Exaggerated systemic oxidative-inflammatory-nitrosative stress in chronic mountain sickness is associated with cognitive decline and depression.

Damian M Bailey,Julien V Brugniaux,Teresa Filipponi,Urs Scherrer,Sylvia Pietri,Stefano F Rimoldi,Shigehiko Ogoh,Jonathan D Smirl,Benjamin Stacey,Emrush Rexhaj,David Cerny,Carlos Salinas Salmòn,Lorenza Pratali,Rodrigo Soria,Christopher J Marley,Claudio Sartori,Mercedes Villena,Carla Murillo Jáuregui

doi:10.1113/jp276898

Abstract

Chronic mountain sickness (CMS) is a maladaptation syndrome encountered at high altitude (HA) characterised by severe hypoxaemia that carries a higher risk of stroke and migraine and is associated with increased morbidity and mortality. We examined if exaggerated oxidative-inflammatory-nitrosative stress (OXINOS) and corresponding decrease in vascular nitric oxide bioavailability in patients with CMS (CMS+) is associated with impaired cerebrovascular function and adverse neurological outcome. Systemic OXINOS was markedly elevated in CMS+ compared to healthy HA (CMS-) and low-altitude controls. OXINOS was associated with blunted cerebral perfusion and vasoreactivity to hypercapnia, impaired cognition and, in CMS+, symptoms of depression. These findings are the first to suggest that a physiological continuum exists for hypoxaemia-induced systemic OXINOS in HA dwellers that when excessive is associated with accelerated cognitive decline and depression, helping identify those in need of more specialist neurological assessment and targeted support. Chronic mountain sickness (CMS) is a maladaptation syndrome encountered at high altitude (HA) characterised by severe hypoxaemia that carries a higher risk of stroke and migraine and is associated with increased morbidity and mortality. The present cross-sectional study examined to what extent exaggerated systemic oxidative-inflammatory-nitrosative stress (OXINOS), defined by an increase in free radical formation and corresponding decrease in vascular nitric oxide (NO) bioavailability, is associated with impaired cerebrovascular function, accelerated cognitive decline and depression in CMS. Venous blood was obtained from healthy male lowlanders (80m, n= 17), and age- and gender-matched HA dwellers born and bred in La Paz, Bolivia (3600m) with (CMS+, n= 23) and without (CMS-, n= 14) CMS. We sampled blood for oxidative (electron paramagnetic resonance spectroscopy, HPLC), nitrosative (ozone-based chemiluminescence) and inflammatory (fluorescence) biomarkers. We employed transcranial Doppler ultrasound to measure cerebral blood flow (CBF) and reactivity. We utilised psychometric tests and validated questionnaires to assess cognition and depression. Highlanders exhibited elevated systemic OXINOS (P< 0.05vs. lowlanders) that was especially exaggerated in the more hypoxaemic CMS+ patients (P< 0.05 vs. CMS-). OXINOS was associated with blunted cerebral perfusion and vasoreactivity to hypercapnia, impaired cognition and, in CMS+, symptoms of depression. Collectively, these findings are the first to suggest that a physiological continuum exists for hypoxaemia-induced OXINOS in HA dwellers that when excessive is associated with accelerated cognitive decline and depression, helping identify those in need of specialist neurological assessment and support.

Highlights

The human brain has evolved a much higher rate of obligatory oxygen (O2) consumption since, unlike most other organs, its evolutionary “drive for size” means that the brain is committed to a continually active state, demanding a disproportionate 20% of the body’s basal O2 budget in the resting state, more than 10 times that expected from its mass alone (Bailey et al, 2017b)
Metabolic data Oxygenation and erythrocytosis As anticipated, highlanders presented with arterial hypoxaemia with the most pronounced erythrocytosis observed in Chronic mountain sickness (CMS)+ (Table 1)
Notwithstanding the experimental limitations as outlined, these findings indicate that a chronic state of disequilibrium potentially exists between free radical formation and antioxidant defence in highlanders causing systemic oxidative-nitrosative-inflammatory stress (OXINOS) to be permanently elevated and especially exaggerated in more hypoxaemic CMS+ patients

Summary

Introduction

The human brain has evolved a much higher rate of obligatory oxygen (O2) consumption since, unlike most other organs, its evolutionary “drive for size” means that the brain is committed to a continually active state, demanding a disproportionate 20% of the body’s basal O2 budget in the resting state, more than 10 times that expected from its mass alone (Bailey et al, 2017b). Highlanders with CMS (CMS+) exhibited more exaggerated increases in ONS and impaired systemic vascular endothelial function, implying a potential metabolic basis to HA maladaptation (Bailey et al, 2013c). In light of these findings, we sought to determine the potential relationships between metabolic (oxidative-inflammatory-nitrosative-stress referred to as OXINOS), haemodynamic (cerebrovascular function) and clinical (cognition and depression) correlates in CMS+ and CMSin order to provide more integrated mechanistic insight into the potential pathophysiology and consequences of neurological maladaptation to HA.

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