Neurofilament light chain and glial fibrillary acid protein levels are elevated in post-mild COVID-19 or asymptomatic SARS-CoV-2 cases, 2024, Plantone

Abstract
Given the huge impact of the COVID-19 pandemic, it appears of paramount importance to assess the cognitive effects on the population returning to work after COVID-19 resolution. Serum levels of neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) represent promising biomarkers of neuro-axonal damage and astrocytic activation.

In this cohort study, we explored the association between sNfL and sGFAP concentrations and cognitive performance in a group of 147 adult workers with a previous asymptomatic SARS-CoV-2 infection or mild COVID-19, one week and, in 49 of them, ten months after SARS-Cov2 negativization and compared them to a group of 82 age and BMI-matched healthy controls (HCs).

sNfL and sGFAP concentrations were assessed using SimoaTM assay Neurology 2-Plex B Kit. COVID-19 patients were interviewed one-on-one by trained physicians and had to complete a list of questionnaires, including the Cognitive Failure Questionnaire (CFQ). At the first assessment (T0), sNfL and sGFAP levels were significantly higher in COVID-19 patients than in HCs (p < 0.001 for both). The eleven COVID-19 patients with cognitive impairment had significantly higher levels of sNfL and sGFAP than the others (p = 0.005 for both). At the subsequent follow-up (T1), sNfL and sGFAP levels showed a significant decrease (median sNfL 18.3 pg/mL; median sGFAP 77.2 pg/mL), although they were still higher than HCs (median sNfL 7.2 pg/mL, median sGFAP 63.5 pg/mL).

Our results suggest an ongoing damage involving neurons and astrocytes after SARS-Cov2 negativization, which reduce after ten months even if still evident compared to HCs.

https://www.nature.com/articles/s41598-024-57093-z

 

See also

• Long COVID: Plasma levels of neurofilament light chain in mild COVID-19 patients with neurocognitive symptoms 2023, Gutman et al
• Association of neuronal injury blood marker neurofilament light chain with mild-to-moderate COVID-19, 2020, Ameres et al
• Blood Neurofilament Light Chain: The Neurologist’s Troponin?, 2020, Thebault et al
• Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment, 2024, Campbell et al
• Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses, 2023, Michael et al
  
• [Preprint] SARS-CoV-2 Spike Protein Accumulation in the Skull-Meninges-Brain Axis: Potential Implications for Long-Term Neurological Complications
• Longitudinal PET and postmortem analysis reveals widespread neuroinflammation in SARS-CoV-2 infected rhesus macaques, 2023, Nieuwland et al.
• Markers of blood-brain barrier disruption increase early and persistently in COVID-19 patients with neurological manifestations, 2022, Bonetto et al
  
• Elevation of neural injury markers in patients with neurologic sequelae after hospitalization for SARS-CoV-2 infection, 2022, Spanos et al
  

as well as negative results such as

• Neurological involvement among non-hospitalized adolescents and young adults 6 months after acute COVID-19

 

I've often thought that ME's core dysfunction might be one of these proteins that no one pays attention to because they're hard to measure in-situ, and might be limited to a small portion of the brain.

 

I'm not sure to what you are referring to? GFAP/NfL was measured in the 10 studies mentioned above and I'm sure there's even more studies, i.e. rare enough to not be part of a standard lab but not rare enough to not have been studied in multiple studies.

 

The problem is that plasma levels may not be useful measurements of abnormal levels in specific parts of the brain. Think of a CPU: if one of those billions of transistors works erratically, it can cause the whole computer to malfunction, but measuring the power supply current isn't going to reveal the problem. Good health is having the right molecules in the right place in the right amounts. I don't think we yet have the technology to map out these protein levels in glial cells in a living brain.

 

I'm not sure I can currently see your point here, at least with respect to this study. The whole point appears to be that the authors argue that using the SimoaTM assay they can find statistically significant differences in both sNfL and sGFAP concentrations. Do you have evidence to suggest that localized measurements in the brain would be more meaningful?

One of the studies mentioned above which found differences in GFAP levels used imaging to techniques to assess localized BBB integrity whilst a different study from above describes how NfL is now reliably quantifiable in blood (so one has less need to look in the CSF).

It seems that in mice and rats localized measurements of GFAP could be possible (see 1 and 2).

Whether any of this means anything is of course a whole different question...

 

My initial comment wasn't so much about this particular study, but rather about how there are so many chemicals in the brain that are localized and inconvenient to measure. Changes in serum levels might indicate something, but if the production, transport, and removal of the chemical isn't well understood, it could mean something not very helpful. For example, elevated circulating GFAP could mean that the liver isn't clearing it out as effectively as normal, due to some downstream effect of the previous viral infection, and has no effect on symptoms.

I hope that the study does result in a biomarker. I think ME does involve glial cells. Whether the glial abnormalities results in abnormal sGFAP, I have no idea, so I'll wait for the experts to figure that out.