Spatial correlation between brain aerobic glycolysis and amyloid-β (Aβ) deposition

Abstract

Amyloid-β (Aβ) plaque deposition can precede the clinical manifestations of dementia of the Alzheimer type (DAT) by many years and can be associated with changes in brain metabolism. Both the Aβ plaque deposition and the changes in metabolism appear to be concentrated in the brain's default-mode network. In contrast to prior studies of brain metabolism which viewed brain metabolism from a unitary perspective that equated glucose utilization with oxygen consumption, we here report on regional glucose use apart from that entering oxidative phosphorylation (so-called "aerobic glycolysis"). Using PET, we found that the spatial distribution of aerobic glycolysis in normal young adults correlates spatially with Aβ deposition in individuals with DAT and cognitively normal participants with elevated Aβ, suggesting a possible link between regional aerobic glycolysis in young adulthood and later development of Alzheimer pathology.Alzheimer's disease | default mode network | positron emission tomography C erebral amyloid-β (Aβ) plaque deposition is a hallmark of Alzheimer's disease (AD) (1, 2), and there is clinical pathological evidence that Aβ deposition may precede clinical manifestation of cognitive deficits and dementia of the Alzheimer type (DAT) (3, 4). However, it is unclear whether the site and extent of Aβ deposition is related to any preceding pattern of brain activity or metabolism.A radiotracer with high affinity to Aβ plaques, N-methyl-[ 11 C] 2-(4′-methylaminophenyl)-6-hydroxybenzothiazole (or 11 C-PIB, for "Pittsburgh Compound-B"), has been developed for PET study and has demonstrated substantially increased regional uptake in individuals with DAT and also in some cognitively normal older persons (5-7). The spatial distribution of Aβ plaques by PET imaging in individuals with DAT appears strikingly similar to the default mode network (DMN), a group of brain regions that are more active when normal individuals are not engaged in attentiondemanding, goal-directed task performance (8-10).The unique distribution of Aβ in DAT suggests that something unique to these brain areas predisposes them to the pathophysiology of AD (9, 11). One of the many features of these areas is their reliance on glucose outside its usual role as substrate for oxidative phosphorylation (12). In adequately oxygenated tissue, this use of glucose usually is referred to as "aerobic glycolysis" and accounts for 10-15% of the glucose metabolized by the brain (13-15). It should be noted that the term "aerobic glycolysis" includes glycolysis itself (metabolism of glucose-6-phosphate to pyruvate) as well as glucose entering the pentose phosphate shunt and glycogen synthesis.Because many critical functions are associated with glucose outside its traditional role in supplying energy through oxidative phosphorylation (16)(17)(18)(19), this relationship might signal a causal element in the chain of events leading to DAT. As a first step in exploring this possibility, we wanted to confirm the apparent spatial relationship between DAT and those brai...

Regional aerobic glycolysis in the human brain

“…1) are nearly identical with those that accumulate amyloid, and exhibit atrophy and disrupted metabolism in Alzheimer's disease as detailed in our companion paper (60) as well as elsewhere (61). This observation suggests to us that a loss of an adaptive advantage provided by aerobic glycolysis in brain systems that are particularly dependent upon it might be a critical component in the pathophysiology of Alzheimer's disease, a subject that we have previously explored in more detail (60).…”

Magnetic resonance spectroscopy reveals abnormalities of glucose metabolism in the Alzheimer's brain

“…The impairment in glucose uptake and metabolism starts decades before classic AD symptoms and worsens steadily with disease progression 4, 5, 6. Studies using positron emission tomography with 2‐[(18)F]fluoro‐2‐deoxy‐D‐glucose (FDG‐PET) have demonstrated a characteristic pattern of hypometabolism, which is most pronounced in the posterior cingulate and medial parieto‐temporal cortices, also notable for their higher reliance on aerobic glycolysis relative to the rest of the brain 7, 8. The precuneus/posterior cingulate region is also a key node of the Default Mode Network (DMN) and shows early and prominent beta‐amyloid (A β ) deposition,9, 10, 11 abnormal functional connectivity,12 decreased glucose utilization,13 and an association with deficits in executive function14 in AD.…”

Correlation of brain amyloid with “aerobic glycolysis”: A question of assumptions?

“…Vaishnavi et al (1) and Vlassenko et al (2) show that higher levels of aerobic glycolysis are concentrated in the default mode network (DMN), an anatomically defined brain network-involving the medial temporal lobe and the medial prefrontal subsystems that converge for integration in the posterior cingulate gyruspreferentially active when individuals Brain regional correlations between markers for amyloid tau deposition, glucose hypometabolism, and neuronal losses and corresponding alterations in neuropsychiatric measures were demonstrated in humans with AD and mild cognitive impairment (MCI) (10). These results strengthened earlier suggestions that clinical symptoms characteristic for AD stem from the disruption of major neuronal circuits caused by the extensive loss of neurons forming these circuits associated with early pathological Aβ and τ deposition initially affecting the entorhinal cortex.…”

“…As referenced in these articles, the molar ratio of O 2 to glucose consumption by the brain is never 6 (the ratio for complete oxidation of glucose to CO 2 and H 2 O). Because the experimentally determined molar ratio is normally ≈5.3, the major portion of glucose flux proceeds through the tricarboxylic acid (TCA) cycle to meet the high ATP demands of the brain, as well as other TCA cycle functions.…”

“…T he articles by Vaishnavi et al (1) and Vlassenko et al (2) in PNAS demonstrate regional variation in aerobic glycolysis vs. oxidative phosphorylation in the human brain and then link aerobic glycolysis to amyloid β (Aβ) deposition on the basis of concordant spatial distributions in Alzheimer's disease (AD). As referenced in these articles, the molar ratio of O 2 to glucose consumption by the brain is never 6 (the ratio for complete oxidation of glucose to CO 2 and H 2 O).…”