1. Investigation of low white matter glucose metabolism in Familial Alzheimer Disease (FAD)
A.B.Madhan Kumar
Mentor: Dr. Charles M. Laymon
Department of Radiology
University of Pittsburgh

2. Project Aims
To learn the principle and application of various radioligand tracers in
AD, FAD and control subjects
To get familiarized with different compartment models for the radiotracers
in the AD, FAD and control subjects
Data analysis of the results from the compartmental model as applied to
FAD and control subjects (FDG as tracer)

3. 18F-FDG for PET imaging 18F-FDG-P (trapped) hexokinase 18F-FDG
metabolically active
cells within a tissue
In AD and certain dementias the 18F-FDG uptake by the cells are greatly diminished
due to lower glucose metabolism
Red-high FDG uptake
blue-low FDG uptake

4. MRI/PET images for FAD subject h3537 (skull removed)
MRI image
FDG-PET image

5. 18F-FDG and 11C-PIB PET imaging
Methodology
18F-FDG half life 110 minutes
11C-PIB half life 20 minutes
PIB alone or (B) PIB and FDG
For investigation in AD, the subjects are administered with:
Sequence of administration:
1. 11C-PIB first
2. 18F-FDG after about 10 half lives of PIB (approx 3-4 h later)

6. Motivation for this study
based on the recent observation that 18F-FDG is accumulated less in subcortical white matter region (SWM) in FAD subjects when compared to control subjects

7. Regional Distribution of FDG uptake in AD, FAD and control subjects
(Concentration ratio to cerebellum at 60 minutes)(static PET data)
cohen’s d value
-FAD patients (15)
Subjects
Control (89)
Region
FAD &control
ACG
0.1958
PAR
0.8081
AVS
0.2947
PRC
0.8049
FRC
0.5621
SWM
1.6085
AD patients (33)
effect size
FRC
ACG
PRC
AVS
LTC
PAR
MTC
OCC
SMC
PON
SWM

8. Compartments are structureless pools containing the tracers in distinct state
perfusion
phosphorylation
Plasma
Brain tissue
1818 k1 k3
18F-FDG
18F-FDG
18F-FDG-2-P k2 k4
k4 unfixed C2 C1 Cp
k4 fixed(k4=0)
dephosphorylation
blood activity
tissue activity
uCi/mL
uCi/mL
Dynamic FDG imaging
Time (min)
Radioactivity decay corrected
Time (min)

9. compartment modeling Blood activity data (.tot files and .cor files)
INPUT
Blood activity data (.tot files and .cor files)
Tissue data (.mic files)
ROI list
OUTPUT
K1, k2, k3, k4
Compartment modeling was performed after fixing and unfixing the k4 values
Number of subjects
FAD subjects
Control

10. FAD subject
SWM region
K4 fixed
K1=
K2=
K3=
K4=0
K1/k2=
DV= 0

11. k3 values k1/k2 in FAD subjects (k4 fixed)
FDG
(plasma)
FDG
(tissue)
FDG-P
(tissue) k2
k3 values k1/k2 in FAD subjects (k4 fixed)
Degree of phosphorylation of FDG
degree of perfusion/tissue extraction
Regions

12. k1/k2 and k3 in control subjects
k3 values
k1/k2 values
degree of phosphorylation
degree of perfusion/ tissue tracer
extraction

13. Control Vs FAD subjects
K3 values in the SWM region in subjects and control (k4 fixed)
Subjects
K3 value
Average
STDEV C1 C2
0.0349
h3537
h3671
h3691
h3762
h3810
15.5%
Phosphorylation of FDG contributes to the observed decreased in the FDG uptake
in FAD subjects compaed to control subjects (SWM region)

14. K1/k2 in the FAD subjects are higher than in the controls
Average
STDEV C1
0.3583
0.3684 C2
0.3785
h3537
0.5286
0.5194
h3671
0.4807
h3691
0.5356
h3762
0.3942
h3810
0.6579
The perfusion or tissue tracer extraction does not contribute for the observed
decrease in the FDG uptake in FAD subjects (SWM region)

15. Fraction of phosphorylation = k3/(k2+k3)
(fraction of FDG undergoing phosphorylation) k1 k3
FDG
(plasma)
FDG
(tissue)
FDG-P
(tissue) k2 k4
K4 fixed
Subjects
k3/(k2+k3)
Average
STDEV C1 C2
h3810
h3762
h3691
h3671
0.3048
h3537
8.5%

16. Application to my research-experimental therapeutics
Tissue targeted encapsulated agents
eg. Tumor targeted nanoparticles carrying drugs v
vvv
tumor tissue v
vvv
Drug resistance v
vvv
nanoparticles
(plasma)
perfusion
nanoparticles
internalized in
tumor cells

17. Conclusions
2 tissue compartment model was applied to the 18F-FDG administered FAD and normal subjects.
Our analysis represented a lower k3 values in the SWM region in FAD and in control subjects compared to other cortex regions.
The values of k3(degree of phosphorylation) in the FAD subjects in the SWM region is lower than in control by 15%
The fraction of FDG undergoing phosphorylation in FAD subjects we analyzed was 8.5 % lower than in control subjects.

18. Thanks Dr. Seong-Gi Kim Dr. William Edy Dr.Charles Laymon (mentor)
Department of Radiology
Carl
Rhaven
Dr. William Klunk
Department of Psychiatry