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

Abstract

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.

A tract-specific approach to assessing white matter in preterm infants

“…Correspondence can be achieved by sampling at equivalent levels along tracts ( Groeschel et al, 2014 , Verde et al, 2014 ) or parameterising WM tracts by arc length, essentially reducing entire tracts to a single, core line ( Corouge et al, 2006 , Goodlett et al, 2009 , O'Donnell et al, 2009 , Verde et al, 2014 , Yeatman et al, 2012 ). These methods have been used to study neurodevelopment in toddlers ( Geng et al, 2012 , Goodlett et al, 2009 ), WM heritability in twin neonates ( Lee et al, 2015 ), infantile Krabbe disease ( Gupta et al, 2015 ), and prenatal exposure to selective serotonin reuptake inhibitors ( Jha et al, 2016 ). However these methods are more suitable for tubular rather than sheet-like tracts.…”

Human iPSC-based neurodevelopmental models of globoid cell leukodystrophy uncover patient- and cell type-specific disease phenotypes

“…A modest psychosine storage may affect murine neuronal and glial differentiation from NPCs (Castelvetri et al, 2011;Santambrogio et al, 2012;Teixeira et al, 2014) before overt toxicity mediated by storage overload (Hawkins-Salsbury et al, 2013;White et al, 2011) (Bongarzone et al, 2016;Ricca and Gritti, 2016). Interestingly, psychosine storage has been detected in the brain of GLD human foetuses (Igisu and Suzuki, 1984) and elevated psychosine blood concentration is considered a specific marker in infantile GLD patients (Escolar et al, 2017), who may display early white matter changes and functional disability (Gupta et al, 2015). The aggravated defects in neuronal/glial differentiation from human NPCs described here are in line with these clinical observations.…”

Newborn screening for Krabbe's disease

“…Interpreting MRI results from newborns is complicated because the degree of myelination is quite variable in this cohort. Gupta and coworkers () recently showed that diffusion tensor imaging (DTI) with quantitative tractography is an effective tool for evaluating infants with KD identified through NBS. However, this technique has not been tested on asymptomatic, at‐risk patients identified by NBS.…”