Widespread grey matter pathology dominates the longitudinal cerebral MRI and clinical landscape of amyotrophic lateral sclerosis

Abstract

Diagnosis, stratification and monitoring of disease progression in amyotrophic lateral sclerosis currently rely on clinical history and examination. The phenotypic heterogeneity of amyotrophic lateral sclerosis, including extramotor cognitive impairments is now well recognized. Candidate biomarkers have shown variable sensitivity and specificity, and studies have been mainly undertaken only cross-sectionally. Sixty patients with sporadic amyotrophic lateral sclerosis (without a family history of amyotrophic lateral sclerosis or dementia) underwent baseline multimodal magnetic resonance imaging at 3 T. Grey matter pathology was identified through analysis of T1-weighted images using voxel-based morphometry. White matter pathology was assessed using tract-based spatial statistics analysis of indices derived from diffusion tensor imaging. Cross-sectional analyses included group comparison with a group of healthy controls (n = 36) and correlations with clinical features, including regional disability, clinical upper motor neuron signs and cognitive impairment. Patients were offered 6-monthly follow-up MRI, and the last available scan was used for a separate longitudinal analysis (n = 27). In cross-sectional study, the core signature of white matter pathology was confirmed within the corticospinal tract and callosal body, and linked strongly to clinical upper motor neuron burden, but also to limb disability subscore and progression rate. Localized grey matter abnormalities were detected in a topographically appropriate region of the left motor cortex in relation to bulbar disability, and in Broca's area and its homologue in relation to verbal fluency. Longitudinal analysis revealed progressive and widespread changes in the grey matter, notably including the basal ganglia. In contrast there was limited white matter pathology progression, in keeping with a previously unrecognized limited change in individual clinical upper motor neuron scores, despite advancing disability. Although a consistent core white matter pathology was found cross-sectionally, grey matter pathology was dominant longitudinally, and included progression in clinically silent areas such as the basal ganglia, believed to reflect their wider cortical connectivity. Such changes were significant across a range of apparently sporadic patients rather than being a genotype-specific effect. It is also suggested that the upper motor neuron lesion in amyotrophic lateral sclerosis may be relatively constant during the established symptomatic period. These findings have implications for the development of effective diagnostic versus therapeutic monitoring magnetic resonance imaging biomarkers. Amyotrophic lateral sclerosis may be characterized initially by a predominantly white matter tract pathological signature, evolving as a widespread cortical network degeneration.

Keywords: biomarker; diffusion tensor imaging; magnetic resonance imaging; motor neuron disease; voxel-based morphometry.

Figure 1

Significant (P < 0.05, family-wise error corrected) fractional anisotropy (A) and grey matter (B) differences between patients and control subjects. Significant (P < 0.05, FWE corrected) longitudinal diffusivity increases (C) and grey matter loss (D) in patients. TBSS results are overlaid onto the group’s mean fractional anisotropy skeleton (green, for region of interest analyses only the intersection of the skeleton with the respective region of interest is shown) and the group’s mean fractional anisotropy image (greyscale). VBM results are overlaid onto the MNI T₁ (2 mm) template (left primary motor cortex and frontal lobe regions of interest are outlined in green where applicable). P = posterior; A = anterior; R = right; L = left; x, y, z = coordinates in MNI space.

Figure 2

Results of significant (P < 0.05, family-wise error corrected) grey matter (VBM) and white matter microstructure (TBSS) correlations with clinical and neuropsychological scores in the patient cohort. TBSS results are overlaid onto the group’s mean fractional anisotropy skeleton (green; for region of interest analyses only the intersection of the skeleton with the respective region of interest is shown) and the group’s mean fractional anisotropy image (greyscale). VBM results are overlaid onto the MNI T₁ (2 mm) template; respective regions of interest are outlined in green. Positive correlations are displayed in red/yellow colour; negative correlations are shown in blue–light blue colour. (A) Left: fractional anisotropy = blue, L1 = red–yellow; Right: mean diffusivity = red–yellow, radial diffusivity = yellow. (D) Fractional anisotropy = red–yellow, radial diffusivity = blue. (E) Fractional anisotropy = red–yellow, radial diffusivity/mean diffusivity/L1 = blue. (F) Fractional anisotropy = blue, radial diffusivity = red–yellow. UMN = upper motor neuron score; P = posterior; A = anterior; R = right; L = left; x, y, z = coordinates in MNI space.