Differential corticospinal tract degeneration in homozygous 'D90A' SOD-1 ALS and sporadic ALS

Abstract

BackgroundThe homogeneous genotype and stereotyped phenotype of a unique familial form of amyotrophic lateral sclerosis (ALS) (patients homozygous for aspartate-to-alanine mutations in codon 90 (homD90A) superoxide dismutase 1) provides an ideal model for studying genotype/phenotype interactions and pathological features compared with heterogeneous apparently sporadic ALS. The authors aimed to use diffusion tensor tractography to quantify and compare changes in the intracerebral corticospinal tracts of patients with both forms of ALS, building on previous work using whole-brain voxelwise group analysis.Method21 sporadic ALS patients, seven homD90A patients and 20 healthy controls underwent 1.5 T diffusion tensor MRI. Patients were assessed using ‘upper motor neuron burden,’ El Escorial and ALSFR-R scales. The intracranial corticospinal tract was assessed using diffusion tensor tractography measures of fractional anisotropy (FA), mean diffusivity, and radial and axial diffusivity obtained from its entire length.ResultsCorticospinal tract FA was reduced in sporadic ALS patients compared with both homD90A ALS patients and controls. The diffusion measures in sporadic ALS patients were consistent with anterograde (Wallerian) degeneration of the corticospinal tracts. In sporadic ALS, corticospinal tract FA was related to clinical measures. Despite a similar degree of clinical upper motor neuron dysfunction and disability in homD90A ALS patients compared with sporadic ALS, there were no abnormalities in corticospinal tract diffusion measures compared with controls.ConclusionsDiffusion tensor tractography has shown axonal degeneration within the intracerebral portion of the corticospinal tract in sporadic ALS patients, but not those with a homogeneous form of familial ALS. This suggests significant genotypic influences on the phenotype of ALS and may provide clues to slower progression of disease in homD90A patients.

Brain connectivity in neurodegenerative diseases—from phenotype to proteinopathy

“…Both studies showed relatively preserved CST connectivity in mutation carriers compared with sporadic cases. 69,70 DTI changes in nonmotor tracts were reported by a recent study, and have been related to changes in social and emotional processing. 71 Motor network damage has been suggested as a potential marker to track disease progression in ALS, with progressive expansion of white matter damage from the CST to extramotor areas.…”

25 years of neuroimaging in amyotrophic lateral sclerosis

“…Patients with ALS caused by homozygous Asp90Ala SOD1 mutations had similar CST FA values to healthy controls, whereas patients with sporadic ALS had lower CST FA values, indicating different disease mechanisms between this familial type and sporadic ALS. 83 Some studies have reported decreased FA, 37,76,82,84–87 increased MD, 81,88 and increased axial diffusivity 76,79,89 in the posterior limb of the internal capsule (PLIC). The PLIC contains densely packed CST fibres and might, therefore, be highly sensitive to DTI alterations.…”

Grey matter correlates of clinical variables in amyotrophic lateral sclerosis (ALS): a neuroimaging study of ALS motor phenotype heterogeneity and cortical focality

“…The imaging signature of this mutation has been elegantly presented in both symptomatic and pre-symptomatic patient cohorts using diffusion tensor imaging,10 magnetic resonance spectroscopy11 and positron emmission tomography imaging 12…”