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David T. Jones, M.D.

Associate Consultant, Department of Neurology, Mayo Clinic

Assistant Professor of Neurology and Radiology, Mayo Clinic College of Medicine

NEUROIMAGING IN ALZHEIMER’S DISEASE:

MEASURING MINDS AND MOLECULES

IMAGING BIOMARKERS

• A biological marker of some state.

• National Institutes of Health Biomarkers Definitions Working Group:

• “[A] characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic

responses to a therapeutic intervention.”

• How can we use biomarkers?

• Diagnosis

• Prognosis

• Monitor progression

• Monitor disease response to therapeutic interventions

• Understand pathophysiology (i.e. the cause of the disease)

WHAT DO GOOD BIOMARKERS LOOK LIKE

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Exactness Precision Accuracy

Brain Aging and Neurodegenerative Physiology

In Vivo Study of Levels of Pathophysiology

Genetic:

Molecular:

Cellular:

Synaptic:

Microcircuits:

Macrocircuits:

Systems:

Global: ”I forget a bit”

Default Mode Network

Tau/Amyloid beta

Neurons and Glia

LTP/LTD

APOE, APP, PS1, PS2

Columnar

Papez

GWAS, DIAN

CSF, Amyloid-PET, Tau-PET

Structural MRI, DTI

FDG-PET, Pharmocological

Electrophysiology

fMRI, FDG-PET

Neuropsychological testing

Clinical evaluation

Complex Systems

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OPUS ADVANCED IMAGING RESEARCH BUILDING

TOMOGRAPHY: VOLUME BY SLICES

http://upload.wikimedia.org/wikipedia/commons/2/25/Tom

ographyPrinciple_Illustration.png

Radiologic

Convention R = L

Neurologic

Convention R = R

MAGNETIC RESONANCE IMAGING (MRI)

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TYPES OF IMAGES: POSITRON EMISSION

TOMOGRAPHY (PET)

Plaque Image courtesy of the National Institute on Aging/National Institutes of Health

Structural MRI

Brain Slices Image courtesy of the National Institute on Aging/National Institutes of Health

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Structural MRI:

Gray Matter

Structural MRI:

Gray Matter

White Matter

Cerebral Spinal Fluid

FDG (glucose) PET

Mitochondria Image courtesy of the National Institute on Aging/National Institutes of Health

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Tau PET

(not FDA Approved)

EMERGING MRI TECHNIQUES:

DIFFUSION TENSOR IMAGING (DTI) AND TASK-

FREE FUNCTIONAL MRI (TF-FMRI)

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Courtesy of Rob Reid

Diffusion Tensor Imaging

FUNCTIONAL MRI IS A FLIP BOOK

TOMOGRAPHY: VOLUME BY SLICES

http://upload.wikimedia.org/wikipedia/commons/2/25/Tom

ographyPrinciple_Illustration.png

Radiologic

Convention R = L

Neurologic

Convention R = R

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FUNCTIONAL MRI IS 4 DIMENSIONAL

-3.00E+01

-2.00E+01

-1.00E+01

0.00E+00

1.00E+01

2.00E+01

3.00E+01

TR

BLOOD OXYGENATION LEVEL DEPENDENT

FROM THE FOLLOWING ARTICLE:

What does fMRI tell us about neuronal activity?

David J. Heeger & David Ress

Nature Reviews Neuroscience 3, 142-151 (February 2002)

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METHODS: SEED-TO-BRAIN

METHODS: SEED-TO-SEED

R² = 0.633

N V

oxe

l T

ime

Ser

ies

Seed Time Series

0.633

METHODS: ROI-TO-ROI USING THE MCSA

FUNCTIONAL BRAIN ATLAS

Jones DT, Vemuri P, Murphy MC, Gunter JL, et al. (2012) Non-Stationarity in the “Resting Brain’s” Modular Architecture. PLoS ONE 7(6): e39731.

doi:10.1371/journal.pone.0039731

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0039731

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METHODS: GRAPH THEORY

Euler (1735)

0

0.1

0.2

0.3

0 0.5 1

Glo

ba

l

Effic

ie

ncy

Network Density (p)

CN

AD

0

0.5

1

1.5

Un

ba

la

nc

ed

P

ath

s

(N

FQ

)

CN AD

*p = 3.6x10-7

Cognition

ADL

Stage 1 Stage 2 Stage 3 MCI Mild AD Moderate AD Severe AD

Aβ

Degeneration

Tau-PET

Amyloid-PET

PART

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MEASURING MINDS AND MOLECULES

Clifford R Jack Jr , David S Knopman , William J Jagust , Ronald C Petersen , Michael W Weiner , et al. Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers The Lancet Neurology Volume 12, Issue 2 2013 207 - 216

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Age-related Brain Network Stress

Compensation

Amyloid

Tau-related Neurodegeneration

Normal Aging

Alz

hei

mer

’s D

isea

se

Mild

Cog

nitiv

e Im

pairm

ent

Dem

entia

HOW DO WE ROBUSTLY MEASURES AN

INDIVIDUALS LARGE-SCALE BRAIN PATTERNS?

http://www.humanconnectome.org/

This individual spent 7% of 20 minute resting task-free functional MRI brain

scanning session in a large-scale brain configuration that looks like this.

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IMAGING BIOMARKERS: MEASURING MINDS AND

MOLECULES

• A biological marker of some state.

• National Institutes of Health Biomarkers Definitions Working Group:

• “[A] characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic

responses to a therapeutic intervention.”

• How can we use biomarkers?

• Diagnosis

• Prognosis

• Monitor progression

• Monitor disease response to therapeutic interventions

• Understand pathophysiology (i.e. the cause of the disease)

Mayo Clinic Alzheimer’s Disease Research Center (ADRC)

Mayo Clinic Study of Aging (MCSA) (PI: Ron Petersen)

Aging and Dementia Imaging Research Laboratory (PI: Cliff Jack)