Biomarkers

While mechanisms underlying post-COVID-19 cognitive impairment are unknown, increased blood-brain barrier (BBB) permeability and immune alterations have been posited as possible contributing factors.

We conducted a cross-sectional study of patients with and without prior laboratory-confirmed COVID-19 (COV+ vs COV-), with no previous history of dementia/cognitive impairment. Brain fog was defined as the subjective symptoms of memory loss, confusion, and/or difficulty concentrating lasting >1 month after index SARS-CoV-2 infection. Fasting plasma biomarkers of inflammation (cytokines), and BBB disruption (Simoa SP-X), as well as phosphorylated tau (pTau) were measured using Simoa HD-X technology. Patients underwent concurrent UDS3 neuropsychiatric testing and received a formal cognitive diagnosis by a consensus group of physicians following NACC criteria. Plasma biomarker levels were compared between patients with and without brain fog, and with and without a diagnosis of MCI using Mann-Whitney U tests.

We enrolled 279 patients: N = 51 (18%) COV-, N = 228 (82%) COV+, N = 96 (34%) with post-COVID brain fog, and N = 35 (13%) COV+ patients with newly diagnosed MCI post-COVID. Several plasma cytokine levels (TNF-a, IL-4, IL-10, IL-22) were significantly lower in those with brain fog compared to those without (all p ≤0.01), while markers of BBB permeability were higher (heparin-binding epidermal growth factor 10.1 pg/mL in brain fog patients vs 7.7 pg/mL without, p <0.001; vascular endothelial growth factor 72 vs. 63 pg/mL, p = 0.055; and placental growth factor 12.4 vs 11.4 pg/mL, p = 0.090). Among COV+ patients diagnosed with MCI, TNF-a was significantly lower compared to cognitively normal subjects (1.3 vs. 1.5 pg/mL, p = 0.031), while pTau-217 was significantly higher in those with MCI due to Alzheimer's (0.21 vs. 0.13 pg/mL, p = 0.009) compared to those without.

Lower cytokine levels, increased markers of BBB disruption, and altered markers of tau pathology were observed in patients with brain fog and COV+ subjects with MCI, which may suggest immune exhaustion, increased BBB permeability, and disrupted tau processing as possible mechanisms of post-COVID-19 brain fog.