Effects of Age on White Matter Microstructure in Children With Neurofibromatosis Type 1

Abstract

Children with neurofibromatosis type 1 (NF1) often report cognitive challenges, though the etiology of such remains an area of active investigation. With the advent of treatments that may affect white matter microstructure, understanding the effects of age on white matter aberrancies in NF1 becomes crucial in determining the timing of such therapeutic interventions. A cross-sectional study was performed with diffusion tensor imaging from 18 NF1 children and 26 age-matched controls. Fractional anisotropy was determined by region of interest analyses for both groups over the corpus callosum, cingulate, and bilateral frontal and temporal white matter regions. Two-way analyses of variance were done with both ages combined and age-stratified into early childhood, middle childhood, and adolescence. Significant differences in fractional anisotropy between NF1 and controls were seen in the corpus callosum and frontal white matter regions when ages were combined. When stratified by age, we found that this difference was largely driven by the early childhood (1-5.9 years) and middle childhood (6-11.9 years) age groups, whereas no significant differences were appreciable in the adolescence age group (12-18 years). This study demonstrates age-related effects on white matter microstructure disorganization in NF1, suggesting that the appropriate timing of therapeutic intervention may be in early childhood.

Age-related white matter differences in children with neurofibromatosis type 1 compared to controls

“…We corroborated findings from our group 24 and other researchers 26 that the magnitude of white matter differences between children with NF1 and controls varies by age. Prior reports were limited to ROI analyses of the fronto-temporal white matter, whole-brain analysis, and tractography of the optic pathway only.…”

“…Patients with NF1 have previously been shown to have abnormal diffusion metrics. 24,26 Most diffusion MRI studies, however, have focused on adult patients with NF1 16,17 17,40 limiting our understanding of NF1-related white matter differences in the developing brain. The definition of normative values for diffusion MRI metrics across ages is an essential step in developing potential diffusion MRI biomarkers, which in turn could facilitate early identification of children with NF1 at risk for neurocognitive or visual deficits.…”

“…Diffusion MRI studies that have examined children with NF1 have either not assessed the effect of age on diffusion metrics 15 or focused on whole-brain analysis with a single white matter pathway 16,26 or were restricted to a set of ROIs. 24…”

“…24 They found that FA was reduced in the corpus callosum and frontal white matter areas in children with NF1 relative to healthy peers. 24 Strikingly, the differences in FA were predominantly driven by the early and middle childhood age groups but not the adolescent one. These findings suggest potential differences in the developmental trajectory of the optic radiations and other white matter areas due to NF1.…”

“…26 A similar effect of age on diffusion MRI metrics in children with NF1 was shown by Tam and colleagues. 24 They found that FA was reduced in the corpus callosum and frontal white matter areas in children with NF1 relative to healthy peers. 24 Strikingly, the differences in FA were predominantly driven by the early and middle childhood age groups but not the adolescent one.…”