Taking a New Look at Psychosis in Alzheimer's Disease

By Robert A. Sweet, M.D. | November 1, 2002

There is emerging neurobiologic evidence suggesting that AD+P is associated with excess neocortical pathology. Functional imaging studies in vivo have found that subjects with AD+P demonstrate excess impairment of frontal, temporal and parietal cerebral blood flow and glucose metabolism in comparison to AD subjects without psychosis (Starkstein et al., 1994; Sultzer et al., 1995). We recently examined post-mortem magnetic resonance spectroscopy in subjects with AD+P, finding significant reductions in neocortical N-acetyl-L-aspartate (NAA, a marker of neuronal integrity) concentrations, with superior temporal, dorsolateral prefrontal and inferior parietal cortex most affected (Sweet et al., 2002b). Subjects with AD+P also demonstrated significant elevations in concentrations of the phosphodiester membrane breakdown product glycerphosphoethanolamine compared to subjects without psychosis. It is noteworthy that similar observations have been emerging in the study of subjects with schizophrenia, in whom studies have also found reduced NAA concentrations and elevated concentrations of phosphodiesters (Keshavan et al., 2000). Similarly, post-mortem studies of subjects with schizophrenia have found evidence of reduced pyramidal cell volume (Pierri et al., 2001; Rajkowska et al., 1998; Sweet et al., 2001a) and reduced numbers of synaptic components in neocortical regions (Garey et al., 1998; Glantz and Lewis, 1997; Rosoklija et al., 2000). Thus, just as psychosis is associated with cognitive impairment in both schizophrenia and AD, there may be factors affecting neuronal and synaptic integrity and number that underlie psychosis in both disorders.

Summary

An emerging body of evidence indicates that AD+P identifies a clinically relevant subtype, characterized by an increased rate of cognitive deterioration, a liability toward aggressive behavior, greater caregiver burden and premature institutionalization. Efforts to identify the distinct genetic and neurobiologic determinants of AD+P are still in the early stages, although some promising leads are already emerging. For example, the association between AD+P and genetic variation in serotonin system receptors might not have been expected, but is consistent with emerging evidence that the selective serotonin reuptake inhibitors provide therapeutic benefit for agitated and psychotic symptoms in subjects with AD+P (Pollock et al., 2002). Whether study of AD+P will lead to additional insights into the biology of psychotic symptoms in AD, and in other psychotic disorders, remains to be determined.

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Taking a New Look at Psychosis in Alzheimer's Disease

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