The objective of this study is to characterise anatomical patterns of subcortical grey matter degeneration in primary lateral sclerosis (PLS) in comparison with ALS and healthy controls.

PLS is a low-incidence upper motor neuron disease. Despite sporadic reports of cognitive and behavioural impairment in PLS and evidence of subcortical grey matter pathology at autopsy, the full spectrum of extra-motor involvement has not been systematically evaluated in vivo. 

A prospective multimodal imaging study was undertaken with 33 PLS patients, 117 healthy controls and 100 ALS patients to assess the integrity of subcortical grey matter structures and determine whether PLS and ALS have distinctive radiological features. Volumetric, morphometric, segmentation and vertex-wise analyses were carried out in the three study groups to evaluate the thalamus, hippocampus, caudate, amygdala, pallidum, putamen and accumbens nucleus in each hemisphere. The hippocampus was further  segmented to characterise the involvement of specific subfields. Comparisons between patient groups were adjusted for differences in symptom duration and demographic variables. Patients were tested for C9orf72 repeat expansions, known ALS and HSP-associated genes.

Considerable thalamic, caudate, and hippocampal atrophy was detected in PLS based on both volumetric and vertex analyses. Significant volume reductions were also detected in the accumbens nuclei. Hippocampal atrophy in PLS is was dominated by dentate gyrus, hippocampal tail and CA4 subfield volume reductions. The morphometric comparison of ALS and PLS cohorts revealed preferential medial bi-thalamic pathology in PLS compared to the predominant putaminal degeneration detected in ALS.

PLS should no longer be regarded as a pure upper-motor-neuron disorder, as it is associated with marked thalamic, hippocampal and basal ganglia atrophy. The severity of subcortical grey matter degeneration observed in PLS is comparable to ALS, but the anatomical patterns are different. These data demonstrate that PLS exhibits distinctive imaging features which may have a biomarker role.