Primary lateral sclerosis (PLS) is an idiopathic, progressive motor neuron disease. In contrast with ALS, the defining clinical and neuropathological features of PLS reflect the selective degeneration of upper motor neurons without evident lower motor neuron involvement. However, as upper motor neuron degeneration is not specific to PLS, recognition of distinctive neuroanatomical patterns of disease involvement would have important implications for diagnostic and prognostic biomarker studies.

The objective of this study is to characterise the extra-motor profile of PLS in contrast to ALS and healthy controls.

A prospective, quantitative neuroimaging study was conducted with 49 PLS patients, 100 ALS patients and 100 healthy controls with comprehensive genetic and clinical profiling. Standardised neurological assessments were performed to explore disease-specific characteristics. Surface-based and voxel-based morphometry and tract-based spatial statistics were used to systematically characterise extra-motor grey and white matter degeneration in PLS compared to controls, controlling for differences in disease duration and demographic factors.

The extra-motor profile of PLS included marked insular, inferior frontal and left pars opercularis pathology. Bilateral corticospinal tract alterations were common to both PLS and ALS and did not differ significantly.  In contrast with ALS , extensive bilateral cerebellar grey and white matter degeneration was identified in PLS which was not accounted for by the longer symptom duration in the PLS group in comparison with ALS. Somatosensory cortex and the corpus callosum genu degeneration were detected only in the ALS group despite prolonged disease duration in PLS. Preferential medial motor cortex degeneration was identified in PLS, consistent the observed lower limb predominant clinical involvement reflected in functional-rating scores and examination metrics. Clinical measures showed somatotopic correlations with imaging metrics in PLS.

PLS and ALS have distinguishing imaging signatures. Given the scarcity of post-mortem studies in PLS, imaging provides invaluable pathological insights.