CLINICAL NEUROCHEMISTRY - DEVELOPMENTS IN DEMENTIA RESEARCH-BASED ON BRAIN BANK MATERIAL

Brain tissue obtained at autopsy continues to provide unique opportuni ties in current dementia research. Not only is tissue analysis still e ssential 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 signalli ng systems. These are relevant to therapy which, with respect to sympt oms such as cognitive impairment, psychosis and depression, is current ly targeted to specific transmitter (cholinergic, dopaminergic and ser otonergic) systems. This paper focuses on dopaminergic, cholinergic an d histaminergic parameters in Alzheimer's disease (AD), Dementia with Lewy bodies (DLB) and Parkinson's disease (PD). In the normal striatum the dopamine transporter and D2 receptor exhibit distinct rostral-cau dal distributions and D2 binding is affected by genetic polymorphism a t the Tag 1A locus. The transporter is reduced in both DLB and PD but not AD, correlating with severity of extrapyramidal dysfunction, and r eceptor abnormalities are apparent in DLB patients responding adversel y to neuroleptics. Striatal nicotine receptors are lost in all 3 disor ders, further reduced as a result of neuroleptic medication, and eleva ted as a result of tobacco use. In the thalamus there are selective re ductions in presynaptic cholinergic activity in DLB in the reticular n ucleus which relate to symptoms of hallucinations and fluctuating cons ciousness prevalent in this disorder. In the hippocampus coupling of m uscarinic M1 receptors, relevant to response to cholinergic therapy, i s impaired in areas most affected by beta-amyloid plaques and intact i n less affected areas. Analysis of histamine H2 receptors indicates th at, despite presynaptic histamine abnormalities in AD, receptor number s are normal. Such clinically and therapeutically relevant observation s on human brain neurochemistry provide a basis for improving therapeu tic strategies and prospects of diagnostic in vivo chemical imaging.