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...

SUMMARY The normal aging human brain experiences global decreases in metabolism, but whether this affects the topography of brain metabolism is unknown. Here we describe PET-based measurements of brain glucose uptake, oxygen utilization and blood flow in cognitively normal adults from 20 to 82 years of age. Age-related decreases in brain glucose uptake exceed that of oxygen use, resulting in loss of brain aerobic glycolysis (AG). Whereas the topographies of total brain glucose uptake, oxygen utilization and blood flow remain largely stable with age, brain AG topography changes significantly. Brain regions with high AG in young adults show the greatest change, as do regions with prolonged developmental transcriptional features (i.e., neoteny). The normal aging human brain thus undergoes characteristic metabolic changes, largely driven by global loss and topographic changes in brain AG.

These findings support the hypothesis that the strategic location of white matter hyperintensities may be critical in late-life depression. Further, the correlation of neuropsychological deficits with the volumes of whole brain white matter hyperintensities and gray and white matter in depressed subjects but not comparison subjects supports the hypothesis of an interaction between these structural brain components and depressed status.

Sex differences influence brain morphology and physiology during both development and aging. Here we apply a machine learning algorithm to a multiparametric brain PET imaging dataset acquired in a cohort of 20- to 82-year-old, cognitively normal adults (n = 205) to define their metabolic brain age. We find that throughout the adult life span the female brain has a persistently lower metabolic brain age—relative to their chronological age—compared with the male brain. The persistence of relatively younger metabolic brain age in females throughout adulthood suggests that development might in part influence sex differences in brain aging. Our results also demonstrate that trajectories of natural brain aging vary significantly among individuals and provide a method to measure this.

Research of the human brain metabolism in vivo has largely focused on total glucose use (via fluorodeoxyglucose positron emission tomography) and, until recently, did not examine the use of glucose outside oxidative phosphorylation, which is known as aerobic glycolysis (AG). AG supports important functions including biosynthesis and neuroprotection but decreases dramatically with aging. This multitracer positron emission tomography study evaluated the relationship between AG, total glucose use (CMRGlc), oxygen metabolism (CMRO), tau, and amyloid deposition in 42 individuals, including those at preclinical and symptomatic stages of Alzheimer's disease. Our findings demonstrate that in individuals with amyloid burden, lower AG is associated with higher tau deposition. No such correlation was observed for CMRGlc or CMRO. We suggest that aging-related loss of AG leading to decreased synaptic plasticity and neuroprotection may accelerate tauopathy in individuals with amyloid burden. Longitudinal AG and Alzheimer's disease pathology studies are needed to verify causality.