Neurocognitive disturbances associated with acute infectious mononucleosis, Ross River fever and Q fever: A preliminary investigation of inflammatory and genetic correlates

Highlight
• Cognitive disturbances are part of the acute sickness response to systemic infection and relate to inflammatory processes and variants in cytokine genes.

Disturbances in neurocognitive performance are a core feature of the acute sickness response to infection; however the underlying mechanisms remain unclear. The current study used a computerised battery to assess neurocognitive functioning in subjects enrolled in the Dubbo Infection Outcomes Study (n = 107) – a prospective cohort of subjects followed from documented acute infection with Epstein Barr virus, Ross River virus, or Coxiella burnetii until recovery. Subjects were assessed when ill, and a subset again after complete recovery. Associations between sickness-related cognitive disturbances and single nucleotide polymorphisms (SNPs) in cytokine (interleukin [IL]-6, IL-10, tumor necrosis factor-α and interferon-γ) and neurobehavioral genes (serotonin transporter and catechol-O-methyltransferase) were explored.During acute infection, subjects exhibited slower matching-to-sample responses (p = 0.03), poorer working memory capacity (p = 0.014), mental planning (p = 0.045), and dual attention task performance (p = 0.02), and required longer to complete discordant Stroop trials (p = 0.01) compared to recovery. Objective impairments correlated significantly with self-reported symptoms (p < 0.05) as well as levels of the inflammation marker, C-reactive protein (p = 0.001). Linear regression analysis identified an association between neurocognitive disturbance during acute illness and functional polymorphisms in inflammatory cytokine genes. Specifically, the high cytokine producing G allele of the IL-6-174G/C SNP was associated with poorer neurocognitive performance when subjects were ill (p = 0.027).These findings confirm that acute infection impacts on neurocognitive performance, manifesting as slowed responses and impaired performance on complex tasks requiring higher-order functioning which has important real-world implications. The data provide the first preliminary evidence for a role of a genetic predisposition to more intense inflammatory responses in objective neurocognitive disturbances during acute infections. These associations require replication in a larger sample size.