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Cortical Hubs and Alzheimer’s Disease

BME 482 Kevin Sylvestre. Cortical Hubs and Alzheimer’s Disease. Background : AD and Aβ. 35 million cases of Alzheimer’s disease (AD) in U.S. alone Causes are widely studied Leading theory- Amyloid Cascade Hypothesis Mismetabolism of APP leads to aggregation of Amyloid beta (Aβ)

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Cortical Hubs and Alzheimer’s Disease

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  1. BME 482 Kevin Sylvestre Cortical Hubs and Alzheimer’s Disease

  2. Background : AD and Aβ • 35 million cases of Alzheimer’s disease (AD) in U.S. alone • Causes are widely studied • Leading theory- Amyloid Cascade Hypothesis • Mismetabolism of APP leads to aggregation of Amyloid beta (Aβ) • Formation of neuritic plaques • Initiating event in AD

  3. Background cont.: Aβ • Peptide of 39-43 amino acids • Mostly concerned with Aβ42 • More fibrillogenic • Formed by cleavage of Amyloid Precursor Protein (APP) • Aβ production follows a circadian rhythm

  4. Cortical Hubs • Study by Randy L. Buckner, et al “Cortical Hubs Revealed by Intrinsic Functional Connectivity: Mapping, Assessment of Stability, and Relation to Alzheimer’s Disease” • Identified as areas with disproportionately greater connectivity compared with other regions

  5. Cortical Hubs

  6. Cortical Hubs • Obvious correlation across 127 samples • Both datasets demonstrate disproportionately high connectivity in same areas • Voxel by voxel comparison; r = 0.93

  7. Cortical Hubs • Some hubs (A and B) are assosicated with common core network • Others associated with distinct networks (C and D) • A: posterior cingulate • B: dorsolateral pre-frontal cortex • C: Supramarginalgyrus • D: Medial prefrontal cortex

  8. Cortical Hubs • Hubs maintain activity during both rest fixation and task performance states • Overlaps “default network”

  9. Cortical Hubs and Aβ • One can readily observe relation between connectivity (cortical hubs) and Aβ deposition • Formally, shown with visual plotting, and correlation of voxels for each of the values • Conclusion: Aβ deposition occurs preferentially in cortical hubs

  10. Cortical Hubs and Aβ

  11. Cortical Hubs and Aβ • Voxel by voxel comparison • Demonstrates a high correlation • Demonstrates parametric relationship: greater level of functional connectivity across brain, greater level of Aβ deposition in AD

  12. Cortical Hubs and Aβ • Cortical hubs maintain activity across task states; may suggest hubs are vulnerable to Aβ deposition due to high, constant baseline activity • APP processing is activity dependant • Neuronal stimulation increases the abundance of Aβ • These conclusions may indicate mechanism for Aβ vulnerability

  13. BME Application • Targeted treatment of AD will become possible • Cortical hubs indicate target areas • May provide insight in future treatments of other diseases

  14. References • “Cortical Hubs Revealed by Intrinsic Functional Connectivity: Mapping, Assessment of Stability, and Relation to Alzheimer’s Disease” Randy L. Buckner et. al.; J. Neuroscience. February 11, 2009 http://www.jneurosci.org/cgi/reprint/29/6/1860?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=1&andorexacttitle=and&titleabstract=mapping&andorexacttitleabs=and&fulltext=Consciousness&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT • “Amyloid Cascade Hypothesis” http://wiki.iop.kcl.ac.uk/default.aspx/Neurodegeneration/Amyloid%20Cascade%20Hypothesis.html • “Beta amyloid”. (2010, January 28). In Wikipedia, The Free Encyclopedia. http://en.wikipedia.org/w/index.php?title=Beta_amyloid&oldid=340508037 • “Alzheimer's Facts and Figures” http://www.alz.org/alzheimers_disease_facts_figures.asp

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