Blood-Brain barrier disruption in long COVID and cognitive correlates: A cross-sectional MRI study, 2025, Rubin et al.

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Blood-Brain barrier disruption in long COVID and cognitive correlates: A cross-sectional MRI study

Spoiler: Authors

Rubin; Shi; Azola; Bhattacharyya; Dastgheyb; Wu; Penna; Parker; Santiuste; Ehrenspeck; Coughlin; Vannorsdall; Lu; Veenhuis

Disruption of the blood–brain barrier (BBB) may contribute to neuropsychiatric symptoms observed in Long COVID (LC). Using a non-contrast magnetic resonance imaging (MRI) technique, we investigated BBB permeability in individuals with LC and its relationship to cognitive function. We hypothesized that LC individuals would show greater BBB permeability than recovered individuals, and that higher permeability would correlate with poorer cognition.

Ninety-seven participants meeting the 2024 NASEM definition of LC with at least one neuropsychiatric symptom and 31 recovered controls completed an MRI scan and cognitive testing. BBB permeability was assessed using water-extraction-with-phase-contrast-arterial-spin-tagging (WEPCAST) MRI, which estimates the permeability-surface-area product (PS) of arterially labeled water entering the brain. Cognitive performance was summarized into eight factor scores derived from principal components analysis.

Compared to controls, the LC group was older (M = 47 vs. 39 years, P = 0.003), less educated (P = 0.02), more likely female (P = 0.04), and had higher hospitalization rates for COVID-19 (P = 0.02). PS was significantly elevated in the LC group after adjusting for age and sex (B = 18.59, SE = 6.11, β = 0.28, P = 0.003). No significant group differences were found in cerebral blood flow, extraction fraction (E), or brain volume. Within the LC group, higher PS was associated with poorer motor function, but not with other cognitive domains.

These findings indicate subtle but persistent BBB disruption in LC individuals over two years post-infection, with a potential link to motor dysfunction. This supports prior evidence of BBB changes following severe COVID-19 and suggests that BBB integrity may be a long-term biomarker of neuropsychiatric complications in LC.

HIGHLIGHTS
• Blood-brain barrier (BBB) disruption may underlie neuropsychiatric symptoms in Long COVID (LC).

• Non-contrast MRI technique reveals higher BBB permeability in LC vs. recovered controls.

• Higher BBB permeability was significantly associated with poorer motor function, but not other cognitive domains.

• Findings indicate persistent BBB disruptions two + years post-infection in LC.

• BBB integrity may be a biomarker of motor dysfunction in LC.

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We identified PEM as a self-reported symptom associated with increased BBB permeability in the LC group. PEM was assessed using a single-item question adapted from RECOVER, which asked participants whether they experienced a "worsening of symptoms after even minor physical or mental effort."

Higher values of AST and ALT were found to be predictors for increased BBB permeability; however, this has limited clinical significance as the liver enzyme values in our cohort were well within the normal range (AST M=22, SD=7; ALT M=24, SD=15) indicating absence of liver pathology. Others have described an elevation of liver enzymes in the LC population [42], but this was linked to the increased severity of acute illness, which was not the case in our cohort as most people in our LC cohort had a mild acute illness. A higher AST/ALT ratio was associated with lower BBB permeability in our LC group, but this finding is clinically insubstantial in the context of normal liver enzyme levels.

Dismissed as in the population normal range, but that may not be normal for the individuals and may be a marker of something going on in the liver.

[42] is Liver Function in Patients with Long-Term Coronavirus Disease 2019 of up to 20 Months: A Cross-Sectional Study (2023)