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

Research output: Contribution to journalArticlepeer-review

Authors

  • Leena Shoemaker
  • Luke Wilson
  • Liana Machado
  • Robert Walker
  • J.D. Cotter

Colleges, School and Institutes

External organisations

  • University of Otago
  • Department of Physiology, Division of Health Sciences, University of Otago, Dunedin, New Zealand
  • University of Otago

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 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.

Bibliographic note

Funding Information: Funding support was received from the School of Physical Education, Sport and Exercise Sciences and Department of Medicine, University of Otago, as well as via a Lottery Health Research grant, Department of Internal Affairs (to LCW), which assisted with the ethics application and protocol design. Publisher Copyright: © 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society

Details

Original languageEnglish
JournalThe Journal of Physiology
Volume599
Issue number4
Early online date13 Nov 2020
Publication statusPublished - 15 Feb 2021

Keywords

  • ageing, cerebral blood flow, cognition, hypercapnia, indomethacin

ASJC Scopus subject areas