Regional aerobic glycolysis in the human brain
S. Neil Vaishnavia, Andrei G. Vlassenkoa, Melissa M. Rundlea, Abraham Z. Snydera,b, Mark A. Mintuna,c,
and Marcus E. Raichlea,b,c,d,1
Departments ofaRadiology,bNeurology,dAnatomy and Neurobiology, andcBiomedical Engineering, Washington University, St. Louis, MO 63110
Contributed by Marcus E. Raichle, August 9, 2010 (sent for review July 28, 2009)
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-centricfocus on the role of glucoseas substrate
for oxidative phosphorylation. As an initial step in redressing this
neglect, we measured the regional distribution of aerobic glycol-
ysis 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 cor-
tices exhibit high metabolic rates for glucose and oxygen con-
sumption but low rates of aerobic glycolysis. These striking re-
gional 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.
blood flow|glucose consumption|metabolism|oxygen consumption|
positron emission tomography
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 phosphor-
ylation. Little attention has been paid to the normal brain in this
regard, despite the well documented presence of aerobic gly-
colysis (6–8; noteworthy recent exception in ref. 9).
Froma whole-brainperspective, aerobicglycolysismayaccount
for ∼10–12% of the glucose used in the adult human (6–8). This
percentage varies in interesting ways. In the newborn, it repre-
sents more than 30% of the glucose metabolized (10). In the
adult,aerobicglycolysisvariesdiurnally froma lowinthemorning
of ∼11% to nearly 20% in the evening (7). In none of these
observations do we have any information on the regional distri-
bution of aerobic glycolysis in the brain or its role in cell biology.
The only information presently on regional brain aerobic gly-
colysis relates to task-induced changes in brain activity. Aerobic
glycolysis has been observed locally to increase in the human
brain during task-induced increases in cellular activity (11–13).
Research on this activity-induced increase in aerobic glycolysis
has focused on the mechanism by which glutamate is moved with
sodium into astrocytes from the synapse. Findings strongly im-
hen glucose metabolism exceeds that used for oxidative
phosphorylation despite sufficient oxygen to metabolize
plicate membrane-bound, astrocyte Na+/K+ATPase (14), which
relies on glycolysis for the energy needed to remove the accu-
mulated sodium from the astrocytes.
The experiments reported herein seek to expand our un-
derstanding of the role of glycolysis in the resting activity of the
adult human brain by determining whether regional variations in
glycolysis exist and how these regional variations might relate
to regional variations in overall brain energy consumption. We
were particularly interested to determine whether known func-
tional specializations among brain areas are reflected in their use
of aerobic glycolysis.
Measures of Resting Oxygen and Glucose Metabolism. The cerebral
metabolic rate for oxygen (CMRO2) and cerebral metabolic
rate for glucose (CMRGlu) as well as the cerebral blood flow
(CBF) were imaged with PET in 33 normal right-handed adults in
the resting awake state with eyes closed. Regional CMRGlu was
measured using [18F]-labeled fluorodeoxyglucose (FDG). Re-
the administration of -labeled water, carbon monoxide, and
oxygen. In each individual, regional CMRO2and CMRGlu were
scaled toawhole-brain meanof1(local-to-global ratio;Methods).
The individual results were averaged over subjects in a standard
Aerobic glycolysis is traditionally assessed in terms of the molar
ratio of oxygen consumption to glucose utilization [i.e., the so-
called oxygen–glucose index (OGI)]. When all of the glucose
metabolized is converted to carbon dioxide and water the OGI
is 6. A number less than 6 indicates that aerobic glycolysis is
present. In this study, we estimated aerobic glycolysis in this tra-
ditional manner by the voxelwise division of relative CMRO2by
relative CMRGlu and scaling the resulting quotient imaging to
obtain a whole-brain molar ratio of 5.323 based on earlier pub-
lished work (6–8).
Although the OGI is a straightforward measure based on well-
established metabolic principles, OGI images may be noisy in
areas of low metabolism because they involve voxelwise division.
Also, the value of the OGI is inversely related to the degree of
aerobic glycolysis, a relationship sometimes confusing to readers.
To overcome these limitations, we defined a previously unchar-
acterized measure of aerobic glycolysis in the brain: the glycolytic
index (GI). The GI is obtained by conventional linear regres-
sion of CMRGlu on CMRO2(Fig. S1) and exhibiting the re-
siduals scaled by 1000 (a procedure generally preferred for re-
moval of covariates in contrast to ratio normalization). Positive
Author contributions: M.A.M. and M.E.R. designed research; S.N.V., A.G.V., and M.M.R.
performed research; S.N.V., A.G.V., M.M.R., A.Z.S., M.A.M., and M.E.R. analyzed data; and
S.N.V. and M.E.R. wrote the paper.
The authors declare no conflict of interest.
Freely available online through the PNAS open access option.
Data deposition: Data reported in this article have been deposited in the Central Neuro-
imaging Data Archive (https://cnda.wustl.edu/) (accession no. NP721).
See Commentary on page 17459.
1To whom correspondence should be addressed. E-mail: email@example.com.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.
| October 12, 2010
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