This is Your Brain on (Low) Glucose

Abstract

Brain functioning and high-order cognitive functions critically rely on glucose as a metabolic substrate. In a recent study, Healy et al. investigated the impact of glucose availability on sickness behavior and delirium in mice and humans. They identified disrupted brain carbohydrate metabolism as a key mechanistic driver of these behaviors.

Metabolic processes support all biological functions. Various environmental constraints force organisms to prioritize certain metabolic programs over others to achieve optimal outcomes [1]. Abundant nutrients (e.g., glucose) drive growth and reproduction through anabolic processes, or energy production; by contrast, a lack of nutrients prioritizes catabolic processes, or energy breakdown. However, the metabolic processes that support immune responses are less straightforward. Inflammation is driven by the expansion of immune cells and biosynthesis of inflammatory mediators (anabolic processes) even though immune responses typically occur at the expense of organismal growth and reproduction [1]. Inflammation can manifest behaviorally as sickness behavior: anorexia, fatigue, loss of libido, and impaired cognition. These behaviors reflect a diversion of metabolic resources from normal functioning toward pathogen defense. Indeed, cognition is barely a requirement for successful defense against pathogens at the organismal level.

Sterile inflammation can also perturb cognition. For example, patients with a hip fracture frequently experience delirium, which is characterized by impaired attention and reduced level of consciousness during the perioperative period [2]. However, whereas the specific cause of infectious inflammation is often well defined (i.e., a certain pathogen), delirium is a complex clinical state with multiple etiologies. In fact, delirium can arise from a range of precipitating factors, including trauma, major surgery, use of psychoactive drugs, and metabolic abnormalities [3]. Yet, not all major surgeries, to name one example, cause delirium. An individual’s vulnerability to delirium depends on various predisposing factors, including pre-existing cognitive impairment, advanced age, history of stroke, and medication [3]. Despite this dizzying array of predisposing and precipitating factors, a recent paper by Kealy et al. [4] pegged disrupted carbohydrate metabolism as the proximate cause of delirium resulting from systemic inflammation in mice and humans.

Conventional wisdom dictates that inflammatory cytokines perpetrate sickness behaviors via actions at the blood-brain barrier and beyond it [5]. Kealy et al. [4] questioned whether inflammatory cytokines were in fact the proximate cause of these behaviors by exploring the glycemic and behavioral effects of systemic inflammation in mice using lipopolysaccharide (LPS) as an inflammatory stimulus. Intraperitoneal injection of LPS decreased glucose levels in the blood and cerebrospinal fluid (CSF), with kinetics that mirrored reductions in spontaneous behavior. The behavioral effect of LPS was also reduced by glucose supplementation and enhanced by 2-deoxyglucose, a glycolytic inhibitor. Interestingly, IL-1β alone was sufficient to induce a hypoglycemic response that was prevented in IL-1RI^−/− mice. With these observations, Kealy et al. [4] pinpointed hypoglycemia, rather than inflammatory cytokines, as the proximate cause of sickness behavior.

Kealy et al. [4] next examined whether disrupted glucose metabolism could explain delirium in a mouse model of delirium superimposed on dementia. Based on previous findings that the ME7 mouse-adapted scrapie strain, which is characterized by chronic neurodegeneration, is particularly sensitive to the cognitive effects of systemic LPS injection, Kealy et al. [4] hypothesized that these mice would display cognitive impairments with reduced glucose availability. The authors initially tested this by treating ME7 and control mice with insulin to reduce blood glucose levels. Insulin was sufficient to induce cognitive deficits in ME7 mice at doses that were ineffective in control mice. The authors subsequently hypothesized that exogenous glucose could rescue the cognitive consequences of LPS injection in ME7 mice, and it did.

Extending their investigation to humans, Kealy et al. [4] also measured metabolic substrates in the CSF of patients with hip fracture with or without prevalent (i.e., present at hospital admission) delirium. This patient population provides a unique opportunity to assay CSF metabolites due to the use of spinal anesthesia during hip fracture repair. Although patients with hip repair and delirium did not exhibit differences in CSF glucose, they did display elevated levels of CSF lactate independent of dementia. Kealy et al. concluded that hip fracture, the presumed cause of delirium in a subset of these patients, perturbed energy metabolism in the brain. (It should be noted that delirium could have precipitated the injurious fall that resulted in hip fracture, but this possibility does not necessarily undercut the authors’ conclusion that disrupted brain energy metabolism was associated with delirium in these patients.)

The study by Kealy et al. raises key questions about the immunometabolic under-pinnings of delirium and dementia in humans, particularly in light of the putatively bidirectional relationship between the two [2]. The available evidence suggests that delirium simultaneously unmasks a premorbid vulnerability to dementia and contributes to it. Can changes in carbohydrate metabolism explain the convergence between delirium and dementia? To what extent can a series of inflammatory episodes cause long-lasting impairments in carbohydrate metabolism?

A recently published longitudinal neuroimaging study of patients with autosomal dominant Alzheimer’s disease (AD) offers food for thought on the putative relationship between delirium and dementia [6]. In this study, amyloid deposition preceded changes in brain glucose metabolism, suggesting that amyloid-β has a key role in perturbing glucose metabolism early in AD. The proposed driver of changes in glucose metabolism during AD is amyloid-β-induced oxidative stress [7]. Oxidative damage can modify the function of key metabolic enzymes (e.g., ATP synthase) and lead to several severe consequences for neurons by preventing their ability to maintain ion gradients and buffer Ca²⁺ [7]. It is intriguing to speculate that episodes of inflammation, particularly on the background of an ongoing neurodegenerative process, hasten the accumulation of oxidative damage in the brain, and thereby explain the contribution of delirium to long-lasting cognitive worsening. Indeed, systemic inflammation may cause oxidative stress in the brain, both directly via the inflammatory actions of immune cells and, in the context of AD, indirectly by increasing amyloid burden [8].

From a historical perspective, the hypothesis that perturbed brain carbohydrate metabolism is sufficient to cause delirium is not new. In fact, in 1944, and before postulating delirium as a ‘syndrome of cerebral insufficiency’, the psychiatrists Engel and Romano discovered that hypoglycemia was sufficient to induce electroencephalogram slowing and delirium in humans that could be rescued by exogenous glucose [9]. The work by Kealy et al. [4] expands these ideas and contributes to a more rounded picture of the immunometabolic interplay that links delirium and neurodegeneration. A goal for future studies is to investigate these phenomena in greater molecular detail, with an eye towards developing therapeutic strategies.