Cerebral gray matter volumes in long-term post-COVID patients are associated with peripheral kynurenine pathway metabolites and the severity of depressive symptoms.

Publication date: Jul 18, 2026

Structural brain changes and immune-metabolic alterations are widely reported in post-COVID condition (PCC), particularly among patients with depressive symptoms. Alterations in gray matter volume (GMV) and dysregulation of the peripheral kynurenine pathway have each been described independently in PCC; however, potential interactions remain unclear. This observational case-control study investigated associations between GMV and peripheral kynurenine-pathway metabolites in patients with PCC compared to unimpaired individuals who recovered after COVID-19. The analysis is based on a sub-cohort from a multicentre, population-based study of individuals who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) between October 2020 and April 2021. We compared 43 patients with PCC (age: M = 47. 63 (SD = 13. 01), 74. 4% female) to 27 age- and sex-matched fully recovered controls (age: M = 47. 44 (SD = 10. 39), 77. 8% female) on average 156 weeks after SARS-CoV-2 infection. GMV was assessed using isotropic T1-weighted magnetic resonance imaging (MRI) data (normalized to total intracranial volume, age, and sex). We analyzed the relation of normalized regional GMV to serum kynurenine-pathway metabolites (kynurenine, kynurenic acid, quinolinic acid, kynurenic/quinolinic acid ratio). Additionally, in patients with PCC, GMV and kynurenine-pathway metabolites were tested for correlations with the severity of depressive symptoms. No significant group-level differences in GMV were observed. Clinical case status moderated the association between the peripheral kynurenic acid/quinolinic acid ratio and GMV of the right cingulate gyrus and right parietal lobe. Post-hoc analyses showed a positive association in PCC. Furthermore, within the PCC group, 60. 5% showed depressive symptoms according to the Patient Health Questionnaire-9, and larger bilateral hippocampal volumes were significantly associated with greater depressive symptom severity. None of the kynurenine pathway metabolites were significantly associated with depressive symptom severity. Our findings may indicate that the peripheral kynurenine metabolism is associated with GMV in PCC, suggesting the presence of facilitated immune-brain interactions. The association between higher hippocampal GMV and depressive symptom severity in PCC-associated depression points to a distinct neurobiological mechanism.

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