THE NEURAL SUBSTRATES OF MEMORY-SYSTEMS IMPAIRMENT IN ALZHEIMERS-DISEASE - A PET STUDY OF RESTING BRAIN GLUCOSE-UTILIZATION

The aim of this study was to determine the neuronal basis for memory i mpairment in Alzheimer's disease by taking advantage of the clinical a nd metabolic heterogeneity of this pathology. To this end, 19 patients satisfying the NINCDS-ADRDA criteria for probable Alzheimer's disease of mild-to-moderate severity underwent a detailed Examination of the five memory systems according to Tulving's model, together with a PET measurement of resting regional cerebral glucose utilization (CMRGlc). Compared with controls, the patients as a group showed the expected m emory and metabolic profiles of impairment. Correlations (corrected fo r the effects of ageing) were calculated between memory scores and CMR Glc (normalized by the vermis CMRGlc) rising two methods: (i) the clas sic regions-of-interest method based on a priori hypotheses and indivi dual coregistered structural MRI; and (ii) the statistical parametric mapping method which allows a systematic voxel-by-voxel analysis, in a more descriptive and exploratory way. Significant correlations were a bove chance levels and largely consistent between the two methods. The y were almost exclusively positive (i.e. in the neurobiologically expe cted direction) and their distribution showed striking differences acc ording to each memory system. Thus, verbal episodic memory impairment was related to changes in a large neuronal network including not only the limbic structures (mesial temporal cortex, thalamus and cingulate gyrus, with left side predominance) but also the parietotemporal and f rontal association cortices of the right hemisphere, possibly on a com pensatory basis. Regardless of modality, short-term memory tests were mainly correlated with bilateral activity in posterior association cor tex, and also with activity in left prefrontal cortex for the visuospa tial span, possibly indicating essentially uniform strategies for the performance of the different tasks. As predicted, semantic memory scor es correlated with activity in temporoparietal and frontal association cortices of the left hemisphere, and also with activity in left cingu late cortex. Thus, for episodic, short-term and semantic memory, many findings fit classical neuropsychology, while most of the less expecte d ones were consistent with recent results from functional neuro-imagi ng in healthy subjects, notably with the hemispheric encoding/retrieva l asymmetry (HERA) model; only few findings suggested possible reorgan ization processes and/or recourse to unexpected cognitive strategy. Fi nally, only negative correlations were found for perceptual priming an d procedural memory; although they could arise by chance, some of thes e unexpected findings give rise to interesting hypotheses about the co gnitive relationships between the most and least affected memory syste ms. This study documents the validity and usefulness of our approach i n unravelling the neural substrates of cognitive impairment in brain p athology without focal tissue loss such as that seen in neurodegenerat ive diseases.