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

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 CO ₂ 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 (MCAv _mean) and its reactivity to hypercapnia (CVR _HYPER) and hypocapnia (CVR _HYPO), respectively. Cognitive function was assessed using a computerized battery including response time tasks. Baseline comparisons revealed that older adults had 14% lower MCAv _mean and 15% lower cognitive performance (all P ≤ 0.048), but not lower CVR _HYPER/HYPO (P ≥ 0.26). Linear and rank-based mixed models revealed that indomethacin decreased MCAv _mean by 31% (95% confidence interval = –35 to –26), CVR _HYPER by 68% [interquartile range (IQR) = –94 to –44] and CVR _HYPO by 50% (IQR = –83 to –33) (treatment-effect; all P < 0.01), regardless of age. Baseline CVR _HYPER/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 MCAv _mean (Young: rho = –0.31, P = 0.30; Older: rho = 0.06, P = 0.86). In conclusion, indomethacin reduced MCAv _mean and impaired cognition slightly; however, no clear association was evident in younger or older adults. Older adults had poorer cognition and lower MCAv _mean, but similar CVR _HYPER/HYPO.