Regional differences in fiber tractography predict neurodevelopmental outcomes in neonates with infantile Krabbe disease

BackgroundKrabbe disease is a fatal neurodegenerative disease caused by rapid demyelination of the central and peripheral nervous systems. The only available treatment, unrelated umbilical cord blood transplantation, is effective only if performed before clinical symptoms appear. Phenotypic expressions of disease-causing mutations vary widely, but genotype–phenotype relationships are unclear. Therefore, we evaluated diffusion tensor imaging (DTI) tractography with volumetric analysis as a biomarker of early white matter changes and functional disability in presymptomatic infants.MethodsWe obtained DTI and structural scans of newborns with early-infantile Krabbe disease (n=9) diagnosed by family history or newborn screening. We compared white matter fiber tract properties to those of normal controls (n=336) and assessed the ability of tract-based properties to predict longitudinal development in four functional domains (cognitive, fine motor, gross motor, adaptive behavior) after treatment with unrelated umbilical cord blood transplantation. We also assessed the relationship between the standard evaluation (modified Loes score) and DTI results, and the volumetric differences between the Krabbe subjects and normal controls.FindingsReductions in fractional anisotropy were significant in the corticospinal tract in the Krabbe patients compared to controls, which strongly correlated with motor and cognitive outcomes after transplantation. Significant regional differences were observed in the splenium and uncinate fasciculus in Krabbe patients and these differences correlated only with cognitive outcomes. Regional brain volumes of Krabbe patients were slightly larger than controls. Loes scores did not correlate with DTI results.InterpretationNeonatal microstructural abnormalities correlate with neurodevelopmental treatment outcomes in patients treated for infantile Krabbe disease. DTI with quantitative tractography is an excellent biomarker for evaluating infants with Krabbe disease identified through newborn screening.Highlights•Reductions in FA and increases in MD and RD in the 6 tracts assessed in Krabbe neonates strongly correlate with motor and cognitive outcomes after cord blood transplantation.•Significant regional differences in the splenium and uncinate fasciculus correlated only with cognitive outcomes.•Regional brain volumes of Krabbe patients were slightly larger than controls.•Loes scores did not correlate with DTI results.•DTI tractography can be a key component of Krabbe newborn screening