11.17.11 CEN Healthcare Chris Schaffer Presentation

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11.17.11 CEN Healthcare Chris Schaffer Presentation

  1. 1. Your brain on Alzheimer's disease: the potential role of slowed blood flow <ul><li>Chris B. Schaffer </li></ul>
  2. 2. Alzheimer’s disease is the leading cause of dementia in the elderly <ul><li>Auguste D., first Alzheimer’s patient described by Alois Alzheimer </li></ul>
  3. 3. Alzheimer’s is caused by neuronal loss due to neurotoxic effects of aggregated A-beta peptide <ul><li>K. Blennow, et al., Lancet (2006) </li></ul>Alzheimer’s pathology molecular mechanisms
  4. 4. <ul><li>K. Blennow, et al., Lancet (2006) </li></ul>Alzheimer’s pathology molecular mechanisms Alzheimer’s is caused by neuronal loss due to neurotoxic effects of aggregated A-beta peptide
  5. 5. A-beta is produced by neurons and cleared through the vasculature cleared through the vasculature
  6. 6. Blood flow deficits to the brain also observed in Alzheimer’s patients
  7. 7. Blood flow deficits to the brain also observed in Alzheimer’s patients <ul><li>20-30% decreased brain blood flow compared to non Alzheimer controls </li></ul><ul><li>This blood flow decrease could be cognitively important, but the origin remains unclear </li></ul>We used advanced imaging techniques to study disruptions in microvascular blood flow in mice that are engineered to get Alzheimer’s disease
  8. 8. Two-photon excitation of fluorescent dyes leads to emission that originates only from the focal volume <ul><li>Z. Huang, et al., belfield.cos.ucf.edu/one vs two-photon excitation.html </li></ul>
  9. 9. Image is formed by scanning laser focus through the sample and recording fluorescence intensity
  10. 10. Image is formed by scanning laser focus through the sample and recording fluorescence intensity
  11. 11. Image fluorescently-labeled features in brain of anesthetized rodent with glass-covered craniotomy
  12. 12. Imaging fluorescent blood plasma yields a 3-D cortical “micro-angiography”
  13. 13. In vivo imaging of vasculature and amyloid plaques in AD mouse models amyloid plaques in AD mouse models plaques labeled by methoxy-X04 vasculature with intravenous dye injection Aged APPswe/PS1 mice with craniotomies
  14. 14. Dye labels blood plasma, but not blood cells, allowing identification of flowing vs. stalled vessels
  15. 15. Fraction of capillaries with stalled blood flow increased to ~2% in mouse models of AD Temporary stalls that shift between capillary segments, rather than permanent occlusions 2843 capillaries in 6 AD mice 2475 capillaries in 4 WT mice
  16. 16. Labeling to distinguish red blood cells, leukocytes, and thrombi as potential cause of stalls leukocytes: rhodamine-6G and Hoechst thrombi: rhodamine-6G red blood cells: unlabeled
  17. 17. In vivo imaging of capillary stalls with rhodamine-6G and Hoechst labeling red - Texas-Red dextran green - rhodamine 6G blue - methoxy-X04 and Hoescht
  18. 18. Majority of capillary stalls in AD mouse models are caused by leukocyte plugs
  19. 19. How does a single stalled capillary affect blood flow? affect blood flow? N. Nishimura, et al., Nature Methods 3, 99 (2006) Laser injury to vessel triggers clotting Map changes in flow after capillary clot baseline flow post-clot flow mm/s
  20. 20. A single stalled capillary causes reduced blood flow in multiple downstream vessel branches N. Nishimura, et al., Nature Methods 3, 99 (2006) Post-clot blood flow speed (fraction of baseline)
  21. 21. Map of blood vessels and amyloid plaques from AD mouse plaques from AD mouse
  22. 22. Location of stalled capillaries
  23. 23. Simulate blood flow changes in capillaries downstream from plugged vessels
  24. 24. Simulate blood flow changes in capillaries downstream from plugged vessels
  25. 25. Simulate blood flow changes in capillaries downstream from plugged vessels
  26. 26. Increases in number of stalled capillaries causes decreases in average cerebral blood flow 2% of capillaries stalled predicts a 30% decrease in flow compared to controls
  27. 27. Leukocyte plugging of capillary segments could explain blood flow deficits observed in AD <ul><li>In humans, blood flow reduced by 20-30% compared to non-AD age-matched controls [1] </li></ul><ul><li>In mouse models of AD, flow reduced by ~30% compared to wild-type animals [2] </li></ul>1. Farkas E, Luiten PG. (2001) Cerebral microvascular pathology in aging and Alzheimer's disease. Prog Neurobiol 64:575-611 2. Niwa K, Kazama K, Younkin SG, Carlson GA, Iadecola C. (2002) Alterations in cerebral blood flow and glucose utilization in mice overexpressing the amyloid precursor protein. Neurobiol Dis 9:61-68
  28. 28. Summary <ul><li>2% of capillaries are stalled in AD mouse models </li></ul><ul><li>Stalls are caused by leukocytes plugging capillary segments </li></ul><ul><li>This rate of capillary stalling could produce ~30% decrease in cerebral blood flow, consistent with observations in humans and mouse models </li></ul><ul><li>Suggests that Aβ aggregates cause vascular inflammation that leads to firm adhesion of leukocytes to the endothelium </li></ul><ul><li>Provides a novel potential target for treatment of blood flow deficits in AD, which could improve cognitive function </li></ul>
  29. 29. Cyclic relationship between vascular stalls and Aβ aggregates as a driver of AD progression leukocyte plugs Aβ aggregates
  30. 30. Collaborators <ul><li>Cornell </li></ul><ul><ul><li>Dr. Nozomi Nishimura </li></ul></ul><ul><ul><li>Calvin Kersbergen </li></ul></ul><ul><ul><li>Gabriel Otte </li></ul></ul><ul><ul><li>Joan Zhou </li></ul></ul><ul><ul><li>Jeff Beverly </li></ul></ul><ul><ul><li>Elizabeth Slack </li></ul></ul><ul><li>Weill Cornell Medical College </li></ul><ul><ul><li>Prof. Costantino Iadecola </li></ul></ul>
  31. 31. Acknowledgements Thanks to William Klunk for donation of methoxy-X04
  32. 33. To occlude a small blood vessel, we optically injure the vessel to initiate endogenous clotting cascade N. Nishimura, et al., Nature Methods 3, 99 (2006)
  33. 34. Femtosecond laser irradiation to produce a clot in a targeted, sub-surface brain capillary

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