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

Abstract

Background: Krabbe 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.

Methods: We 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.

Findings: Reductions 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.

Interpretation: Neonatal 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.

Figures

Fig. 1

Axial, coronal, and sagittal slices of the normal control diffusion tensor imaging atlas from 336 controls (a, b, c). Three-dimensional visualization of target fiber tracts colored by regions of interest (genu, red; splenium, yellow; left and right internal capsule, celeste and smalt; left and right uncinate, peachblow and green) (d). Krabbe disease patient, the atlas, and Krabbe disease patient registered to the atlas (e, f, g).

Fig. 2

Figure shows the fiber tract (colored by fractional anisotropy [FA] values) in the brain and on the FA scalar image (derived from diffusion tensor imaging), FA profiles along the length of the tract of the Krabbe subjects with mean and standard deviation when compared to controls, and scatter plot of normalized FA values plotted against gestational age (in weeks) for the corticospinal internal capsule (left), genu, splenium, and uncinate tracts (left). The yellow window in the FA tract profile indicates values considered for statistical analysis.

Fig. 3

Plot showing correlation between the fractional anisotropy score (normalized mean ratio) within the internal capsule left tract and the gross motor and cognitive function scores.