BME 482Kevin Sylvestre

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

Peptide of 39-43 amino acidsMostly concerned with Aβ42

More fibrillogenicFormed by cleavage of Amyloid

Precursor Protein (APP)Aβ production follows a circadian

rhythm

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

Obvious correlation across 127 samples

Both datasets demonstrate disproportionately high connectivity in same areas

Voxel by voxel comparison; r = 0.93

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: Supramarginal gyrus D: Medial prefrontal

cortex

Hubs maintain activity during both rest fixation and task performance states

Overlaps “default network”

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

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

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

Targeted treatment of AD will become possible

Cortical hubs indicate target areas

May provide insight in future treatments of other diseases

“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