Study: Persistent CNS immune activation not main driver of neurologic long COVID

Exhausted older woman

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Persistent central nervous system (CNS) immune activation is not the primary cause of neurologic long COVID, suggests a case-control study by Yale researchers.

The research, published today in JAMA Network Open, involved 37 US patients who self-reported neurologic long-COVID, also known as post-COVID-19 condition (PCC), and 22 asymptomatic controls recruited for other studies before the pandemic. All participants underwent a large-volume lumbar puncture and blood draw for analysis of cerebrospinal fluid (CSF).

The median age of the 37 case-patients was 48 years, 73.0% were women, 10.8% were Black, and 78.4% were White; 27 women had tested positive for COVID-19 from March 2020 to July 2022, 78% of them during SARS-CoV-2 Alpha variant predominance. Among the 22 controls, the median age was 51.5 years, 31.8% were women, 27.3% were Hispanic, and 45.5% were Black.

"A subset of people with PCC report neuropsychiatric symptoms (neuro-PCC); however, the mechanisms behind this phenomenon are not yet understood," the study authors wrote. "Cerebrospinal fluid (CSF) circulates throughout the central nervous system, serving as a window to the brain and providing a means to study neuropathology in living people."

No evidence of overt neuroinflammation

The most common long-COVID symptoms among case-patients were cognitive impairment (84%) and excessive fatigue (84%). CSF white blood cell counts and protein levels weren't elevated in neurologic long-COVID patients, nor was the ratio of CSF to blood albumin, which is altered in cases of blood-brain barrier degeneration.

Cerebrospinal fluid (CSF) circulates throughout the central nervous system, serving as a window to the brain and providing a means to study neuropathology in living people.

The CSF immunoglobulin G (IgG; a type of antibody) index and a comparison of Ig levels (an inflammatory biomarker) in the CSF and blood didn't show evidence of Ig production in the intrathecal space (spinal cord and surrounding membranes).

Levels of indicators of possible inflammation were altered in neurologic long-COVID patients. Tumor necrosis factor-α levels in the CSF were higher in neurologic long-COVID patients (0.66 vs 0.55 picogram/microliter [pg/ul]), and levels of monocyte chemoattractant protein-1 and interleukin-6 (IL-6) were lower (499 vs 697 pg/ul and 1.2 vs 1.8 pg/ul, respectively).

But after accounting for multiple comparisons, these differences were not statistically significant, and no significant differences in other cytokine or chemokine levels tested in the CSF or plasma were noted. Nor was neopterin, a marker of neurologic disease, elevated in case-patients.

"When comparing individuals with neuro-PCC with control participants who had never had COVID-19, we found no evidence of overt neuroinflammation (normal CSF cell count, inflammatory cytokines) or blood-brain barrier dysfunction (normal albumin ratio), suggesting that persistent central nervous system immune activation is not a primary driver of neurological long COVID-19," the researchers wrote.

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