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A.B.Madhan KumarMentor: Dr. Charles M. LaymonDepartment of RadiologyUniversity of PittsburghInvestigation of low white matter glucose metabolism in Familial Alzheimer Disease (FAD)

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 radiotracersin 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 imaging18F-FDGhexokinase18F-FDG-P(trapped)metabolically activecells within a tissue In AD and certain dementias the 18F-FDG uptake by the cells are greatly diminisheddue to lower glucose metabolism

Red-high FDG uptakeblue-low FDG uptake

MRI imageFDG-PET imageMRI/PET images for FAD subject h3537 (skull removed) 18F-FDG and 11C-PIB PET imaging18F-FDG half life 110 minutes

11C-PIB half life 20 minutesSequence of administration:

1. 11C-PIB first

2. 18F-FDG after about 10 half lives of PIB (approx 3-4 h later)PIB alone or (B) PIB and FDGFor investigation in AD, the subjects are administered with:MethodologyMotivation 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 subjectsFRCACGPRCAVSLTCPARMTCOCCSMCPONSWMRegional Distribution of FDG uptake in AD, FAD and control subjects(Concentration ratio to cerebellum at 60 minutes)(static PET data)-FAD patients (15)Subjects

Control (89)

AD patients (33)

RegionFAD &controlACG0.1958PAR0.8081AVS0.2947PRC0.8049FRC0.5621SWM1.6085cohens d valueeffect size181818F-FDGk1k2k3PlasmaBrain tissue18F-FDG18F-FDG-2-PC1C2k4Cpperfusion

phosphorylationdephosphorylationk4 unfixedk4 fixed(k4=0)Compartments are structureless pools containing the tracers in distinct stateuCi/mLTime (min)Dynamic FDG imagingRadioactivity decay correctedtissue activityblood activityuCi/mLTime (min)

compartment modelingINPUTBlood activity data (.tot files and .cor files)Tissue data (.mic files)ROI list

OUTPUTK1, k2, k3, k4

Number of subjects

FAD subjects 5

Control 2Compartment modeling was performed after fixing and unfixing the k4 values

SWM regionK4 fixedK1= 0.02972K2=0.05622K3=0.02728K4=0

K1/k2= 0.5287DV= 0FAD subjectk3 values k1/k2 in FAD subjects (k4 fixed)

RegionsDegree of phosphorylation of FDG degree of perfusion/tissue extractionFDG(tissue)k1k2k3FDG-P(tissue)FDG(plasma)FAD subjectsk1/k2 and k3 in control subjectsk1/k2 valuesk3 valuesdegree of phosphorylationdegree of perfusion/ tissue tracer extractionSubjectsK3 valueAverageSTDEVC10.038470.036680.002524C20.0349h35370.027280.0309960.005062h36710.03105h36910.03624h37620.03568h38100.02473K3 values in the SWM region in subjects and control (k4 fixed)15.5%Phosphorylation of FDG contributes to the observed decreased in the FDG uptakein FAD subjects compaed to control subjects (SWM region) Control Vs FAD subjectsSubjectsk1/k2AverageSTDEVC10.35830.36840.01428C20.3785h35370.52860.51940.09580h36710.4807h36910.5356h37620.3942h38100.6579K1/k2 in the FAD subjects are higher than in the controlsThe perfusion or tissue tracer extraction does not contribute for the observeddecrease in the FDG uptake in FAD subjects (SWM region)Subjectsk3/(k2+k3)AverageSTDEVC10.3583940.3459930.010807573C20.341009h38100.3824030.3197300.03773781h37620.292531h36910.292211h36710.3048h35370.326707Fraction of phosphorylation = k3/(k2+k3)(fraction of FDG undergoing phosphorylation)FDG(tissue)k1k2k3k4FDG-P(tissue)FDG(plasma)K4 fixed8.5%Application to my research-experimental therapeuticsTissue targeted encapsulated agents

eg. Tumor targeted nanoparticles carrying drugsvvvvvvvvvvvvvvvvvvvvvvvvvvvnanoparticles(plasma)vvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvtumor tissuevvvvvvvvvvvvvvvvvDrug resistancenanoparticles internalized in tumor cellsperfusionConclusions2 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.

ThanksDr. Seong-Gi KimDr. William Edy

Dr.Charles Laymon (mentor) Department of Radiology

CarlRhavenDr. William Klunk Department of Psychiatry