Cerebrospinal Fluid Biomarkers and Their Relevance to COVID-19 Neurological Manifestations

By SWA

Understanding How COVID-19 Affects the Brain Through Key Protein Markers

As the COVID-19 pandemic unfolded, it became clear that SARS-CoV-2, the virus behind the disease, does more than just affect the lungs. Increasing evidence suggests it also impacts the brain and nervous system—causing symptoms ranging from brain fog to confusion and even stroke-like events. But how exactly does this happen? A recent study titled "Elucidating SARS-CoV-2 Neurotropism: A Comprehensive Mendelian Randomization Study on Cerebrospinal Fluid Biomarkers and their Relevance to COVID-19 Neurological Manifestations" sheds new light on this critical question.
https://www.researchsquare.com/article/rs-5574959/v1

What Are Cerebrospinal Fluid (CSF) Biomarkers?

Cerebrospinal fluid (CSF) is the clear liquid that surrounds the brain and spinal cord, acting as a cushion and a messenger. When the brain experiences inflammation or damage, certain biomarkers—proteins that indicate biological changes—rise in CSF levels. This study focused on several key proteins found at elevated levels in COVID-19 patients with neurological symptoms:

Key CSF Biomarkers Linked to COVID-19

1. CHI3L1 (YKL-40)

  • Function: A protein made by immune cells and brain support cells (astrocytes), CHI3L1 is involved in inflammation, tissue repair, and cell survival.

  • Why it matters: High levels are associated with neuroinflammation and have been observed in Alzheimer’s disease, multiple sclerosis, and now COVID-19.

  • COVID-19 relevance: CHI3L1 levels were significantly higher in patients with neurological complications, suggesting brain inflammation.

2. NGF-β (Nerve Growth Factor beta)

  • Function: Helps maintain and regenerate nerve cells.

  • COVID-19 relevance: Elevated levels may reflect the brain’s attempt to respond to injury caused by the virus or its immune effects.

3. KLK6 (Kallikrein-6)

  • Function: Associated with the breakdown of brain proteins and linked to neurodegenerative diseases.

  • COVID-19 relevance: Its rise in CSF points to potential nerve cell damage in infected individuals.

4. GFAP (Glial Fibrillary Acidic Protein)

  • Function: Released when astrocytes (support cells in the brain) are damaged.

  • COVID-19 relevance: Elevated in patients with more severe symptoms, especially those experiencing reduced consciousness.

5. S100B

  • Function: A marker of blood-brain barrier disruption and brain cell damage.

  • COVID-19 relevance: High levels were observed in patients with neurological symptoms, reinforcing the evidence of CNS injury.

COVID-19 and the Brain: What Changes?

Alongside biomarker analysis, researchers also used brain imaging and Mendelian randomization techniques to explore structural changes. They found that:

  • Severe COVID-19 was linked to increased size in certain brain regions, such as the left caudal middle frontal gyrus, which is involved in attention and decision-making.

  • Other changes were observed in the anterior cingulate cortex and cuneus cortex, which help regulate emotions and visual processing.

These structural changes, combined with elevated biomarkers, support the idea that SARS-CoV-2 can influence both brain function and structure—especially in patients with severe or prolonged illness.

Decreased Consciousness and Brain Inflammation

One of the more alarming findings in the study was that patients with reduced consciousness (confusion, drowsiness, or coma) had significantly higher levels of GFAP and S100B in their CSF. This indicates potential inflammation or injury in brain cells, possibly caused by:

  • Direct viral effects on brain tissue

  • Immune system overactivation

  • Compromised blood-brain barrier

How Is CHI3L1 (YKL-40) Tested?

✅ 1. Sample Collection

  • Blood Test: A simple blood draw to measure CHI3L1 levels in plasma or serum.

  • CSF Test (Lumbar Puncture): In more severe cases or research settings, spinal fluid is collected via a lumbar puncture.

✅ 2. Lab Testing: ELISA

  • The standard method used is ELISA (Enzyme-Linked Immunosorbent Assay).

  • This test uses antibodies that detect CHI3L1 in the sample.

  • A color change indicates how much CHI3L1 is present.

Where Is It Tested?

  • Primarily in research or specialized hospital labs.

  • Not yet a routine test in general hospitals, but gaining traction for use in diseases like COVID-19, Alzheimer’s, and MS.

What Do High CHI3L1 Levels Mean?

FindingInterpretation
Elevated CHI3L1Suggests brain inflammation or injury
Even higher levelsMay indicate more severe disease or neurological involvement
Comparison to controlsHelps doctors and researchers understand the impact of COVID-19 on the brain

Final Thoughts

The results from this comprehensive study offer strong evidence that SARS-CoV-2 may invade or affect the brain, especially in severe cases. Biomarkers like CHI3L1, NGF-β, and KLK6, along with GFAP and S100B, serve as crucial indicators of this process. Understanding and tracking these biomarkers may help healthcare providers better diagnose, monitor, and treat neurological complications related to COVID-19.

As we continue to learn about the long-term impacts of COVID-19, especially on the brain, studies like this one offer valuable insights into the biological clues hidden in our cerebrospinal fluid.

© 2000-2025 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right. Library of Congress Card Number: LCN 00-192742 ISBN: 0-9703195-0-9

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