Psychosis in Alzheimer disease: postmortem magnetic resonance spectroscopy evidence of excess neuronal and membrane phospholipid pathology

Background: The presence of psychotic symptoms in Alzheimer Disease subjects (AD+psychosis, AD+P) is a marker for a phenotype characterized by more severe cognitive impairment and a more rapidly deteriorating course. Although AD+P has been inconsistently associated with more severe neuropathology, no prior studies have examined measures of neuronal and synaptic integrity. Objective: To determine whether AD+P is associated with evidence of disrupted neuronal and synaptic integrity, as indicated by magnetic resonance spectroscopy (MRS) measurement of N-acetyl- l-aspartate and the membrane breakdown products, glycerophosphocholine and glycerophosphoethanolamine. Methods: 31P and 1H MRS studies of perchloric acid extract from postmortem brain of AD subjects with and without a history of psychotic symptoms. All subjects were characterized for the presence of comorbid cortical Lewy body pathology and for history of neuroleptic use. Brain tissue from dorsolateral prefrontal, superior temporal, inferior parietal, and occipital cortex, amygdala, and cerebellum were examined in all subjects. Statistical analysis accounted for correlated observations across brain regions within-subjects. Results: AD+P subjects demonstrated significant elevations of glycerophosphoethanolamine and significant reductions of N-acetyl- l-aspartate. Between group differences were greatest in neocortical brain regions. Conclusion: Excess impairment of neocortical neuronal and synaptic integrity may provide the structural substrate underlying AD+P. Confirmation of these findings using in vivo MRS measures is indicated.