The Brain at High Altitude: Hypometabolism as a Defense against Chronic Hypoxia?

Abstract

Summary: The brain of hypoxia-tolerant vertebrates is known to survive extreme limitations of oxygen in part because of very low rates of energy production and utili zation. To assess if similar adaptations may be involved in humans during hypoxia adaptation over generational time, volunteer Quechua natives, indigenous to the high Andes between about 3,700 and 4,900 m altitude, served as subjects in positron emission tomographic measure ments of brain regional glucose metabolic rates. Two met abolic states were analyzed: (a) the presumed normal (high altitude-adapted) state monitored as soon as possi ble after leaving the Andes and (b) the de acclimated state monitored after 3 weeks at low altitudes. Proton nuclear magnetic resonance spectroscopy studies of the Quechua brain found normal spectra, with no indication of any unusual lactate accumulation; in contrast, in hypoxia-The central nervous system in humans as in most mammals displays surprisingly high mass-specific metabolic rates and is widely considered to be the most hypoxia sensitive organ in the body. For this reason, and because cerebrovascular disease re mains an unacceptably frequent cause of death in modern societies, a very large research interest fo cuses on mechanisms of defense against O2 limita tion in the mammalian brain. Most studies in this area deal with acute (hypoxia or ischemic) exposure and concentrate (a) on mechanism of damage, and 671tolerant species, a relatively large fraction of the glucose taken up by the brain is released as lactate. Positron emis sion tomographic measurements of [18P]2-deoxy-2-fluoro-o-glucose (PDG) uptake rates, quantified in 26 re gions of the brain, indicated systematically lower region by-region glucose metabolic rates in Quechuas than in lowlanders. The metabolic reductions were least pro nounced in primitive brain structures (e.g., cerebellum) and most pronounced in regions classically associated with higher cortical functions (e.g., frontal cortex). These differences between Quechuas with lifetime exposure to hypobaric hypoxia and lowlanders, which seem to be ex pressed to some degree in most brain regions examined, may be the result of a defense adaptation against chronic hypoxia. Key Words: Brain [18P]deoxyglucose-Brain hypoxia adaptation-Brain glucose metabolism.

Our ancestral physiological phenotype: An adaptation for hypoxia tolerance and for endurance performance?

“…Of the above O 2 sensor-linked response systems, for example, the blunting of HVR in Quechuas (40) and Sherpas (41) and the increase in RBC mass in Andeans (7,(14)(15)(16) are more robust than in Tibetans (40). Similarily, glucose metabolic rates are downregulated mildy in the central nervous system in Quechuas, hypometabolism seemingly being used as an hypoxia defense strategy (13), but this trait is not expressed in Sherpas (14). Such differences in some physiological characters are not unexpected, given the length of time these lineages have been evolving separately (see below), and they do not alter our impression of a high altitude physiological phenotype based on many similar traits in Quechuas and Sherpas.…”

“…As in the pinniped example, current evidence indicates that ''conservative'' and ''adaptable'' physiological characters are involved in human responses to hypoxia. Because now we are dealing with traits within a single species, conservative characters clearly are dominant and are too numerous to outline in detail; three examples are Hb O 2 affinity and regulation (36), muscle organization into different fiber types (11,38,39), and the region-specific organization of brain metabolism with the brain's almost exclusive preference for glucose as a fuel (13,14). These kinds of physiological traits-which in sum make up most of our physiology-appear to be conserved through phylogenetic time by negative selection, and the ways they are used on hypoxia exposure appear common in humans no matter what the O 2 content of the inspired air in the normal environment.…”

Long‐term acclimatization to high‐altitude hypoxia modifies interhemispheric functional and structural connectivity in the adult brain

“…In addition to brain hypometabolism (Hochachka et al. 1994; Richardson et al. 2011), neuroimaging studies in recent years have revealed compensatory processes for brain structure and function in indigenous residents and immigrants who were born and raised in HA (Yan et al.…”

Cortical Thickness of Native Tibetans in the Qinghai-Tibetan Plateau

“…High-altitude (HA) natives have developed distinctive biologic characteristics in respiratory and circulatory functions, 1,2 hemoglobin concentration, 3 arterial oxygen saturation, 4 energy metabolism, 5 and genes 6 to offset the stresses of HA environmental factors. Previous studies have revealed the adaptation of the cerebral glucose metabolic rate 7 in HA Quechua natives and the adaptation of cerebral autoregulation in HA Himalayan natives 8 and Ethiopian natives. 9 However, existing studies provided no assessments of the cerebral structures in HA natives.…”