Jeffrey R. Petrella , MD Associate Professor of Radiology
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Transcript of Jeffrey R. Petrella , MD Associate Professor of Radiology
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
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•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
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PM
C c
lus
ter)
y = -0.1002x + 0.5029
2R = 0.2524
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-1
0
1
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-1 4 9 14 19
Control
MCI
AD
(Petrella et al, Radiology, 2007) CVLT-II delayed recall score
Sign
al I
nten
sity
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-0.5
0
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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
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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