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.
Highlights
The neurodegenerative pathology in amyotrophic lateral sclerosis (ALS) is characterized by loss of upper motor neurons of the primary motor cortex and corticospinal tract, lower motor neurons of the brainstem and spinal cord; and extramotor pathology that has clinical, pathological and genetic overlap with frontotemporal dementia (Kiernan et al, 2011)
A very rare variant known as primary lateral sclerosis demonstrates only upper motor neuron involvement clinically, with characteristically long survival, and those with ‘pure’ lower motor neuron involvement are typically slower in rate of progression (Turner et al, 2003)
To achieve age matching between groups, structural scans (T0) of 36 patients (54.2 Æ 8.6 years) were selected from the available 60 scans for the voxelbased morphometry (VBM) comparison with structural data of all 36 controls (P = 0.652)
Summary
The neurodegenerative pathology in amyotrophic lateral sclerosis (ALS) is characterized by loss of upper motor neurons of the primary motor cortex and corticospinal tract, lower motor neurons of the brainstem and spinal cord; and extramotor pathology that has clinical, pathological and genetic overlap with frontotemporal dementia (Kiernan et al, 2011). A very rare variant known as primary lateral sclerosis demonstrates only upper motor neuron involvement clinically, with characteristically long survival, and those with ‘pure’ lower motor neuron involvement are typically slower in rate of progression (Turner et al, 2003). Genetic factors may influence the dominance of pathological involvement to some extent (Al-Chalabi et al, 2012), 95% of patients report no family history of ALS or frontotemporal dementia, and currently have no obvious single genetic mutation that accounts for their disease despite indistinguishable clinical appearances
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