Elaine Perry

The cholinergic system in Alzheimer's disease

Abstract The cholinergic abnormality in Alzheimers disease, the most prevalent form of dementia amongst elderly people, has aroused new interest in the neurochemical pathology of this disorder. The connection between the loss of cholinergic activities in the brain and the classical neuropathological features of the disease — neocortical senile plaques and neurofibrillary tangles — is, however, far from clear. A recent report in Science 13 suggests that a critical neuropathological abnormality may be a loss of the neurons from the basal nucleus of Meynert, a subcortical nucleus which supplies the neocortex with cholinergic afferent processes.

Clinical neurochemistry: developments in dementia research based on brain bank material

Summary. Brain tissue obtained at autopsy continues to provide unique opportunities in current dementia research. Not only is tissue analysis still essential for diagnosis, but investigation of neurochemical pathology, at a level of resolution beyond current in vivo imaging, continues to provide new insights into the involvement of neurotransmitter signalling systems. These are relevant to therapy which, with respect to symptoms such as cognitive impairment, psychosis and depression, is currently targeted to specific transmitter (cholinergic, dopaminergic and serotonergic) systems. This paper focuses on dopaminergic, cholinergic and histaminergic parameters in Alzheimers disease (AD), Dementia with Lewy bodies (DLB) and Parkinsons disease (PD). In the normal striatum the dopamine transporter and D2 receptor exhibit distinct rostral-caudal distributions and D2 binding is affected by genetic polymorphism at the Taq 1A locus. The transporter is reduced in both DLB and PD but not AD, correlating with severity of extrapyramidal dysfunction, and receptor abnormalities are apparent in DLB patients responding adversely to neuroleptics. Striatal nicotine receptors are lost in all 3 disorders, further reduced as a result of neuroleptic medication, and elevated as a result of tobacco use. In the thalamus there are selective reductions in presynaptic cholinergic activity in DLB in the reticular nucleus which relate to symptoms of hallucinations and fluctuating consciousness prevalent in this disorder. In the hippocampus coupling of muscarinic M1 receptors, relevant to response to cholinergic therapy, is impaired in areas most affected by β-amyloid plaques and intact in less affected areas. Analysis of histamine H2 receptors indicates that, despite presynaptic histamine abnormalities in AD, receptor numbers are normal. Such clinically and therapeutically relevant observations on human brain neurochemistry provide a basis for improving therapeutic strategies and prospects of diagnostic in vivo chemical imaging.