Investigation of low white matter glucose metabolism in familial alzheimer disease fad
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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

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Investigation of low white matter glucose metabolism in Familial Alzheimer Disease (FAD)

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Investigation of low white matter glucose metabolism in familial alzheimer disease fad

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


Investigation 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 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)


18 f fdg for pet imaging

18F-FDG for PET imaging

18F-FDG-P

hexokinase

18F-FDG

(trapped)

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


Investigation of low white matter glucose metabolism in familial alzheimer disease fad

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

FDG-PET image

MRI image


18 f fdg and 11 c pib pet imaging

18F-FDG and 11C-PIB PET imaging

Methodology

18F-FDG half life 110 minutes

11C-PIB half life 20 minutes

For investigation in AD, the subjects are administered with:

  • PIB alone or (B) PIB and FDG

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

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


Investigation of low white matter glucose metabolism in familial alzheimer disease fad

Regional Distribution of FDG uptake in AD, FAD and control subjects

(Concentration ratio to cerebellum at 60 minutes)(static PET data)

cohen’sd value

Control (89)

AD patients (33)

effect size

-FAD patients (15)

Subjects


Compartments are structureless pools containing the tracers in distinct state

Compartments are structureless pools containing the tracers in distinct state

phosphorylation

perfusion

Plasma

Brain tissue

1818

k1

k3

18F-FDG

18F-FDG-2-P

18F-FDG

k2

k4 unfixed

k4

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

compartment modeling

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


Investigation of low white matter glucose metabolism in familial alzheimer disease fad

FAD subject

SWM region

K4 fixed

K1= 0.02972

K2=0.05622

K3=0.02728

K4=0

K1/k2= 0.5287

DV= 0


Investigation of low white matter glucose metabolism in familial alzheimer disease fad

k1

FAD subjects

k3

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


Investigation of low white matter glucose metabolism in familial alzheimer disease fad

k1/k2 and k3 in control subjects

k3 values

k1/k2 values

degree of phosphorylation

degree of perfusion/ tissue tracer

extraction


Investigation of low white matter glucose metabolism in familial alzheimer disease fad

Control Vs FAD subjects

K3 values in the SWM region in subjects and control (k4 fixed)

15.5%

Phosphorylation of FDG contributes to the observed decreased in the FDG uptake

in FAD subjects compaed to control subjects (SWM region)


Investigation of low white matter glucose metabolism in familial alzheimer disease fad

K1/k2 in the FAD subjects are higher than in the controls

The perfusion or tissue tracer extraction does not contribute for the observed

decrease in the FDG uptake in FAD subjects (SWM region)


Investigation of low white matter glucose metabolism in familial alzheimer disease fad

Fraction of phosphorylation = k3/(k2+k3)

(fraction of FDG undergoing phosphorylation)

k1

k3

FDG

(plasma)

FDG

(tissue)

FDG-P

(tissue)

k2

k4

K4 fixed

8.5%


Application to my research experimental therapeutics

Application to my research-experimental therapeutics

Tissue targeted encapsulated agents

eg. Tumor targeted nanoparticles carrying drugs

perfusion

Drug resistance

v

v

vvv

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vvv

v

vvv

vvv

vvv

v

v

v

vvv

v

v

v

v

v

v

v

vvv

v

v

v

vvv

v

v

v

vvv

v

v

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vvv

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vvv

vvv

vvv

v

vvv

vvv

nanoparticles

(plasma)

v

vvv

tumor tissue

nanoparticles

internalized in

tumor cells


Conclusions

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

Thanks

  • Dr. Seong-Gi Kim

  • Dr. William Edy

  • Dr.CharlesLaymon (mentor)

    Department of Radiology

  • Carl

  • Rhaven

  • Dr. William Klunk

    Department of Psychiatry


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