Imaging the Abeta-related neurotoxicity of Alzheimer disease.

BACKGROUND

Neurotoxicity related to the Abeta 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 Abeta-related neurotoxicity remains unknown.

OBJECTIVE

To study Abeta-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 wild-type 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 Abeta-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 Abeta peptide can be captured in vivo by functional imaging and suggest hippocampal subregions most vulnerable to its toxic effects.