Aerobic glycolysis is defined as glucose utilization in excess of that used for oxidative phosphorylation despite sufficient oxygen to completely metabolize glucose to carbon dioxide and water. Aerobic glycolysis is present in the normal human brain at rest and increases locally during increased neuronal activity; yet its many biological functions have received scant attention because of a prevailing energy-centric focus on the role of glucose as substrate for oxidative phosphorylation. As an initial step in redressing this neglect, we measured the regional distribution of aerobic glycolysis with positron emission tomography in 33 neurologically normal young adults at rest. We show that the distribution of aerobic glycolysis in the brain is differentially present in previously well-described functional areas. In particular, aerobic glycolysis is significantly elevated in medial and lateral parietal and prefrontal cortices. In contrast, the cerebellum and medial temporal lobes have levels of aerobic glycolysis significantly below the brain mean. The levels of aerobic glycolysis are not strictly related to the levels of brain energy metabolism. For example, sensory cortices exhibit high metabolic rates for glucose and oxygen consumption but low rates of aerobic glycolysis. These striking regional variations in aerobic glycolysis in the normal human brain provide an opportunity to explore how brain systems differentially use the diverse cell biology of glucose in support of their functional specializations in health and disease. W hen glucose metabolism exceeds that used for oxidative phosphorylation despite sufficient oxygen to metabolize glucose to carbon dioxide and water, it has traditionally been referred to as aerobic glycolysis. Aerobic glycolysis has a long history in cancer cell biology, where the phenomenon was first noted by Otto Warburg (1), for whom it is often referred to as the "Warburg effect." Since Warburg's early work (2), much research has focused on the reasons for aerobic glycolysis mainly in cancer cells (3-5). Topics have included, but are not limited to, the role of aerobic glycolysis in biosynthesis, the maintenance of cellular redox states, the regulation of apoptosis and the provision of ATP for membrane pumps and protein phosphorylation. Little attention has been paid to the normal brain in this regard, despite the well documented presence of aerobic glycolysis (6-8; noteworthy recent exception in ref. 9).From a whole-brain perspective, aerobic glycolysis may account for ∼10-12% of the glucose used in the adult human (6-8). This percentage varies in interesting ways. In the newborn, it represents more than 30% of the glucose metabolized (10). In the adult, aerobic glycolysis varies diurnally from a low in the morning of ∼11% to nearly 20% in the evening (7). In none of these observations do we have any information on the regional distribution of aerobic glycolysis in the brain or its role in cell biology.The only information presently on regional brain aerobic glycolysis relates to task...

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...

OASIS-3 is a compilation of MRI and PET imaging and related clinical data for 1098 participants who were collected across several ongoing studies in the Washington University Knight Alzheimer Disease Research Center over the course of 15 years. Participants include 605 cognitively normal adults and 493 individuals at various stages of cognitive decline ranging in age from 42 to 95 years. The OASIS-3 dataset contains over 2000 MR sessions, including multiple structural and functional sequences. PET metabolic and amyloid imaging includes over 1500 raw imaging scans and the accompanying post-processed files from the PET Unified Pipeline (PUP) are also available in OASIS-3. OASIS-3 also contains post-processed imaging data such as volumetric segmentations and PET analyses. Imaging data is accompanied by dementia and APOE status and longitudinal clinical and cognitive outcomes. OASIS-3 is available as an open access data set to the scientific community to answer questions related to healthy aging and dementia.

Coupling of cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2) in physiologically activated brain states remains the subject of debates. Recently it was suggested that CBF is tightly coupled to oxidative metabolism in a nonlinear fashion. As part of this hypothesis, mathematical models of oxygen delivery to the brain have been described in which disproportionately large increases in CBF are necessary to sustain even small increases in CMRO2 during activation. We have explored the coupling of CBF and oxygen delivery by using two complementary methods. First, a more complex mathematical model was tested that differs from those recently described in that no assumptions were made regarding tissue oxygen level. Second, [ 15 O] water CBF positron emission tomography (PET) studies in nine healthy subjects were conducted during states of visual activation and hypoxia to examine the relationship of CBF and oxygen delivery. In contrast to previous reports, our model showed adequate tissue levels of oxygen could be maintained without the need for increased CBF or oxygen delivery. Similarly, the PET studies demonstrated that the regional increase in CBF during visual activation was not affected by hypoxia. These findings strongly indicate that the increase in CBF associated with physiological activation is regulated by factors other than local requirements in oxygen. It was long assumed that changes in cerebral blood flow (CBF) and in the cerebral metabolic rate of oxygen (CMRO 2 ) are tightly coupled in both resting and active brain states. This assumption resulted from the premises that the brain needs oxygen, that CBF is a main homeostatic factor for oxygen supply regulation, and that oxygen availability should be adjusted to meet tissue needs (1). It is known that the brain needs an abundant supply of oxygen and that, at rest, 80-92% of its ATP comes from oxidative metabolism of glucose. Early studies by Kety and Schmidt (2) and Cohen et al. (3) demonstrated that resting CBF does change with hypoxia and hyperoxia, thereby suggesting that CBF regulates oxygen delivery, although it was noted that blood oxygen levels but not tissue oxygen levels likely triggered these CBF changes (1). Therefore, if the cerebral oxygen supply was closely regulated to match tissue demands, then functional activation, which implies the need for additional ATP and oxygen, should cause a coupled increase in both CBF and CMRO 2 . However, two positron emission tomography (PET) studies conducted by Fox et al. (4,5) revealed that in humans large, stimulus-induced increases in CBF (Ϸ30% and 50%) were accompanied by only small increases in CMRO 2 (Ϸ5%). Others using PET and functional MRI confirmed these findings (6-10). The data indicated that, during short-term functional activation, CBF and CMRO 2 are not directly coupled.Recently, several reports using theoretical models suggested that the apparent uncoupling of CMRO 2 and CBF might actually be a tight nonlinear coupling. Mathematical models of oxygen delivery to the brai...

In vivo quantification of β-amyloid deposition using positron emission tomography is emerging as an important procedure for the early diagnosis of the Alzheimer's disease and is likely to play an important role in upcoming clinical trials of disease modifying agents. However, many groups use manually defined regions, which are non-standard across imaging centers. Analyses often are limited to a handful of regions because of the labor-intensive nature of manual region drawing. In this study, we developed an automatic image quantification protocol based on FreeSurfer, an automated whole brain segmentation tool, for quantitative analysis of amyloid images. Standard manual tracing and FreeSurfer-based analyses were performed in 77 participants including 67 cognitively normal individuals and 10 individuals with early Alzheimer's disease. The manual and FreeSurfer approaches yielded nearly identical estimates of amyloid burden (intraclass correlation = 0.98) as assessed by the mean cortical binding potential. An MRI test-retest study demonstrated excellent reliability of FreeSurfer based regional amyloid burden measurements. The FreeSurfer-based analysis also revealed that the majority of cerebral cortical regions accumulate amyloid in parallel, with slope of accumulation being the primary difference between regions.