Regional Brain Volumes and the Relationship to Neurocognitive Outcomes in Children with Severe Hemophilia A

1. Cerebellar gray matter volume in our hemophilia A cohort is disproportionately smaller compared to healthy controls.

2. Smaller cerebellum gray matter volume was associated with measures of executive dysfunction in hemophilia A.

The effect of factor VIII (FVIII) deficiency, a protein essential for blood coagulation, on neurocognitive outcomes in children with hemophilia A (HA) is not well characterized.

To examine differences in brain volume and neurocognition between children with severe HA and healthy controls.

This single-center study included 32 males aged 6-16 years, nine with severe FVIII deficiency and 23 healthy controls. Volumetric data from magnetic resonance imaging (MRI) and neurocognitive testing were compared using linear models including age to evaluate the association between regional brain volume and function.

Cerebellar gray matter volume was significantly smaller in the HA cohort compared to healthy controls, (Estimate=-0.375, 95% CI=-0.732:-0.019), t₍₂₆₎=2.07, p = 0.049). A reduction in cerebellar gray matter was associated with neurocognitive executive dysfunction as noted by abnormal scores on two executive function assessments: the Delis-Kaplan Executive Function System total switching accuracy (Estimate=0.549, 95% CI= -0.876:0.221), t₍₂₅₎ = -3.28, p=0.003) and total correct category switching (Estimate=0.538, 95% CI=-0.868:0.207), t₍₂₅₎= -3.19, p=0.004), as well as the Behavioral Regulation Index of Executive Function behavioral regulation index score (Estimate=0.531, 95% CI=0.228:0.835), t₍₂₅₎=3.44, p=0.002).

Our study provides new key insight into the lower brain volumes found in patients with HA and corresponding executive dysfunction. Quantitative brain volume assessment in patients with HA may provide an integrated measure and with further research could be a useful clinical tool when assessing risk for neurocognitive dysfunction.