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Jeffrey R. Petrella , MD Associate Professor of Radiology

From Molecules to Networks to Behavior. cognition. behavior. Jeffrey R. Petrella , MD Associate Professor of Radiology Director, Alzheimer’s Imaging Research Laboratory Duke University Medical Center, Durham NC. temperment. Clinical Progression of AD and MCI. Time (y). 1-10 y. 0 y.

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Jeffrey R. Petrella , MD Associate Professor of Radiology

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  1. From Molecules to Networks to Behavior cognition behavior Jeffrey R. Petrella, MD Associate Professor of Radiology Director, Alzheimer’s Imaging Research Laboratory Duke University Medical Center, Durham NC temperment

  2. Clinical Progression of AD and MCI Time (y) 1-10 y 0 y 10 y MCIMMSE 24–30 Mild ADMMSE 20–23 • Mild subjective/objective memory loss • Normal function • Forgetfulness • Repetitive questions • Daily function impaired Moderate ADMMSE 10–19 • Progression of cognitive deficits • Short-term memory loss • Word-finding difficulties Cognitive function Severe ADMMSE 0–9 • Agitation • Altered sleep patterns • Total dependence: dressing, feeding, bathing

  3. Evolution of the Disease Neurofibrillary Changes in Early AD Early Stage Middle Stage Adapted from: Braak H, Braak E. Acta Neuropathol (Berl). 1991;82:239-259

  4. Amyloid Accumulation Plateaus Early Petersen RC, Jack CR, Clinical Pharmacology & Therapeutics (2009) 86 4, 438–441

  5. Cell damageCell death Pathophysiology of Alzheimer’s Disease Genetic Amyloid Inflammation Risk Tangles Oxidation Neuropsychologic Testing CSF, Blood Biomarkers MR Perfusion fMRI DTI Symptoms Birth 60 100 Molecular Imaging FDG- PET MR Spectro-scopy Quantitative/ Structural MR Years Reproduced from Doraiswamy 2000, Sunderland 1999

  6. Intracellular Effects of Soluble Amyloid

  7. Functional MRI

  8. Paradigm Petrella et al., Radiology 2006

  9. Hippocampal Activation @ 4T Encode: novel vs familiar

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

  11. Control 3 MCI y = -0.1002x + 0.5029 2 AD 2 R = 0.2524 1 0 -1 -2 -1 4 9 14 19 Signal Intensity (Petrella et al, Radiology, 2007) CVLT-II delayed recall score

  12. Activation Parameter Estimate Activation Parameter Estimate PMC region of interest (Petrella, et al., PLoS ONE Oct 2007)

  13. APOE E3 – E4 Rieman EM et al, PNAS 2004

  14. Cortical “Hubs” Buckner et al., Journal of Neuroscience (2009)

  15. Cortical Connectivity and Amyloid Deposition Buckner et al., Journal of Neuroscience (2009)

  16. DMN Integrity and Amyloid Burden Sperling RA et al. Neuron 2009

  17. Neurodegenerative Diseases Target Large-Scale Human Brain Networks Seeley WW et al., Neuron 2009

  18. Graph Theoretical Network Analysis Adapted from Stam CJ Cerebral Cortex 2006

  19. Construction of Structural Cortical Networks Adapted from He, Chen and Evans, J Neurosci 2008

  20. Loss of Small World Network Characteristics in Alzheimer’s Disease Path Length Cluster Coefficient Small Worldness Supekar PLoS Comp Biol 2008

  21. Topological Robustness in Structural Cortical Networks He, Chen and Evans, J Neurosci 2008

  22. Summary cognition behavior temperament Cells: subtle molecular bottlenecks Genes: multiple alleles each of small effect Systems: Variable development/ information processing Behavior: complex functional interactions and emergent phenomena

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