In many neurological disorders such as sporadic Alzheimer's disease (AD) where clear-cut focal tissue loss is not a feature at structural imaging, it is difficult if not impossible to determine the brain regions that underlie cognitive impairment. Mapping synaptic function with resting-state metabolic PET and gray matter density with MRI-based voxel-based morphometry (VBM) makes it possible to address this issue in vivo. Applying this approach to AD and its pre-dementia stage (known as mild cognitive impairment, MCI) and to the Wernicke-Korsakoff syndrome of permanent amnesia, we find significant glucose hypometabolism in the limbic and paralimbic regions, particularly targeting the posterior cingulate/retrosplenial cortices and hippocampal region, but also in the posterior association cortex and occasionally in prefrontal regions. Correlative analysis with memory scores show that while some of these focal synaptic changes subtend early episodic memory impairment, others seem to represent compensatory use of semantic areas with progressing impairment. In MCI, dissociations the correlations between encoding/retrieval performance and resting glucose metabolism/gray matter density suggest some areas such as the posterior cingulate/retrosplenial cortices may be dysfunctional on the basis of disconnection from hippocampal area damage rather than reflecting local pathology, an idea supported by parallel studies in the non human primate. These findings indicate the power of combined PET measurement of resting metabolism and VBM measurement of gray matter loss to unravel the mechanisms and localization of cognitive impairment in various neurological entities.

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