Brain Advance Access originally published online on May 6, 2004
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Brain, Vol. 127, No. 6, 1237-1251, 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh132
Cortical selective vulnerability in motor neuron disease: a morphometric study
Departments of 1 Neuropathology, 2 Neurology and 3 Biostatistics and Computing, Institute of Psychiatry and 4 Department of Anatomy and Developmental Biology, University College London, London, UK and 5 Department of Psychiatry, Education and Resource Centre, Royal College of Surgeons in Ireland, Beaumont Road, Dublin 9, Dublin, Ireland
Correspondence to: P. Nigel Leigh, PO 41, Department of Neurology, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK. E-mail: spgtpnl{at}iop.kcl.ac.uk
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-D28K (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.
Key Words: motor neuron disease; selective vulnerability; primary motor cortex; dorsolateral prefrontal cortex; anterior cingulate cortex
Abbreviations: ACC = anterior cingulate cortex; CB = calbindin-D28K; CBP = calcium-binding protein; CR = calretinin; DLPFC = dorsolateral prefrontal cortex; DMND = motor neuron disease with frontotemporal dementia; ICI = intracortical inhibition; IR = immunoreactive; LMN = lower motor neuron; MND = motor neuron disease; PMC = primary motor cortex; PMI = post-mortem interval; PV = parvalbumin; SMI-32 = mouse monoclonal antibody against an epitope of non-phosphorylated neurofilament heavy chain
Received October 22, 2003. Revised December 19, 2003. Accepted December 23, 2003.
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