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

Abstract

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.

Fontan Circulation Associated Organ Abnormalities Beyond the Heart, Lungs, Liver, and Gut: A Systematic Review

“…Fontan patients underperform compared to their peers on several functional measures, including visual processing speed, psychomotor function, emotional cognition, and gross motor function ( 10 , 23 , 24 ). Imaging abnormalities related to functional outcomes in some ( 9 , 13 , 14 ), but not all studies ( 10 , 16 ).…”

“…Structural abnormalities on central nervous system (CNS) imaging have been assessed in 14 studies using multiple imaging modalities ( Table 1 ). CNS abnormalities noted included (multi)focal abnormalities, developmental malformations, and ischemic changes in watershed areas ( 9 – 16 ). Most of these studies included only adolescent Fontan patients.…”

“…Most of these studies included only adolescent Fontan patients. Verall et al found adult patients had more impaired neurocognitive scores compared to adolescent patients, however, no relation was found between age and severity of abnormalities on neuro-imaging ( 16 ). Diffuse CNS abnormalities in univentricular CHD patients are present even before birth, possibly relating to exposure to hypoxia in utero ( 10 , 11 ).…”

“…Structural brain abnormalities are common in Fontan patients ( 9 – 11 , 13 , 14 , 16 ). The volume of several brain structures was decreased ( 17 , 19 – 22 ).…”

A diffusion MRI study of brain white matter microstructure in adolescents and adults with a Fontan circulation: Investigating associations with resting and peak exercise oxygen saturations and cognition

“…We recently demonstrated significant cognitive impairments in an older Fontan population that included adolescents and adults (aged 13–49 years). Worse neurological and cognitive outcomes were identified in the adult Fontan cohort, suggestive of continued pathophysiological alterations in the brain of Fontan subjects as they age ( Verrall et al, 2021 ). Cognitive impairments of particular concern included attention and reduced processing speed that impacted one-third of our cohort, with 16% and 13% demonstrating severe dysfunction in these domains, respectively.…”