Neuronal changes in the cerebral cortex of human brain in Huntington’s Disease

Abstract

Huntington's disease (HD) is characterised by a major loss of neurons mainly in the basal ganglia but recent evidence by Macdonald and Halliday (2002) and others have shown that the cerebral cortex is also affected. In this study, neuronal changes in the primary motor cortex (Brodmann's area 4), primary sensory cortex (Brodmann's area 3), anterior cingulate cortex (Brodmann's area 24) and superior frontal cortex (Brodmann's area 8) were investigated in 16 HD cases and 15 age, sex and postmortem-delay matched normal cases. Immunohistochemical techniques and light microscopy were used to compare the pattern of neuronal loss between the normal and HD cortices. The total neuronal population (NeuN) and pyramidal subpopulation (SMI32) in a subvolume of specific Brodmann's areas were investigated using unbiased stereological counting techniques. The results demonstrated a marked neuronal reduction in these cortical regions in HD compared to normal cases, and this reduction was greater as the "striatal" neuropathological grade increased in the primary motor and primary sensory cortex. However, in the anterior cingulate and superior frontal cortex, marked reduction was also demonstrated in the early grade cases. Despite this, there is also a large variation in the pattern of cell loss between HD cases of the same neuropathological grade, prompting the hypothesis that other factors may be influencing the extent of cell degeneration. To investigate this, the HD cases in this study were grouped into "mainly motor", "mainly mood" and "mixed" symptomatology groups. The results have shown that regardless of their striatal neuropathological grade, the pattern of cell loss in the cerebral cortex is correlated to the various clinical symptomatologies of HD. Another major finding is the demonstration of marked dystrophic changes in the remaining pyramidal neurons in HD cortex, suggesting major ongoing neuronal dysfunction. In addition, cortical interneurons (calbindin, calretinin and parvalbumin) are also shown to be affected in HD. These overall findings, together with the demonstration that there is no statistically significant correlation between the extent of neuronal cell death in the cortex and the CAG expansion number in the HD IT15 gene, show that HD is a heterogeneous disease where the pattern of cell loss in the cerebral cortex is as variable as the pattern of symptomatology. These findings provide a major contribution to the scientific understanding of the pathogenesis of HD in the human brain.