Imaging the Aβ-related neurotoxicity of Alzheimer disease

Background: Neurotoxicity related to the A beta peptide is thought to be a primary mechanism of dysfunction in Alzheimer disease ( AD). Although numerous imaging studies have observed brain dysfunction in AD, whether these imaged defects reflect A beta-related neurotoxicity remains unknown. Objective: To study A beta-related neurotoxicity by means of functional imaging maps of the hippocampal formation in human patients and mouse models. Design: Cross-sectional study comparing humans with AD and control subjects, cross-sectional study of J20 mice, a transgenic mouse model of AD, and a longitudinal study of flurbiprofen administration to transgenic mice. Setting: Alzheimer disease research center. Subjects: Eleven subjects with probable Alzheimer disease and 11 age-matched controls, plus J20 mice and wildtype littermates. Interventions: In the first study, human subjects and controls underwent magnetic resonance imaging. In the second study, mice underwent imaging at 3, 6, 12, 15, and 21 months of age, for a total of 57 imaging experiments. In the third study, 12 J20 mice underwent imaging repeatedly over time; 6 received flurbiprofen to ameliorate A beta-related neurotoxicity and 6 received vehicle control. Main Outcome Measures: Comparison of hippocampal functional maps. Results: Among all hippocampal subregions, the entorhinal cortex was the dominant site of dysfunction observed in both human patients and J20 mice. Long-term administration of flurbiprofen rescued entorhinal cortex dysfunction in transgenic mice. Conclusion: Our results establish that the neurotoxicity related to the A beta peptide can be captured in vivo by functional imaging and suggest hippocampal subregions most vulnerable to its toxic effects.