Upper motor neuron and extra-motor neuron involvement in amyotrophic lateral sclerosis: a clinical and brain imaging review

Neuromuscul Disord. 2009 Jan;19(1):53-8. doi: 10.1016/j.nmd.2008.10.002. Epub 2008 Dec 12.


There is an ongoing discussion whether ALS is primarily a disease of upper motor neurons or lower motor neurons. We undertook a review to assess how new insights have contributed to solve this controversy. For this purpose we selected relevant publications from 1995 onwards focussing on (1) primary targets and disease progression in ALS and variants of ALS, (2) brain imaging markers for upper motor neuron lesion, and (3) evidence for ALS being a multisystem disorder. Clinically, upper motor and lower motor neuron symptoms can occur in any order over time. Brain imaging markers show upper motor neuron involvement in early disease. Overlap syndromes of ALS and dementia, and involvement of autonomic and sensory nerves occur frequently. PET/SPECT scans, functional MRI and voxel based morphometry studies clearly show abnormalities in extra-motor areas of the brain. Pathologically, the 43 kDa TAR DNA-binding protein (TDP-43) provides a clue to these overlapping disorders. In conclusion, evidence accumulates that ALS is a multisystem disorder rather than a pure lower and/or upper motor neuron disorder.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amyotrophic Lateral Sclerosis / complications
  • Amyotrophic Lateral Sclerosis / pathology
  • Amyotrophic Lateral Sclerosis / physiopathology*
  • Autonomic Nervous System Diseases / etiology
  • Autonomic Nervous System Diseases / pathology
  • Autonomic Nervous System Diseases / physiopathology
  • Brain / diagnostic imaging
  • Brain / pathology
  • Brain / physiopathology*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Dementia / etiology
  • Dementia / pathology
  • Dementia / physiopathology
  • Diagnostic Imaging
  • Humans
  • Motor Neuron Disease / complications
  • Motor Neuron Disease / pathology
  • Motor Neuron Disease / physiopathology*
  • Radionuclide Imaging
  • Spinal Cord / diagnostic imaging
  • Spinal Cord / pathology
  • Spinal Cord / physiopathology*


  • DNA-Binding Proteins