Early brain vulnerability in Wolfram syndrome

Abstract

Wolfram Syndrome (WFS) is a rare autosomal recessive disease characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, diabetes insipidus, deafness, and neurological dysfunction leading to death in mid-adulthood. WFS is caused by mutations in the WFS1 gene, which lead to endoplasmic reticulum (ER) stress-mediated cell death. Case studies have found widespread brain atrophy in late stage WFS. However, it is not known when in the disease course these brain abnormalities arise, and whether there is differential vulnerability across brain regions and tissue classes. To address this limitation, we quantified regional brain abnormalities across multiple imaging modalities in a cohort of young patients in relatively early stages of WFS. Children and young adults with WFS were evaluated with neurological, cognitive and structural magnetic resonance imaging measures. Compared to normative data, the WFS group had intact cognition, significant anxiety and depression, and gait abnormalities. Compared to healthy and type 1 diabetic control groups, the WFS group had smaller intracranial volume and preferentially affected gray matter volume and white matter microstructural integrity in the brainstem, cerebellum and optic radiations. Abnormalities were detected in even the youngest patients with mildest symptoms, and some measures did not follow the typical age-dependent developmental trajectory. These results establish that WFS is associated with smaller intracranial volume with specific abnormalities in the brainstem and cerebellum, even at the earliest stage of clinical symptoms. This pattern of abnormalities suggests that WFS has a pronounced impact on early brain development in addition to later neurodegenerative effects, representing a significant new insight into the WFS disease process. Longitudinal studies will be critical for confirming and expanding our understanding of the impact of ER stress dysregulation on brain development.

Figure 1. Regional subcortical brain volumes by significance level.

Regions were segmented in Freesurfer. Left and right volumes were averaged and are shown on the right side of the brain only. The brainstem, cerebellar gray matter and cerebellar white matter were significantly reduced in the WFS compared to controls and survived Bonferroni multiple comparison correction (in red; p<.0038). In addition, the thalamus and pallidum were also reduced in WFS compared to controls, but did not survive correction (p<.05, in yellow). Finally, the corpus callosum, hippocampus, amygdala, caudate, putamen and accumbens were not different between groups (p>.05, in purple).

Figure 2. Volume of brainstem segments by diagnosis and age.

(A) The WFS group has reduced volumes in all three brainstem segments after adjusting for intracranial volume. A repeated measures general linear model analysis found a segmental volume by diagnosis interaction (F(4,112) = 7.6, p<.001). Volume in the WFS group was significantly different from the control groups for all three segments (*), but the effect was most striking in the pons. (B) The pons appeared to be reduced in volume in almost all WFS individuals even after adjusting for intracranial volume. This figure shows the relationship between pontine volume and age. HC  =  healthy controls; T1C  =  diabetic controls; WFS  =  Wolfram group.

Figure 3. Regions with cortical thinning in the WFS group.

After multiple comparison correction and adjustment for age and gender, (A and B) the rostral middle frontal cortex was found to be thinner bilaterally (right cluster-wise p = .001; left cluster-wise p = .0001 and p = .0304), as was (B) the left precentral (cluster-wise p = .0008) and (C) the left lingual (cluster-wise p = .0113) cortex.

Figure 4. Voxel-based morphometry (VBM) findings.

Gray and white matter clusters where WFS have lower volumes than controls. (A) Gray matter clusters included right cerebellum (p = .0008), and left cerebellum (p = .0125), while (B) white matter clusters included a large cluster consisting of much of the cerebellum, brainstem, and subcortex (p<.001), and a small cluster in the parietal-occiptal cortex (p = .0239). Glass brain (all results shown collapsed on a single slice) view shown on left, and the significant cluster on an average MR overlay is shown on the right. Cross hairs are placed in the voxel with a peak t value in the cluster.

Figure 5. Results from tract-based spatial statistics (TBSS) analysis.

Fractional anisotropy (FA) and axial diffusivity (AD), but not radial diffusivity, were reduced in the WFS group compared to controls (healthy and diabetic control groups combined), even after multiple comparison correction. There were no significant findings in the opposite direction (WFS > controls). White matter tracts in the cerebellum, brainstem, and optic radiations were prominently affected, but changes were also noted in other areas as well. The multiple comparison corrected p values are represented in the color coding. Z  =  the Talairach coordinate for the transverse plane.