Clinicopathological investigations of the cholinergic basal forebrain in Lewy body disorders and ageing

Abstract

Cholinergic dysfunction has long been associated with cognitive impairment in Alzheimer’s disease (AD). However, neuropathological and functional imaging studies have also found significant cortical cholinergic deficit in Lewy body disorders (LBD), but in a different pattern from that in AD. There is topographical cholinerigic innervation to the cortex and the hippocampus from the basal forebrain. In light of differences in cognitive deficits seen in LBD and AD, I hypothesised that cholinergic basal forebrain subregions are differentially affected in these disorders.

In this thesis, novel tissue techniques have been developed for the visualisation of pathology in human post-mortem brain tissue in three-dimensions. Based on a thorough review of the literature and my personal observations, I have established a simplified subdivisional scheme of the nucleus basalis of Meynert (nbM) in the human brain. Using this scheme, a quantification of nbM cholinergic neurons and assessment of neuropathological burden were performed in a large cohort of LBD and AD cases. Severe neuronal depletion across the entire nbM was observed in LBD with cognitive impairment and relative sparing of the anterior nbM was found in AD, supporting findings from previous neuropathological and imaging studies. Further investigation was carried out in the more rostral, hippocampal-projecting cholinergic group in the vertical limb of the nucleus of the diagonal band of Broca. Significant neurodegeneration in this area was identified in LBD with cognitive impairment, but not AD, suggesting its possible role in retrieval memory function via projection to the hippocampal CA2 subfield. In the final section, it was demonstrated that lactacystin injection into the rat nbM can replicate certain pathological and clinical features of LBD with dementia and this may be a useful model for the disease.

Results from these studies support my initial hypothesis regarding differential susceptibility of the basal forebrain subregions in LBD and AD.