Objective: Behavioral and Psychological Symptoms of Dementia (BPSD) are a major clinical feature of Alzheimer's disease (AD) in addition to cognitive impairments. However, the biochemical basis of BPSD is poorly understood. As previous studies have implicated brain serotonin (5-HT) and 5-HT receptors in several CNS functions including cognition, mood and emotional states, we have systematically investigated abnormalities in the serotonergic system in AD.
Design: Community-based, clinically diagnosed dementia patients were recruited for a longitudinal study of behavioral changes in dementia. Consent for post-mortem brain donation was obtained for diagnostic verfication and research.
Materials and Methods: Behavioral abnormalities in the dementia patients were assessed from study entry till death at four-monthly intervals with the Present Behavioural Examination. The selection of subjects was based on the neuropathological diagnosis of AD and tissue availability, and not on disease severity or presence of behavioral symptoms. The serotonergic system was examined by immunohistochemistry of the raphe nuclei, high performance liquid chromatography of 5-HT and its metabolites and radioligand assays for pre- and post-synaptic 5-HT receptors in the neocortex.
Results: Whilst the raphe nuclei were significantly affected by the pathology of AD, there was a lack of correlation between reduced 5-HT neurone density and clinical disease parameters. There was significant reduction in the number of 5-HT uptake sites in AD temporal but not frontal cortex. However, there was no significant alteration in the concentrations of 5-HT or 5-HIAA in either region. AD patients who had persistent depressive symptoms during life had significantly fewer 5-HT uptake sites. 5-HT1A receptor binding affinity and density (Bmax) were unchanged in AD compared with controls. Within the AD group, 5-HT1A Bmax in the temporal cortex inversely correlated with aggression and dementia severity. However, multiple regression analyses showed that 5-HT1A receptor Bmax remained the best predictor for aggression, while temporal cortical neurofibrillary tangle grading was the best predictor for dementia severity. This suggests that 5-HT1A receptor alterations is directly related to aggression in AD, while dementia severity is more strongly related to the neurodegenerative process. By contrast, 5-HT4 receptors were not altered in AD and did not correlate with behavioural symptoms.
Conclusion: Using postmortem tissue of well-characterized AD subjects, we have demonstrated that the serotonergic system in AD displays considerable plasticity and diversity. The correlation of certain neurochemical parameters to clinical symptoms provides a basis for further studies into rational treatment with 5-HT drugs as well as the in vivo screening for patients at risk of developing behavioral symptoms.
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