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Cortical Pyramidal Neurone Loss May Cause Glutamatergic Hypoactivity and Cognitive Impairment in Alzheimer's Disease: Investigative and Therapeutic Perspectives

In the 1960s it became generally accepted that the cognitive impairment associated with old age was due to disorders with specific histological features rather than being an inevitable part of the aging process (see, e.g., Corsellis, 1962). Furthermore, two disorders appeared to account for the majority of cases of dementia amongst the elderly, one characterised by prominent disease of the cerebral vasculature and one with histological features similar to those described in a patient in her fifties by Alois Alzheimer early in the century. Alzheimer’s disease (AD) was therefore recognised as a major cause ofdementia, rather than a rare neurodegenerative disease giving rise to presenile dementia. This observation, coupled with the identification of the neurochemical pathology underlying Parkinson’s disease and the success of L-DOPA treatment following its introduction in 1968, set the scene for the systematic biochemical study ofdementia in old age with the hope of producing similarly dramatic treatments. The demonstration of substantial cholinergic abnormalities in the brains of patients with AD suggested a basis for such rational pharmacological treatments. However, cases have been reported that raise some doubts as to the validity of the view of AD as a primary disorder of the cholinergic system (Bowen et al., 1977). One subset of patients with dementia had typical neuropathological findings of AD, yet their cortical choline acetyltransferase (ChAT) activity was not selectively reduced (Palmer et al., 1986). Other demented patients with AD had normal numbers of cholinergic neurones in the nucleus basalis of Meynert (Perry et al., 1982; Pearson et al., 1983). A reduction in numbers of basal forebrain neurones and cortical ChAT specific activity of a magnitude similar to that seen in moderate to severe AD occurs in another neurodegenerative condition, olivopontocerebellar atrophy, yet cognitive impairment in this condition is not prominent (Kish et al., 1988). It appears likely that the neocortical cholinergic deficit in AD can explain only a part of the entire clinical syndrome. Since 1982 this group (Bowen, 1983) has focused much attention on the intrinsic neurones of the cerebral cortex. An extensive body of literature describes effects on learning and memory in humans exerted by lesions of the cerebral cortex and the hippocampus (Dudai, 1989). Experimental studies in animals have also sought to define the role of these structures in cognition. Lashley (as reviewed by Dudai, 1989) used conditioned rats and monkeys to perform various tasks, mechanically damaged the neocortex either before or after training, and then measured the effect of the lesions on acquisition and retention. He found that the amount of reduction in learning was dependent on the amount of neocortical tissue removed and, also, that the more complex the task, the greater the effect of the removal of neocortex. Studies have been extended to include the hippocampus and have also increased in subtlety by using excitotoxins, with analogous changes in behaviour (Francis et al., 1992~). The excitatory amino acids (EAA), glutamic (Glu) and aspartic acid, are the proposed transmitters of the cortical pyramidal cells and have been the subject of detailed studies in recent years. There is now strong evidence for an excitotoxic role of these amino acids in the pathogenesis of cerebral ischaemia (German0 et al.. 1987: Park et al., 1988: Sheardown et al., 1990).