Cortical selective vulnerability in motor neuron disease: a morphometric study

Abstract

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.

Neonatal Neuronal Circuitry Shows Hyperexcitable Disturbance in a Mouse Model of the Adult-Onset Neurodegenerative Disease Amyotrophic Lateral Sclerosis

“…Together with reports of interneuronal loss in spinal cord and cortex of human ALS patients (Maekawa et al, 2004;Stephens et al, 2006) and in transgenic mice overexpressing mutant hSOD1 (Morrison et al, 1998), this suggests that early hyperexcitability in interneurons may also contribute to interneuronal loss at later stages in ALS.…”

Lactate dyscrasia: a novel explanation for amyotrophic lateral sclerosis

“…The cognitively impaired patients also had UIBs in the temporal, occipital, and entorhinal cortices, posterior cingulate gyrus, caudate, and putamen. Computerized morphometry revealed a 25% reduction in the pyramidal neuronal density in layer V of the premotor cortex, dorsolateral prefrontal cortex, and anterior cingulate cortex compared with age-matched controls (Maekawa et al, 2004). This is particularly relevant in the context of findings from positron emission tomography neuroimaging which identified decreased binding of the GABAergic ligand (11C)-flumazenil in the prefrontal cortex (Lloyd et al, 2000;Turner et al, 2005) and increased microglial activation (implicated in mechanisms of neuronal cell death) in the dorsolateral prefrontal cortex (Turner et al, 2004).…”

“…The major pathological features of ALS include: (1) degeneration of the corticospinal tracts and extensive loss of lower motoneurons or anterior horn cells (Garofalo et al, 1995;Ghatak et al, 1986;Hughes, 1982); (2) degeneration and loss of Betz cells and other pyramidal cells in the primary motor cortex (Hammer et al, 1979;Maekawa et al, 2004;Udaka et al, 1986); and (3) reactive gliosis in the motor cortex and spinal cord (Ekblom et al, 1994;Kawamata et al, 1992;Murayama et al, 1991;Schiffer et al, 1996).…”

Altered cortical beta‐band oscillations reflect motor system degeneration in amyotrophic lateral sclerosis

“…Pathological studies demonstrate a particular vulnerability of parvalbumin‐positive interneurons [Maekawa et al, 2004; Nihei et al, 1993], later shown to contribute to reduced inhibitory GABA‐ergic tone in animal models [McGown et al, 2013; Nieto‐Gonzalez et al, 2011]. Neuroimaging studies across multiple modalities have supported the concept of reduced cortical inhibition.…”