Excitotoxic mechanisms in the pathogenesis of dementia

Alzheimer disease and related dementias, in common with most major neurological diseases, are characterized by localized brain damage. An abundance of senile plaques and neurofibrillary tangles in certain brain areas is pathognomic of the disease: of the two, the density of tangles may correlate more closely with disease severity ante mortem. Clinical manifestation of the disease also results from a locally severe loss of neurones. This might be caused by over-stimulation by excitant amino acid transmitters such as glutamate, which would promote cell death. Mechanisms which might give rise to the localization of Alzheimer pathogenesis include hypersensitivity to damage because a cell carries a particular sub-set of post-synaptic receptors; local variations in the efficiency of excitatory amino acid transport; and, possibly, local exacerbation of toxicity by substances such as beta-amyloid. Elucidation of such mechanisms could lead to new pharmacotherapies of dementia.