Multiparametric MRI study of ALS stratified for the C9orf72 genotype

Abstract

Objective: To describe the patterns of cortical and subcortical changes in amyotrophic lateral sclerosis (ALS) stratified for the C9orf72 genotype.

Methods: A prospective, single-center, single-protocol, gray and white matter magnetic resonance case-control imaging study was undertaken with 30 C9orf72-negative patients with ALS, 9 patients with ALS carrying the C9orf72 hexanucleotide repeat expansion, and 44 healthy controls. Tract-based spatial statistics of multiple white matter diffusion parameters, cortical thickness measurements, and voxel-based morphometry analyses were carried out. All patients underwent comprehensive genetic and neuropsychological profiling.

Results: A congruent pattern of cortical and subcortical involvement was identified in those with the C9orf72 genotype, affecting fusiform, thalamic, supramarginal, and orbitofrontal regions and the Broca area. White matter abnormalities in the C9orf72-negative group were relatively confined to corticospinal and cerebellar pathways with limited extramotor expansion. The body of the corpus callosum and superior motor tracts were affected in both ALS genotypes.

Conclusions: Extensive cortical and subcortical frontotemporal involvement was identified in association with the C9orf72 genotype, compared to the relatively limited extramotor pathology in patients with C9orf72-negative ALS. The distinctive, genotype-specific pathoanatomical patterns are consistent with the neuropsychological profile of the 2 ALS cohorts. Our findings suggest that previously described extramotor changes in ALS could be largely driven by those with the C9orf72 genotype.

Figure 1. Patterns of significant white matter diffusivity differences between patients with ALS carrying the C9orf72 hexanucleotide repeat expansion and patients with ALS without it

Highlighted clusters are shown in coronal and sagittal representations and indicated by green crosshairs. Regions of increased mean diffusivity (MD) in the C9pos cohort are highlighted in blue, regions of increased axial diffusivity (AD) in red. The coordinates are with reference to the Montreal Neurological Institute stereotactic template. ALS = amyotrophic lateral sclerosis.

Figure 2. Patterns of white matter pathology in ALS genotypes compared to healthy controls

Blue indicates white matter regions uniquely affected in patients with amyotrophic lateral sclerosis (ALS) carrying the C9orf72 hexanucleotide repeat expansion. Green shows white matter regions exclusively affected in patients with ALS without the C9orf72 hexanucleotide repeat. Red indicates the overlap of white matter involvement in both C9orf72-negative and C9orf72-positive ALS compared to healthy controls (HC). AD = axial diffusivity; FA = fractional anisotropy; MD = mean diffusivity; RD = radial diffusivity.

Figure 3. Key brain regions with significant cortical thickness differences between patients with ALS carrying the C9orf72 hexanucleotide repeat expansion and patients with ALS without it (p < 0.05 corrected for multiple comparisons)

Pial surfaces are shown. ALS =amyotrophic lateral sclerosis.

Figure 4. Concordance of key C9orf72-specific gray and white matter clusters with reference of healthy controls as identified by various imaging techniques

(A) Cortical thickness measurements (C9pos vs healthy controls [HC] p < 0.05, false discovery rate corrected). (B) Tract-based spatial statistics (for radial diffusivity: C9pos vs HC p < 0.05, threshold-free cluster enhancement [TFCE] corrected). (C) Voxel-based morphometry (C9pos vs HC p < 0.005, TFCE corrected). (D) Neuroanatomically associated gray and white matter structures affected in C9orf72-positive amyotrophic lateral sclerosis (ALS). A = anterior; P = posterior; RD = radial diffusivity.