Globally Reduced Brain Volume in Rett Syndrome

To compare global and regional brain volumes between individuals with Rett syndrome (RTT) and two independent control groups (typically developing [TD], idiopathic developmental delay [DD]) using direct patient:control matching, higher-resolution magnetic resonance imaging (MRI) scans, and larger samples than were available in prior RTT studies.

Control cohorts were age and sex matched 1:1 with RTT. We utilized the PSTAPLE algorithm to conduct MRI-based anatomic segmentations and quantify global and regional volumetry.

A total of 42 subjects (14 per group) were included with mean age 8.0 years ± 6.1 S.D. (range: 1.4-20.7 years). Global and regional brain volumes were compared between groups with analysis of covariance. Intracranial cavity volume was regressed as a variable of interest; the log of age at scan was regressed as a variable of no interest. Global and regional volumes were reduced in RTT (versus DD and TD). Total gray matter was reduced by 19% in RTT (versus TD and DD). Similar volumetric reductions were noted in occipital, parietal, and temporal cortices in RTT (versus TD and DD). Cerebellar white matter was reduced in RTT (3.4%; versus DD only).

MRI findings in individuals with RTT demonstrated global reductions in brain volume with relatively uniform involvement of cortical and subcortical structures. Cerebellar white matter volume may be reduced in individuals with RTT (versus DD). These findings underscore the importance of correcting for global volume abnormalities when assessing regional volumetry and suggest that neuroimaging evaluations may distinguish children with RTT from those with idiopathic DD.