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

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)

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

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

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)

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

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

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)

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 5 Control 2

FAD subject SWM region K4 fixed K1= 0.02972 K2=0.05622 K3=0.02728 K4=0 K1/k2= 0.5287 DV= 0

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

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

Control Vs FAD subjects K3 values in the SWM region in subjects and control (k4 fixed) Subjects K3 value Average STDEV C1 0.03847 0.03668 0.002524 C2 0.0349 h3537 0.02728 0.030996 0.005062 h3671 0.03105 h3691 0.03624 h3762 0.03568 h3810 0.02473 15.5% Phosphorylation of FDG contributes to the observed decreased in the FDG uptake in FAD subjects compaed to control subjects (SWM region)

K1/k2 in the FAD subjects are higher than in the controls Average STDEV C1 0.3583 0.3684 0.01428 C2 0.3785 h3537 0.5286 0.5194 0.09580 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)

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 0.358394 0.345993 0.010807573 C2 0.341009 h3810 0.382403 0.319730 0.03773781 h3762 0.292531 h3691 0.292211 h3671 0.3048 h3537 0.326707 8.5%

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

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.

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