Early-onset (Type I) AxD is defined by macrocephaly and extensive frontal white matter T2 hyperintensity and basal ganglia signal abnormality or swelling.

Type I AxD participants with research 3T MRI scans were included. Whole brain (WB), white matter (WM), and gray matter (GM) volumes were calculated using SIENAX (part of the FSL toolkit). The ratios of absolute WM and GM to absolute WB volumes and normalized WM, GM, and WB volumes for head size (NWMV, NGMV, and NWBV, respectively) were computed. Similar methods were utilized in age- and sex-matched healthy controls (HC) from the Philadelphia Neurodevelopmental Cohort (PNC) and compared to AxD subjects using 2-sample t tests.

AxD Type 1 subjects (N=11, mean age at scan 12.2 years, range 5.2–20.2) were compared to HC (N=11, 9 matched within 1 year; one 5.9 and one 5.2-year-old were matched to the closest PNC ages: 8.4 and 8.2 years). NWBV did not differ between groups (p=0.13); however, AxD subjects had a larger average head size, as indicated by the SIENAX-derived scaling factor of 1.17 in AxD vs. 1.36 in HC (p<0.01). NWMV was significantly greater in HC (769505 mm³) than in AxD (645805 mm³, p<0.001). NGMV did not significantly differ between groups (HC 907362 mm³ vs. AxD 955422 mm³, p=0.21). However, AxD subjects had a greater proportion of GM contributing to total brain volume (60%) compared to HC (54%, p<0.001) and a smaller proportion of WM (40%) compared to HC (46%, p<0.001). The greater proportion of GM volume persisted even in those AxD subjects with reduced total brain volumes compared to HC.

Early-onset AxD is characterized by a disproportionate increase in GM, likely reflective of the astrocytic and neuronal pathology, and by loss of WM, consistent with AxD designation as a leukodystrophy.