Neurocognitive Dysfunction and Smaller Brain Volumes in Adolescents and Adults With a Fontan Circulation
Authors: Verrall Charlotte E. , Yang Joseph Y.M. , Chen Jian , Schembri Adrian , d’Udekem Yves , Zannino Diana , Kasparian Nadine A. , du Plessis Karin , Grieve Stuart M. , Welton Thomas , Barton Belinda , Gentles Thomas L. , Celermajer David S. , Attard Chantal , Rice Kathryn , Ayer Julian , Mandelstam Simone , Winlaw David S. , Mackay Mark T. , Cordina Rachael 
Published: November 2020

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 postnatal clinical factors.

Methods:
In a binational study, participants with a Fontan circulation without a preexisting major neurological disability were prospectively recruited from the Australia and New Zealand Fontan Registry. Neurocognitive function was assessed by using Cogstate software in 107 participants with a Fontan circulation and compared with control groups with transposition of the great arteries (n=50) and a normal circulation (n=41). Brain MRI with volumetric analysis was performed in the participants with a Fontan circulation and compared with healthy control data from the ABIDE I and II (Autism Brain Imaging Data Exchange) and PING (Pediatric Imaging, Neurocognition, and Genetics) data repositories. Clinical data were retrospectively collected.

Results:

Of the participants with a Fontan circulation who had a neurocognitive assessment, 55% were male and the mean age was 22.6 years (SD 7.8). Participants with a Fontan circulation performed worse in several areas of neurocognitive function compared with those with transposition of the great arteries and healthy controls (
P
<0.05). Clinical factors associated with worse neurocognitive outcomes included more inpatient days during childhood, younger age at Fontan surgery, and longer time since Fontan procedure (
P
<0.05). Adults with a Fontan circulation had more marked neurocognitive dysfunction than adolescents with a Fontan circulation in 2 domains (psychomotor function,
P
=0.01 and working memory,
P
=0.02). Structural brain injury was present in the entire Fontan cohort; the presence of white matter injury was associated with worse paired associate learning (
P
<0.001), but neither the presence nor severity of infarct, subcortical gray 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 most 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 gray and white matter brain volume. Understanding modifiable factors that contribute to brain injury to optimize neurocognitive function is paramount.