Indomethacin markedly blunts cerebral perfusion and reactivity, with little cognitive consequence in healthy young and older adults

Abstract

Key points: Cognitive function depends on adequate cerebrovascular perfusion and control. However, it is unknown whether acutely-reduced cerebral blood flow (CBF) impairs cognition in healthy adults. In the present study, we used a placebo-controlled, single-blinded, randomized cross-over design to test the hypothesis that acutely-reduced CBF (using a pharmacological aid; indomethacin) would impair cognition in young and older healthy adults. At baseline, older adults had lower cognitive performance and CBF, but similar cerebrovascular reactivity to CO2 and dynamic cerebral autoregulation compared to young adults. In both young and older adults, cognitive performance on a mental switching task was slightly (7%) reduced after indomethacin, but not significantly associated with reductions in CBF (∼31%). These results indicate that cognitive performance is broadly resilient against a ∼31% reduction in CBF per se in healthy young and older adults. Abstract: Cognitive function depends on adequate cerebrovascular perfusion and control. However, it is unknown whether acutely-reduced cerebral blood flow (CBF) impairs cognition in healthy adults. Using a placebo-controlled, single-blinded, randomized cross-over design, we tested the hypothesis that acutely-reduced CBF (using indomethacin [1.2 mg kg–1 oral dose]) would impair cognition in young (n = 13; 25 ± 4 years) and older (n = 12; 58 ± 6 years) healthy adults. CBF and cerebrovascular control were measured using middle cerebral artery blood velocity (MCAvmean) and its reactivity to hypercapnia (CVRHYPER) and hypocapnia (CVRHYPO), respectively. Cognitive function was assessed using a computerized battery including response time tasks. Baseline comparisons revealed that older adults had 14% lower MCAvmean and 15% lower cognitive performance (all P ≤ 0.048), but not lower CVRHYPER/HYPO (P ≥ 0.26). Linear and rank-based mixed models revealed that indomethacin decreased MCAvmean by 31% (95% confidence interval = –35 to –26), CVRHYPER by 68% [interquartile range (IQR) = –94 to –44] and CVRHYPO by 50% (IQR = –83 to –33) (treatment-effect; all P < 0.01), regardless of age. Baseline CVRHYPER/HYPO values were strongly associated with their indomethacin-induced reductions (r = 0.70 to 0.89, P < 0.01). Mental switching performance was impaired 7% (IQR = 0–19) after indomethacin (P = 0.04), but not significantly associated with reductions in MCAvmean (Young: rho = –0.31, P = 0.30; Older: rho = 0.06, P = 0.86). In conclusion, indomethacin reduced MCAvmean and impaired cognition slightly; however, no clear association was evident in younger or older adults. Older adults had poorer cognition and lower MCAvmean, but similar CVRHYPER/HYPO.