Region-specific interneuronal degeneration in the human cerebral cortex in Huntington’s disease correlates with symptomatology

Abstract

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterised by variable symptoms (choreiform movements, cognitive, mood and neuropsychological changes), with variable neuropathology of the basal ganglia and cerebral cortex. Recent studies from our laboratory have shown that the pattern of cortical pyramidal cell loss in 8 different cortical regions correlates with the phenotypic variability in HD; and that in 2 regions of the cerebral cortex (the primary motor cortex, and the anterior cingulate gyrus) the pattern of interneuronal degeneration correlates with pyramidal cell death and variable HD symptom profiles. The present study completes this overview of human cortical neuronal degeneration in the human brain in HD. This study of the HD human brain specifically examines the pattern of interneuronal degeneration in the primary sensory cortex, superior frontal cortex, and superior parietal cortex, and correlates these findings with the well characterised clinical and pathological history of the HD cases. To undertake this investigation, unbiased stereological counting methods were used to quantify the three major types of interneurons immunoreactive for calbindin-D28k, calretinin, and parvalbumin in the three cortical regions of 14 HD and 13 control cases of post-mortem human brain. Based on their predominant symptom, the HD cases were categorised into three groups (“motor”, “mood”, “mixed”). The results demonstrated a heterogeneous loss of interneurons across the three cortical regions, which paralleled the heterogeneous pattern of pyramidal cell loss in the same cortical areas. Most interestingly, the pattern of GABAergic interneuronal loss in these cortical regions correlated with the variable symptom profiles in different human HD cases. These findings extend our understanding about the role of the cerebral cortex in the HD pathogenesis and symptomatology by showing a precise correlation between the cortical interneuronal loss and heterogeneous symptomatology in HD.