Cortical selective vulnerability in motor neuron disease: a morphometric study

Brain. 2004 Jun;127(Pt 6):1237-51. doi: 10.1093/brain/awh132. Epub 2004 May 6.


Neuroimaging and neuropsychological studies have revealed that the primary motor cortex (PMC) and the extramotor cortical areas are functionally abnormal in motor neuron disease (MND, amyotrophic lateral sclerosis), but the nature of the cortical lesions that underlie these changes is poorly understood. In particular, there have been few attempts to quantify neuronal loss in the PMC and in other cortical areas in MND. We used SMI-32, an antibody against an epitope on non-phosphorylated neurofilament heavy chain, to analyse the size and density of SMI-32-positive cortical pyramidal neurons in layer V of the PMC, the dorsolateral prefrontal cortex (DLPFC) and the supragenual anterior cingulate cortex (ACC) in 13 MND and eight control subjects. There was a statistically significant reduction in the density of SMI-32-immunoreactive (IR) pyramidal neurons within cortical layer V in the PMC, the DLPFC and the ACC in MND subjects compared with controls [t (19) = 2.91, P = 0.009; estimated reduction 25%; 95% CI = 8%, 40%]. In addition, we studied the density and size of interneurons immunoreactive for the calcium-binding proteins calbindin-D(28K) (CB), parvalbumin (PV) and calretinin (CR) in the same areas (PMC, DLPFC and ACC). Statistically significant differences in the densities of CB-IR neurons were observed within cortical layers V (P = 0.003) and VI (P = 0.001) in MND cases compared with controls. The densities of CR- and PV-IR neurons were not significantly different between MND and control cases, although there were trends towards reductions of CR-IR neuronal density within the same layers and of PV-IR neuronal density within cortical layer VI. Loss of pyramidal neurons and of GABAergic interneurons is more widespread than has been appreciated and is present in areas associated with neuroimaging and cognitive abnormalities in MND. These findings support the notion that MND should be considered a multisystem disorder.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antibodies, Monoclonal / immunology
  • Calcium-Binding Proteins / analysis
  • Cell Count
  • Cell Size
  • Cerebral Cortex / chemistry
  • Cerebral Cortex / pathology*
  • Female
  • Humans
  • Image Processing, Computer-Assisted / methods
  • Immunoenzyme Techniques
  • Interneurons / pathology
  • Male
  • Middle Aged
  • Motor Cortex / pathology
  • Motor Neuron Disease / metabolism
  • Motor Neuron Disease / pathology*
  • Motor Neurons / pathology
  • Neurofilament Proteins / analysis
  • Prefrontal Cortex / pathology
  • Pyramidal Cells / pathology


  • Antibodies, Monoclonal
  • Calcium-Binding Proteins
  • Neurofilament Proteins
  • calcium-binding protein (brain)
  • neurofilament protein H