Age-related impairment of coupling mechanism between neuronal activation and functional cerebral blood flow response was restored by cholinesterase inhibition: PET study with microdialysis in the awake monkey brain

The effects of three cholinesterase inhibitors (physostigmine, E2020, and T acrine). all of which are to be cognitive enhancers, on the functional regi onal cerebral blood flow (rCBF) response were studied in young (5.9 +/- 1.8 years old) and aged (18.0 +/- 3.3 years old) monkeys under awake condition s using high-resolution positron emission tomography (PET). Under control c ondition, vibrotactile stimulation elicited increases in the rCBF response in the contralateral somatosensory cortices of both young and aged monkeys, but the degree of increase in rCBF response was significantly lower in age d (115.8%) than that in young monkeys (139.9%). Regional cerebral metabolic rate of glucose (rCMRglc) response to the stimulation, measured using [F-1 8]-2-fluoro-2-deoxy-D-glucose (FDG) as an index of neuronal activation, was slightly, bur not significantly, lower in aged than in young monkeys. The lower rCBF response to the stimulation in aged monkeys was improved by admi nistration of the cognitive enhancers with c cholinesterase inhibition (phy sostigmine, E2020 and Tacrine) at a dose of 50 mu g/kg. The order of improv ement of rCBF response (physostigmine > E2020 > Tacrine) at 0.5 h after inj ection and that of duration of effect (E2020 > Tacrine > physostigmine) wer e consistent with the data obtained by microdialysis. In contrast, the cogn itive enhancers did not alter rCBF response to stimulation in young monkeys . The present results demonstrated that the functional change in rCBF respo nse to the stimulation was induced during the aging process by impairment o f the coupling mechanism between the neuronal activation and rCBF response. Furthermore, the: observation that cognitive enhancers partly restored the functional rCBF response suggested that the coupling mechanism might be re gulated via cholinergic neuronal transmission. (C) 2000 Elsevier Science B. V. All rights reserved.