The clinical and radiological profile of primary lateral sclerosis: a population-based study

J Neurol. 2019 Nov;266(11):2718-2733. doi: 10.1007/s00415-019-09473-z. Epub 2019 Jul 19.


Background: Primary lateral sclerosis is a progressive upper-motor-neuron disorder associated with markedly longer survival than ALS. In contrast to ALS, the genetic susceptibility, histopathological profile and imaging signature of PLS are poorly characterised. Suspected PLS patients often face considerable diagnostic delay and prognostic uncertainty.

Objective: To characterise the distinguishing clinical, genetic and imaging features of PLS in contrast to ALS and healthy controls.

Methods: A prospective population-based study was conducted with 49 PLS patients, 100 ALS patients and 100 healthy controls using genetic profiling, standardised clinical assessments and neuroimaging. Whole-brain and region-of-interest analyses were undertaken to evaluate patterns of grey and white matter degeneration.

Results: In PLS, disease burden in the motor cortex is more medial than in ALS consistent with its lower limb symptom-predominance. PLS is associated with considerable cerebellar white and grey matter degeneration and the extra-motor profile of PLS includes marked insular, inferior frontal and left pars opercularis pathology. Contrary to ALS, PLS spares the postcentral gyrus. The body and splenium of the corpus callosum are preferentially affected in PLS, in contrast to the genu involvement observed in ALS. Clinical measures show anatomically meaningful correlations with imaging metrics in a somatotopic distribution. PLS patients tested negative for C9orf72 repeat expansions, known ALS and HSP-associated genes.

Conclusions: Multiparametric imaging in PLS highlights disease-specific motor and extra-motor involvement distinct from ALS. In a condition where limited post-mortem data are available, imaging offers invaluable pathological insights. Anatomical correlations with clinical metrics confirm the biomarker potential of quantitative neuroimaging in PLS.

Keywords: Amyotrophic lateral sclerosis; Genetics; MRI; Neuroimaging; Primary lateral sclerosis.

MeSH terms

  • Aged
  • Amyotrophic Lateral Sclerosis / diagnostic imaging
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / pathology
  • Brain / diagnostic imaging
  • Brain / pathology*
  • C9orf72 Protein / genetics
  • Female
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Motor Neuron Disease / diagnostic imaging
  • Motor Neuron Disease / genetics
  • Motor Neuron Disease / pathology*
  • Neuroimaging
  • Prospective Studies


  • C9orf72 Protein
  • C9orf72 protein, human