Context-dependent, neural system-specific neurophysiological concomitants of ageing: mapping PET correlates during cognitive activation

Abstract

We used PET to explore the neurophysiological changes that accompany cognitive disability in ageing, with a focus on the frontal lobe. Absolute regional cerebral blood flow (rCBF) was measured in 41 healthy volunteers, evenly distributed across an age range of 18-80 years, during two task paradigms: (i) the Wisconsin Card Sorting Test (WCST), which depends heavily on working memory and is particularly sensitive to dysfunction of the dorsolateral prefrontal cortex (DLPFC); and (ii) Raven's Progressive Matrices (RPM), which may also have a working memory component, but depends more on visuo-spatial processing and is most sensitive to dysfunction of postrolandic regions. We used voxel-wise correlational mapping to determine age-related changes in WCST and RPM activation and developed a method to quantitate and localize statistical differences between the correlation maps for the two task paradigms. Because both WCST and RPM performance declined with age, as expected, correlational analyses were performed with and without partialling out the effect of task performance. Task-specific reductions of rCBF activation with age were found in the DLPFC during the WCST and in portions of the inferolateral temporal cortex involved in visuo-spatial processing during the RPM. We also found reduced ability to suppress rCBF in the right hippocampal region during the WCST and in mesial and polar portions of the prefrontal cortex during both task conditions. Task-dependent alterations with age in the relationship between the DLPFC and the hippocampus were also documented; because the collective pattern of changes in the hippocampal-DLPFC relationship with ageing was opposite to that seen in a previous study using dextroamphetamine, we postulated a dopaminergic mechanism. These results indicate that, despite some cognitive overlap between the two tasks and the age-related cognitive decline in both, many of the changes in rCBF activation with age were task-specific, reflecting functional alteration of the different neural circuits normally engaged by young subjects during the WCST and RPM. Reduced activation of areas critical for task performance (i.e. the DLPFC during the WCST and posterior visual association areas of the inferolateral temporal cortex during the RPM), in conjunction with the inability to suppress areas normally not involved in task performance (i.e. the left hippocampal region during the WCST and mesial polar prefrontal cortex during both the WCST and RPM), suggest that, overall, reduced ability to focus neural activity may be impaired in older subjects. The context dependency of the age-related changes is most consistent with systems failure and disordered connectivity.