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Herman Moreno, MD; William E. Wu, BA; Thomas Lee, BA; Adam Brickman, PhD; Richard Mayeux, MD, MSE; Truman R. Brown, PhD; Scott A. Small, MD

Arch Neurol. 2007;64(10):1467-1477.

Background  Neurotoxicity related to the Aβ 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 Aβ-related neurotoxicity remains unknown.

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

Author Affiliations: Departments of Neurology and Pharmacology/Physiology, Robert S. Furchgott Center for Neural and Behavioral Sciences, State University of New York Downstate Medical Center, Brooklyn (Dr Moreno), Taub Institute for Research on Alzheimer's Disease and the Aging Brain, New York (Messrs Wu and Lee and Drs Brickman, Mayeux, and Small), and Departments of Radiology (Dr Brown) and Neurology (Drs Moreno, Mayeux, and Small), Columbia University, College of Physicians and Surgeons, New York, New York.

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