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

Abstract

Key points: 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.

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. 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 (80 m, n = 17), and age- and gender-matched HA dwellers born and bred in La Paz, Bolivia (3600 m) 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 < 0.05 vs. 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.

Keywords: cerebrovascular function; chronic mountain sickness; cognition; dementia; depression; free radicals.

Figure 1. Functionally integrated translational hypothesis

CMS−/CMS+, highlanders without/with chronic mountain sickness; +++, comparatively more hypoxaemic; OXINOS, oxidative–inflammatory–nitrosative stress.

Figure 2. Experimental design

CMS−/CMS+, highlanders without/with chronic mountain sickness; NO, nitric oxide; O₂, oxygen; CVR, cerebrovascular reactivity; CO₂, carbon dioxide; dCA, dynamic cerebral autoregulation.

Figure 3. Typical electron paramagnetic resonance (EPR) spectra of the plasma ascorbate radical (A–C) and ozone‐based chemiluminescence detection of bioactive (nitrite + S‐nitrosothiols) nitric oxide metabolites (D–F) at rest in the systemic circulation of a lowlander and highlanders without (CMS−) and with (CMS+) chronic mountain sickness

A–C, oxidation of the ascorbate monoanion (AH⁻) by any free radical (R^•) with a one‐electron reduction potential that exceeds +282 mV will yield A^•− (schematic illustrated above). The unpaired electron is delocalised over a highly conjugated tri‐carbonyl π‐system, rendering it resonance‐stabilised and thereby facilitating direct detection by EPR spectroscopy. At the current settings, A^•− appears as a (filtered) doublet with a hydrogen hyperfine coupling constant (a _H ^β) of ∼1.76 G (see inset to A for simulated spectrum). D–F, filtered traces of bioactive nitric oxide (NO) metabolites (nitrite + S‐nitrosothiols) generated via ozone‐based chemiluminescence involving the reaction of NO with ozone (O₃) that yields a photon (hv) and subsequent conversion to a potential difference. Insert top right highlights the composite signals (before and after sulphanilamide incubation) for separate measurement of nitrite (${\mathrm{NO}}_2^{-}$) and S‐nitrosothiols (RSNO). Note general elevations in the signal intensity (AU, arbitrary units) of A^•− and reciprocal decrease in the circulating concentration of bioactive NO metabolites in the highlanders, especially in the patient with CMS. Spectra were chosen to best reflect the average signal intensities observed in each of the respective groups.

Figure 4. Cerebrovascular reactivity to carbon dioxide (CVR_CO2)

Values are mean ± SD; CMS−/CMS+, highlanders without/with chronic mountain sickness; ^*different vs. lowlanders for respective challenge (P < 0.05). Individual hypocapnia and hypercapnia datasets were analysed using one‐way ANOVAs and post hoc Bonferonni‐adjusted independent samples t‐tests.

Figure 5. Typical waveforms and spectral analysis of haemodynamic responses observed during spontaneous (A) and repeated squat‐stand manoeuvres (B, C) in a representative patient with chronic mountain sickness

BP, blood pressure; MCAv, middle cerebral artery velocity; PSD, power spectral density; V/LF, very/low frequency. Note the markedly amplified and coherent oscillations in MAP and MCAv during the repeated squat‐stand manoeuvres compared to resting (spontaneous) measures, leading to improved estimation of transfer function of dynamic cerebral autoregulation at the frequency of interest.

Figure 6. Transfer function analysis of the cerebral pressure–flow relationship during spontaneous (A–C) and driven (D–F) oscillations in blood pressure and middle cerebral artery velocity

Values are mean ± SD; CMS−/CMS+, highlanders without/with chronic mountain sickness; ^*different vs. lowlanders for the given frequency (P < 0.05). Individual frequency data sets were analysed using using one‐way ANOVAs and post hoc Bonferonni‐adjusted independent samples t‐tests.

Figure 7. Relationships between metabolic, haemodynamic and clinical correlates in lowlanders and highlanders with and without chronic mountain sickness (CMS)

A, ascorbate radical; $S_{\mathrm{a}{\mathrm{O}}_2}$, arterial oxyhaemoglobin saturation; NO, nitric oxide; MCAv, middle cerebral artery blood flow velocity; CDO₂, cerebral oxygen delivery; CVR_CO2Hyper, cerebrovascular reactivity to carbon dioxide in the hypercapnic range; MoCA, Montreal Cognitive Assessment. Data were analysed using a Pearson product moment correlation.