Jeffrey R. Petrella, MDJeffrey R. Petrella, MD

Associate Professor of RadiologyAssociate Professor of Radiology

Director, Alzheimer’s Imaging Research LaboratoryDirector, Alzheimer’s Imaging Research Laboratory

Duke University Medical Center, Durham NCDuke University Medical Center, Durham NC

From Molecules to Networks to BehaviorFrom Molecules to Networks to Behavior

behavior

The Wisconsin Card Sorting Task

cognition

temperment

Clinical Progression of AD and MCI

Clinical Progression of AD and MCI

Co

gn

itiv

e fu

nct

ion

•Forgetfulness

•Repetitive questions

•Daily function impaired

•Progression of cognitive deficits

•Short-term memory loss

•Word-finding difficulties

•Agitation

•Altered sleep patterns

•Total dependence: dressing, feeding, bathing

MCIMMSE 24–30 Mild AD

MMSE 20–23

Moderate ADMMSE 10–19

Severe ADMMSE 0–9

•Mild subjective/objective memory loss

•Normal function

10 y0 yTime (y)

1-10 y

Early Stage Middle StageAdapted from: Braak H, Braak E. Acta Neuropathol (Berl). 1991;82:239-259

Evolution of the Disease Evolution of the Disease Neurofibrillary Changes in Early AD

Amyloid Accumulation Plateaus EarlyAmyloid Accumulation Plateaus Early

Petersen RC, Jack CR, Clinical Pharmacology & Therapeutics (2009) 86 4, 438–441

Pathophysiology of Alzheimer’s Pathophysiology of Alzheimer’s DiseaseDisease

Genetic Amyloid InflammationRisk Tangles

Oxidation

Birth 60100

Symptoms

Cell damage Cell death

YearsReproduced from Doraiswamy 2000, Sunderland 1999

CSF, Blood

Biomarkers fMRIMR

Perfusion DTI

Quantitative/Structural MR

MRSpectro-

scopy

MolecularImaging

FDG-PET

NeuropsychologicTesting

Intracellular Effects of Soluble AmyloidIntracellular Effects of Soluble Amyloid

Functional MRIFunctional MRI

ParadigmParadigm

Petrella et al., Radiology 2006

Hippocampal Activation @ 4THippocampal Activation @ 4T

Encode: novel vs familiar

Distribution of Left and Right Hippocampal Voxel Counts (normalized, Distribution of Left and Right Hippocampal Voxel Counts (normalized, age-adjusted) and MMSE (age-adjusted) in MCI and Control subjectsage-adjusted) and MMSE (age-adjusted) in MCI and Control subjects

-1

-0.5

0

0.5

1

1.5

Control MCI AD

Pa

ram

ete

r E

sti

mat

e (

PM

C c

lus

ter)

y = -0.1002x + 0.5029

2R = 0.2524

-2

-1

0

1

2

3

-1 4 9 14 19

Control

MCI

AD

(Petrella et al, Radiology, 2007) CVLT-II delayed recall score

Sign

al I

nten

sity

-1

-0.5

0

0.5

1

1.5

ONS MCI-Nonconverter MCI-Converter AD

Act

ivat

ion

Par

amet

er

Est

ima

te

-1

-0.5

0

0.5

1

1.5

MCI-Nonconverter MCI-Converter

PMC region of interest

-1

-0.5

0

0.5

1

1.5

Control MCI AD

Act

iva

tion

Pa

ram

ete

r E

stim

ate

(Petrella, et al., PLoS ONE Oct 2007)

APOE E3 – E4

Rieman EM et al, PNAS 2004

Cortical “Hubs”

Buckner et al., Journal of Neuroscience (2009)

Cortical Connectivity and Amyloid Deposition

Buckner et al., Journal of Neuroscience (2009)

DMN Integrity and Amyloid Burden

Sperling RA et al. Neuron 2009

Neurodegenerative Diseases Target Large-Scale Human Brain Networks

Seeley WW et al., Neuron 2009

Graph Theoretical Network AnalysisGraph Theoretical Network Analysis

Adapted from Stam CJ Cerebral Cortex 2006

Construction of Structural Cortical NetworksConstruction of Structural Cortical Networks

Adapted from He, Chen and Evans, J Neurosci 2008

Loss of Small World Network Characteristics in Loss of Small World Network Characteristics in Alzheimer’s DiseaseAlzheimer’s Disease

Path Length Cluster Coefficient Small Worldness

Supekar PLoS Comp Biol 2008

Topological Robustness in Structural Cortical Topological Robustness in Structural Cortical NetworksNetworks

He, Chen and Evans, J Neurosci 2008

Genes:

multiple alleles each of small

effect

Cells:

subtle molecular bottlenecks

Systems:

Variable development/ information processing

behavior

Behavior:

complex functional interactions and

emergent phenomena

SummarySummary

The Wisconsin Card Sorting Task

temperament

cognition