Neurocognitive Dysfunction and Smaller Brain Volumes in Adolescents and Adults with a Fontan Circulation.

Background: Neurocognitive outcomes beyond childhood in people with a Fontan circulation are not well-defined. This study aimed to investigate neurocognitive functioning in adolescents and adults with a Fontan circulation and associations with structural brain injury, brain volumetry and post-natal clinical factors. Methods: In a bi-national study, participants with a Fontan circulation without a pre-existing major neurological disability were prospectively recruited from the Australia and New Zealand Fontan Registry. Neurocognitive function was assessed using Cogstate software in 107 Fontan-participants and compared with control groups with transposition of the great arteries (TGA; n=50) and a normal circulation (n=41). Brain MRI with volumetric analysis was performed in the Fontan-participants and compared with healthy control data from the ABIDE I and II and PING data repositories. Clinical data were retrospectively collected. Results: Of the Fontan-participants with neurocognitive assessment, 55% were male and the mean age was 22.6 years (SD 7.8). Fontan-participants performed worse in several areas of neurocognitive function compared with those with TGA and healthy controls (p<0.05). Clinical factors associated with worse neurocognitive outcomes included more inpatient days during childhood, younger age at Fontan and longer time since Fontan procedure (p<0.05). Fontan-adults had more marked neurocognitive dysfunction than Fontan-adolescents in two domains (psychomotor function, p=0.01 and working memory, p=0.02). Structural brain injury was present in the entire Fontan cohort; presence of white matter injury was associated with worse paired associate learning (p<0.001), but neither the presence or severity of infarct, subcortical grey matter injury and microhemorrhage was associated with neurocognitive outcomes. Compared with healthy controls, people with a Fontan circulation had smaller global brain volumes (p<0.001 in all regions) and smaller regional brain volumes in the majority of cerebral cortical regions (p<0.05). Smaller global brain volumes were associated with worse neurocognitive functioning in several domains (p<0.05). A significant positive association was also identified between global brain volumes and resting oxygen saturations (p≤0.04). Conclusions: Neurocognitive impairment is common in adolescents and adults with a Fontan circulation and is associated with smaller grey and white matter brain volume. Understanding modifiable factors that contribute to brain injury to optimize neurocognitive function is paramount.