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One of the most interesting clinical applications of 18F-FDG PET imaging in neurodegenerative pathologies is that of establishing the prognosis of patients with mild cognitive impairment (MCI), some of whom have a high risk of progressing to Alzheimer's disease (AD). One method of analyzing these images is to perform statistical parametric mapping (SPM) analysis. Spatial normalization is a critical step in such an analysis. The purpose of this study was to assess the effect of using different methods of spatial normalization on the results of SPM analysis of 18F-FDG PET images by comparing patients with MCI and controls.We evaluated the results of three spatial normalization methods in an SPM analysis by comparing patients diagnosed with MCI with a group of control subjects. We tested three methods of spatial normalization: MRI-DARTEL and MRI-SPM8, which combine structural and functional images, and FDG-SPM8, which is based on the functional images only.The results obtained with the three methods were consistent in terms of the main pattern of functional alterations detected; namely, a bilateral reduction in glucose metabolism in the frontal and parietal cortices in the patient group. However, MRI-SPM8 also revealed differences in the left temporal cortex, and MRI-DARTEL revealed further differences in the left temporal cortex, precuneus, and left posterior cingulate.The results obtained with MRI-DARTEL were the most consistent with the pattern of changes in AD. When we compared our observations with those of previous reports, MRI-SPM8 and FDG-SPM8 seemed to show an incomplete pattern. Our results suggest that basing the spatial normalization method on functional images only can considerably impair the results of SPM analysis of 18F-FDG PET studies.