In Long COVID, blood markers are associated with neuropsychiatric symptoms


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

Source: UCSF

In a new study from Long COVID published March 13, 2022 in the Annals of NeurologyUC San Francisco researchers identified biomarkers that are present at elevated levels and can persist for many months in the blood of study participants who had long had COVID with neuropsychiatric symptoms.

The results show promise for the development of laboratory tests to assess long-term COVID risks and evaluate new therapies to combat a form of COVID that is sometimes thought of as a subjective syndrome that is difficult to describe and measure.

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

“Now we’re beginning to identify objective biological measurements that correlate to what people tell us about their longstanding COVID symptoms.”

Long COVID is characterized by persistent or emerging symptoms such as fatigue, shortness of breath, cognitive difficulties, cardiac arrhythmia, sleep disturbances, and muscle and joint pain, which can persist for months after acute infection with the SARS-CoV2 virus.

Researchers estimate that between 10% and 30% of those infected with the SARS-CoV-2 virus have long-standing COVID symptoms (although this seems less likely in vaccinated individuals). According to a recent report by the US Government Accountability Office, as many as 23 million people in the United States could already be affected by chronic health problems caused by infection.

Long COVID can even affect people who initially had only mild illness, and perhaps even those who were asymptomatic despite testing positive for an infection.

Viral proteins reside in brain cells

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

In addition, for comparison, laboratory researchers analyzed blood plasma samples from 12 never-infected controls without neuropsychiatric symptoms.

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

The study’s original intention was to follow patients over time to track natural immunity after COVID infection, but once it became clear that patients continued to have symptoms on return visits many weeks after infection, the understanding was clear of these long COVID symptoms became a focus of the study.

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

Blinded to patient identity and symptom status, the team then used a blood plasma sample-based technique developed by corresponding author Edward Goetzl, MD, a professor emeritus of medicine at UCSF, to measure viral and patient proteins produced by neurons come.

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

The analysis found much higher average levels of two SARS-CoV-2 virus proteins they measured — the nucleocapsid protein and the spike protein — in blood plasma samples taken between six and 12 weeks after diagnosis from COVID-infected patients, which compared exhibited neuropsychiatric symptoms in samples from those who had long had COVID but had no neuropsychiatric symptoms.

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

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

Long COVID is characterized by persistent or emerging symptoms such as fatigue, shortness of breath, cognitive difficulties, cardiac arrhythmia, sleep disturbances, and muscle and joint pain, which can persist for months after acute infection with the SARS-CoV2 virus. The image is in the public domain

Researchers measured significant differences in levels of several mitochondrial proteins between long-COVID patients with and without neuropsychiatric symptoms, which Goetzl says indicates changes in mitochondrial function within neurons.

“I think the majority of scientists who have considered this could say that it’s very unlikely that the virus particles remain infectious at this stage, but these viral proteins hanging around the cell can still do bad things arrange,” said Goetzl. He is optimistic about developing small molecule drugs that can enter infected cells and destroy certain viral proteins.

On the way to diagnosis and treatment

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

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

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

About this long piece of news from COVID and mental health research

Author: Jeffrey Norris
Source: UCSF
Contact: Jeffrey Norris-UCSF
Picture: The image is in the public domain

Original research: Open access.
“SARS-CoV-2 and mitochondrial proteins in neurally derived exosomes of COVID-19” by Michael J. Peluso et al. Annals of Neurology


SARS-CoV-2 and mitochondrial proteins in neurally derived exosomes from COVID-19


Since SARS-CoV-2 is known to enter the mitochondria of neurons, a plasma system for quantifying central nervous system proteins in living humans was used to study the neuropathogenic mechanisms of long-COVID-19.


SARS-CoV-2 proteins and mitochondrial proteins (MPs) in enriched plasma neuron-derived extracellular vesicles (NDEVs) and astrocyte-derived EVs (ADEVs) have been resolved in acute COVID-19 without post-acute sequelae of SARS- CoV-2 quantified (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 with NP than without NP. Exosome marker CD81-normalized NDEV mean values ​​of MP respiratory chain complex I subunit 6 and complex III subunit 10, as well as neuroprotective MP humanin and mitochondrial 12S rRNA-c open reading frame (MOTS-c) were all significantly reduced PASC with NP , but not in PASC without NP compared to controls. NDEV levels of voltage-dependent anion-selective channel protein 1 (VDAC1) and N-methyl-D-aspartate receptor 1 (NMDAR1) of MPs were decreased in PASC without and with NP, while those of mitochondrial calcium uniporter (MCU) calcium channel MPs were reduced. , sodium/calcium exchanger (NCLX) and leucine zipper EF hand with transmembrane 1 protein (LETM1) were reduced only in PASC with NP. In PASC without and with NP, only MCU and NCLX ADEV levels were elevated.


Abnormal NDEV and ADEV levels of SARS-CoV-2 N and S1 protein and MPs correlate with NP and may be biomarkers for long-term COVID prognosis and therapy studies. ANN NEUROL 2022;91:772-781

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