Objectives: To differentiate the brain metabolic patterns associated with the spectrum of treatment responses to the cholinesterase inhibitor galantamine as visualized with [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET). Background: The regional metabolic correlates of treatment with cholinesterase inhibitors are unknown.

Methods: This was a hypothesis driven, prospective, open-label, study of eighteen mild to moderate AD patients recruited from the community who were evaluated before, and after treatment with the cholinesterase inhibitor galantamine. Patients were given 16 to 24 mg of galantamine per day (based upon dosage tolerance) for 8 weeks. Major clinical evaluations included the cognitive portion of the Alzheimer's Disease Assessment Scale (ADAS-cog), Mini Mental State Examination (MMSE), and Neuropsychiatric Inventory (NPI). Imaging was carried out using FDG-PET. The PET studies, registered to a probabilistic anatomic atlas were subjected to a voxel by voxel subtraction of the post-treatment minus pre-treatment studies within and across three patient subgroups: treatment responders, non-responders, and unchanged patients. Sub-Volume Thresholding (SVT) corrected random lobar noise to produce 3D functional significance maps.

Results: The criterion for treatment response (! 4 point improvement from baseline in NPI total score) was met in 6 patients while the criterion for nonresponse (! 4 point worsening from baseline in NPI total score) was met in 5 patients; the 7 remaining patients fell between these criteria and were considered unchanged. The responders also had significantly improved ADAS-cog scores compared to the non-responder group (p < 0.05). The significant NPI subscale changes distinguishing the responders from the non-responders were agitation, euphoria, apathy, and irritability (p " 0.05) while ADAS-cog subscores showed significant improvement in learning and recognition between the two groups. The clinical benefits observed with galantamine were associated with metabolic activation of a lateral orbitofrontal defect at baseline in responders with an increase in thalamic activation that accompanied this and other brain changes. Conclusion: Future studies should explore the specificity of this distributed neural network across other cholinesterase inhibitor therapies.