Brain clues in the battle against long COVID: study pinpoints neuroinflammation

By Dr. Priyom Bose, Ph.D.Oct 25 2023Reviewed by Lily Ramsey, LLM

The coronavirus disease 2019 (COVID-19) pandemic has led to a public health crisis known as long-COVID, or post-acute sequelae of COVID-19 (PASC).

A recent study published on the bioRxiv* preprint server analyzed the relationship between circulating markers of vascular dysfunction and neuroinflammation in patients with diverse symptoms of PASC. The study used [11C]PBR28 PET neuroimaging to detect neuroinflammation

Study: Neuroinflammation in post-acute sequelae of COVID-19 (PASC) as assessed by [¹¹C]PBR28 PET correlates with vascular disease measures. Image Credit: Meeko Media/Shutterstock.com

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Background

The ongoing COVID-19 pandemic has been caused by the rapid outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a highly contagious respiratory virus. According to the recent US Census Bureau’s Household Pulse Survey report, 11% of adults who contracted SARS-CoV-2 infection developed PASC.

Several non-specific neurological and neuropsychiatric symptoms, such as brain fog, intense fatigue, difficulty in concentrating, depression, anxiety, body pain, and irregular sleep, have been identified as long-COVID manifestations.

These symptoms significantly affect the quality of life. Long-COVID is not only linked with severe infection, but mild SARS-CoV-2 infection can also lead to PASC.

Vascular-related issues, inflammation, and coagulation developed during acute SARS-CoV-2 infection may persist for a prolonged period and may lead to the development of PASC.

Several studies have shown that the brain is exceptionally vulnerable to disruptions to vascular health. These studies have also indicated that SARS-CoV-2 infection is vulnerable to vascular health disorders. For instance, survivors of acute COVID-19 were found to be at a higher risk of hemorrhagic stroke and cerebral venous thrombosis, particularly in the year following the infection.

A longitudinal study compared the structural neuroimages of the same person, pre-pandemic and post-COVID. A small but significant decrease in the grey matter thickness and whole-brain volume was observed. In addition, elevated markers of tissue damage were observed in post-COVID samples.

A neuroimaging study based on arterial spin labeling fMRI revealed a decreased neurovascular perfusion in long-COVID patients. No PASC study has explored the direct link between neuroinflammation and vascular dysfunction.

About the study

The current cross-sectional, case-control study determined whether long-COVID patients with a range of symptoms experience an increased risk of neuroinflammation compared to healthy controls with no history of SARS-CoV-2 infection. This study also investigated whether PASC neuroinflammation was linked to vascular health measures.

The current study compared PASC with control individuals without a history of COVID-19. Positron emission tomography (PET) neuroimaging was used to determine neuroinflammation in PASC. Here, [¹¹C]PBR28 PET neuroimaging standardized uptake value ratios (SUVR) were compared between PASC and controls.

All participants were asked to complete a questionnaire regarding pain and depression. PASC participants answered additional questions linked to their PASC symptoms.

Peripheral blood samples collected from PASC participants immediately before PET scans were analyzed to understand the association between central nervous system (CNS) glial activation in PASC and measures related to inflammation, vascular health, and angiogenesis.

Furthermore, platelet-poor plasma (PPP) was estimated for the PASC group immediately before [¹¹C]PBR28 exposure.

A modified myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) International Consensus Criteria (ICC) was used as the PASC group inclusion criteria. A total of 12 individuals were recruited for PASC group. These individuals were compared with an existing normative dataset of 43 healthy controls.

Study findings

The majority of the participants with PASC did not require hospitalization for their acute SARS-CoV-2 infection. A significant increase in [¹¹C]PBR28 signal was observed in a wide area of the brain, including the thalamus, midcingulate cortex, corpus callosum, anterior cingulate cortex, basal ganglia/striatum, medial frontal gyrus, subfornical organ, and precentral gyrus.

Contradicting the findings of a previous study, the current study indicated that the average depression score of the PASC group was mild. In contrast, the control group reported depression in the pre-COVID period. Future research must include additional COVID-19-recovered individuals for a reference group.

The intensity of the whole-brain PET signal indicated significant positive correlations with blood measures and vascular health. The variability in PET signal across brain structures reflected the difference in vascular anatomy and perivascular immune penetration.

An elevated level of fibrinogen and sL-selectin, markers of vascular health multiplex panel, were significantly correlated with neuroinflammation-related PET signals. A previous study indicated that enhanced fibrinogen levels lead to adverse COVID-19 outcomes.

Activated perivascular glia triggers glia from within the brain parenchyma and circulating immune factors to migrate from neurovascular blood into the brain.

This study also revealed that a vascular-related anatomical pattern differs among patients. An increased PET signal, particularly within the left lentiform nucleus of the basal ganglia, was observed.

Conclusions

This study has some limitations, including a small number of participants in the PASC group compared to the control group. There is a need to design a well-defined cohort of PASC phenotypes.

In addition, the majority of participants in the PASC group were female. Despite the limitations, the current study documented evidence that processes related to vascular dysfunction and neuroinflammation are directly linked to PASC.

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.