New evidence for biological basis of “COVID-19 brain fog”

Most patients with cognitive post-acute sequelae of SARS-CoV-2 infection (PASC) who had mild COVID-19 symptoms had elevated levels of CSF immune activation and immunovascular markers compared with controls. These findings confirm the hypothesis that the condition often referred to as “brain fog” has a neurological (as opposed to psychological) basis and is linked to immune dysfunction.

Initial findings of the presented study were published in early 2022, in which the authors reported a high rate (77%; 10/13) of cognitive PASC patients with a CSF abnormality on clinically available tests versus 0% (0/4) of cognitive controls [1]. To further clarify how to identify patients with cognitive PASC and its biological correlates, 23 patients were followed who presented with new, persistent, cognitive PASC while recovering from relatively mild SARS-CoV-2 infection not requiring hospitalisation [2]. Ten recovering patients without PASC served as a control group. All participants underwent neurological examination and neuropsychological testing; 54% (n=13 cognitive PASC, n=5 controls) also agreed to lumbar puncture enabling analysis of immune activation and immunovascular markers in CSF. Lumbar puncture was performed after a median of 10.2 months following initial COVID-19 symptoms. Dr Joanna Hellmuth (University of California, CA, USA) shared the results.

CSF of participants with cognitive PASC contained higher median levels of the acute-phase reactant C-reactive protein (0.007 vs 0.000 mg/L; P=0.004) and of serum amyloid A (0.001 vs 0.000 mg/L; P=0.001) compared with controls. Furthermore, the PASC group had non-significantly higher levels of the CSF immune activation markers IFN-γ-inducible protein (IP-10; P=0.059) and IL-8 (P=0.059); and of the immunovascular markers vascular endothelial growth factor-C (VEGF-C, P=0.095) and VEGFR-1 (P=0.059).

Within the cognitive PASC group, early onset of “brain fog” was associated with higher levels of CSF VEGF-C compared with delayed-onset cognitive PASC, defined as ≥1 month after the first COVID-19 symptoms. In 7 participants with acute-onset cognitive PASC, mean VEGF-C in CSF was 173 pg/mL compared with 99 pg/mL in 5 participants with delayed-onset cognitive PASC (P=0.048) and compared with 79 pg/mL in controls (P=0.048). Compared with controls, participants with acute-onset cognitive PASC also had elevated levels of CSF IP-10 (P=0.030), IL-8 (P=0.048), placental growth factor (P=0.030), and intercellular adhesion molecule-1 (P=0.045). Overall, Dr Hellmuth concluded that acute cognitive changes may be linked to prolonged disruption of immune homeostasis. A limitation of the study was the small number of participants.

1. Apple AC, et al. Ann Clin Transl Neurol. 2022;9(2):221–6.
2. Oddi A, et al. Cognitive Symptoms After Mild SARS-CoV-2 Infection Associate with Higher Levels of CSF Immune Activation and Immunovascular Markers. Emerging Science, AAN 2022, 02–07 April, Seattle, USA.

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Posted on 2 June 202215 February 2024