The neural substrates of cognitive impairment in Alzheimer's disease and normal aging: positron emission tomography studies

Both neurodegenerative diseases and, to a lesser extent, normal aging, have characteristic profiles of cognitive decline, with however marked intersubject differences. Although these cognitive alterations are presently getting better defined thanks to extensive neuropsychological investigations, little is known about the brain structures whose neuronal damage underlies them, because of the lack of structural lesion easily detectable in vivo. Thanks to the measurement of resting cerebral metabolic rate of glucose (CMR-Glc), positron emission tomography permits to assess quantitatively the local baseline synaptic function, which reflects both the density and the functional activity of the synapses. Earlier studies have shown this variable to be sensitive to both Alzheimer's disease and normal aging. Capitalizing on the variance that exists in both cognitive performances and CMR-Glc across lesser aging and in Alzheimer's disease, it becomes possible to correlate this quantitative variable with performances in cognitive tasks, and significant correlations will reveal the structures that underlie the particular neuropsychological alteration. This novel approach opens the way to a "functional neuropsychology" in subjects,whose brain damage is inapparent with standard structural imaging. We report two studies in,Alzheimer's disease that validate this approach, one in the domain of writing impairment, and the other in memory. Regarding the latter, we place emphasis on story recall, a task probing verbal episodic memory. Significant correlations between performances in this task and CMR-Glc in a group of patients with mild-to-moderate Alzheimer's disease were located in medial temporal cortex and cingulate gyrus, with clear-cut left-sided predominance. At variance with these relatively expected findings in Alzheimer's disease, the performances in this task across a sample of healthy subjects of variable age (which constitutes a substantial source of variance in both memory performance and CMR-Glc) were significantly correlated to die prefrontal cortex bilaterally. These findings would be consistent with the impairment of different processes, namely the episodic memory proper due to limbic system alterations in the;Alzheimer's disease, and the use of this system in normal aging, as a result of prefrontal cortex dysfunction. Over and above its applications in neurological research, our approach also constitutes a new source of inferences in neuropsychology to better understand the functional organization of the normal brain.