Primary lateral sclerosis (PLS) is a low incidence motor neuron disease manifesting in progressive limb spasticity, gait impairment, bulbar dysfunction and often in pseudobulbar affect. Varying degree of frontotemporal involvement has also been recently confirmed. Postmortem data is scarce in PLS and disease burden patterns are best characterised in vivo by purpose-designed neuroimaging protocols.

A large prospective neuroimaging study has been undertaken to explore cerebral involvement patterns in PLS using a both structural T1-weighted data and diffusion MRI data. Neuroimaging data were complemented by genetic screening and comprehensive clinical profiling. Brain involvement patterns have been first characterised by standard morphometric and diffusivity analyses. Resulting disease burden maps were then correlated to physiological mitochondrial density (MitoD) maps. In an additional, region-of-interest analysis, brain regions with significant topological associations between neurodegeneration and MitoD were ranked based on their r -values.

Grey matter degeneration in PLS is not limited to the motor cortex, but also encompasses frontotemporal, caudate, thalamic, cerebellar and cingulate regions. Voxelwise statistics confirm topological associations between atrophy and physiological mitochondrial density. The most significant associations between neurodegeneration and MitoD were detected in the cerebellum, superior temporal lobe, precentral gyrus, inferior operculum, and orbitofrontal gyrus. Similarly, white matter degeneration is not limited to the corticospinal tracts, but includes the corpus callosum, frontotemporal association fibres, the cingulum, cerebellar peduncles, and the fornix. Anatomical associations were also detected between diffusivity alterations and focal MitoD.

PLS is associated with a selective disease burden pattern, and our data suggest that brain regions with high baseline metabolic activity are more likely to succumb to neurodegeneration. Cerebral areas showing the most significant anatomical associations between atrophy and mitochondrial density (precentral gyrus, cerebellum, frontotemporal regions) are pathognomonic brain regions of PLS driving its core clinical manifestations.