Glucose Metabolism

Pentose Phosphate Pathway (PPP)

Glucose NADPH, Ribulose 5-P

Glycolysis
G3P+F6P
Pyruvate
Pyruvate
Carboxylation
(PC) Acetyl Co-A
CO2

OAA

TCA Cycle Efflux

α-KG Glu Gln

NH3

Blood NH3
Measurement of PC and PPP Flux in
Brain: Metabolism of [2-13C]Glucose
[2-13C]glucose [2-13C]glucose

4
5

2
3

6
2
3

4
5
1

1
PPP PPP
1 1
1 1 1 1 1 1
2 2
2 2 2 2 2 2
3 3
3 3 3 3 3 3
PC PDH PDH
SCoA SCoA
PDH PDH
1 1
2 1 1 2
2 Vcyc 2
1
3 3
2
4 4
3
4 5 5
Glu Glu

1 1
2 Vcyc 2
3 3

Astrocytes 4
Gln
Gln 4 Neurons
5 5

Tiwari and Patel (2014), J. Alz. Dis.

13C-[1H]-& 1H-[13C]-NMR spectrum of cerebral
extract from [2-13C]glucose infusion
GluC5 PDH
GluC5
PPP + GluC3 x [Glu]
GlnC3 x [Gln] PC
PC flux GluC3 GlnC3
GluC4
GlnC5flux
PDH GluC5 x [Glu]
GlnC4

PPP flux 3/2 x (GluC4 + GluC3 + GluC2 ) x [Glu]

PDH flux GluC5 x [Glu]

PPP
PC
Animal Glutamate Glutamine

C3 C4 C5 C3
Wild-Type 1.9±0.3 1.6±0.1 23.8±1.1 3.6±1.0
AβPP-PS1 1.5±0.3 0.9±0.1 19.7±3.1 2.1±0.5
PDH
PC and PPP Fluxes are also impaired in
APP-PS1 Mice
Reduced PC flux indicates
 Reduced anaplerotic activity for
PCde novo synthesis
PPP of TCA cycle
intermediates
AD Brain might show reduced ammonia detoxification rate that
may lead to toxicity in brain

Flux (µmol/g/min)
*
*

* p< 0.05
Spectrum
Positron Emission Tomography
 PET

PET a radioactive tracer is injected into a subject intravenously and is chemically

incorporated into a biologically active molecule of interest. The PET cameras capture
the gamma rays that are produced when the tracer decays and undergoes an
annihilation reaction. The common radioactive tracers use 11C, 15O and 18 F isotopes
 PET-FDG
18F-FDG reflects the uptake of glucose within the cell.

18)F-fluorodeoxyglucose (FDG) FDG is

a glucose analogue that is actively
transported across the blood-brain
barrier (BBB) and phosphorylated within
cells. FDG uptake reflects the tissue
glucose metabolism and is usually high in
high-grade tumors and relatively low in
low-grade tumors.
 Basics of FDG PET
Like glucose, FDG is taken up by the cancer cells through facilitative glucose transporters (GLUTs).

Once in the cell, glucose or FDG is phosphorylated by hexokinase to glucose-6-phospate or FDG-6-phosphate,

respectively.

Glucose-6-phosphate travels farther down the glycolytic or oxidative pathways to be metabolized,

FDG-6-phosphate cannot be metabolized.

In normal cells, glucose-6-phosphate or FDG-6-phosphate can be dephosphorylated and exit the cells.

In cancer cells, however, expression of glucose-6-phosphatase is usually significantly decreased, and glucose-6-
phosphate or FDG-6-phosphate therefore can become only minimally dephosphorylated and remains in large part
within the cell. Because FDG-6-phosphate cannot be metabolized, it is trapped in the cancer cell as a polar
metabolite, and it constitutes the basis for tumor visualization on FDG-PET scans.
 PET-MR Imager

(a) Tandem design with two imagers mounted back-to back (like that in PET/CT instrumentation) to allow sequential
rather than simultaneous acquisition,

(b) Insert design with PET imager (P) inserted between radiofrequency coil (R) and gradient set (G) of MR imager,

(c) Fully integrated design with two imagers in same gantry. Radiofrequency coil, gradient set, PET imager, and
patient bed (B) are shown for all configurations.
 MRI and PET Imaging of Tumor Lesions

MRI PET
MRI and PET Imaging in AD
 PET Imaging Modalities
 The three main PET methods that are used for imaging dementias are:
amyloid imaging (11C- or 18 F-based), fluorodeoxyglucose (18 F-FDG) imaging, and tau (18 F-based) imaging.

 The first and most studied of these is C-11 Pittsburgh B compound (PIB), developed from thioflavin T,
a fluorescent dye used to evaluate amyloid. C-11 PIB has high-affinity binding to insoluble fibrillary Aβ
but not to neurofibrillary plaques or amorphous Aβ.

 Aβ accumulation occurs in asymptomatic elderly patients, increasing from 10% in those younger than 70
years of age to 30% to 40% by age 80.

 The binding of C-11 PIB does not always mirror areas of abnormality seen with F-18 FDG.

 C-11 PIB uptake is high in the frontal, temporal, parietal, and occipital cortices and the striatum early on.

 The high levels of uptake do not significantly change over time, even as F-18 FDG shows growing areas
of metabolic decline with disease progression.
 PET and PIB-Compound for Amyloid Detection

Gamma Radiation emitted from a radiopharmaceutical injected

intravenously into a patient is registered by external detectors
positioned at different orientations.

Pittsburgh compound B (PiB) is a radioactive analog
of thioflavin T, which can be used in positron emission
tomography scans to image beta-amyloid plaques in neuronal
tissue.
N-methyl-11C]2-(4′-methylaminophenyl)-6-
hydroxybenzothiazole
(Pittsburgh compound B or [11C]PiB)
[11C]PiB, which is an uncharged thioflavin
analog,
 Aβ peptide, either the 40 or the more amyloidogenic 42 amino acid species,
can self assemble into oligomeric forms

Aβ can diffuse throughout the brain. Soluble forms of Aβ undergo β-sheet conformational
change, forming intermediates such as spheroids and “protofibrils,” but eventually form
fibrillar aggregates.

β-Sheet protein folding is responsible for the characteristic, traditional staining properties
of amyloids (e. g. the apple-green birefringence with Congo red).

The β-sheet is also responsible for the binding of thioflavin related compounds such as
PIB.

Pittsburgh compound B (PiB), also known as benzothiazole-1

(BTA-1),
The cerebellum is nearly devoid of amyloid plaques in post-mortem analysis of
patients with AD34 and cerebellar gray matter shows little 11C-PIB retention