-2 protein N and S1 and MP correlate with NP and may be biomarkers for long-term COVID prognoses and therapeutic trials. ANN NEUROL 2022;91:772–781

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