1. The Glymphatic System A New Player in Alzheimer Disease?Maiken Nedergaard Univ. of Rochester

2. CNS is a metabolic highly active organ 3. CNS is a metabolic highly active organ ~ 2% of the body weight (3 pounds) 4. CNS is a metabolic highly active organ ~ 2% of the body weight (3 pounds) ~ 15% of the cardiac output ~ 20% of total body O2 consumption ~ 25% of total body glucose consumption 5. CNS is a metabolic highly active organ ~ 2% of the body weight (3 pounds) ~ 15% of the cardiac output ~ 20% of total body O2 consumption ~ 25% of total body glucose consumptionAll biological activity is associated with production of waste products 6. CNS is a metabolic highly active organ ~ 2% of the body weight (3 pounds) ~ 15% of the cardiac output ~ 20% of total body O2 consumption ~ 25% of total body glucose consumptionAll biological activity is associated with production of waste products 7. CNS is a metabolic highly active organ ~ 2% of the body weight (3 pounds) ~ 15% of the cardiac output ~ 20% of total body O2 consumption ~ 25% of total body glucose consumptionAll biological activity is associated with production of waste productsDoes the brain really recycle all cellular waste products? 8. CNS is lacking a lymphatic system 9. CNS is lacking a lymphatic systemelephantiasis 10. CSF has been proposed to act as a sink for wasteB/Y? 11. CSF has been proposed to act as a sink for wasteWaste diffusion?B/Y? 12. Pulsatility may drive CSF into brainCSF pulsationB/Y? 13. In vivo imaging of CSF tracers 14. In vivo imaging of CSF tracersVasculature CSF tracer 180 m below the surface 15. Ex vivo imaging of CSF tracersTexasred dextranFITC dextran 5 min 16. Ex vivo imaging of CSF tracersTexasred dextranFITC dextran 5 min 17. CSF tracers rapidly enter brain along the vasculatureTexasred dextranFITC dextran 5 min5 min 18. CSF tracers rapidly enter brain along the vasculatureAstrocytic Vascular EndfeetAQP4 GFAP DAPI 19. Does AQP4Brain AquaporinsCSF influx? promoteBrain Bulk FlowAstrocytic Vascular EndfeetWild TypeAQP4 GFAP DAPITracer DAPI 30 min 20. Does AQP4Brain AquaporinsCSF influx? promoteBrain Bulk FlowAQP4 KOAstrocytic Vascular EndfeetWild TypeAQP4 GFAP DAPITracer DAPI 30 min 21. Novel macroscopic clearance path in CNSScience, 2013 22. Glymphatic systemJeff Iliff, 2012 23. Brain Bulk FlowDoes AQP4Brain Aquaporins in amyloid clearance? play a role 24. Brain Bulk FlowDoes AQP4Brain Aquaporins in amyloid clearance? play a role125IAmyloid1-40 25. Brain Bulk FlowDoes AQP4Brain Aquaporins in amyloid clearance? play a role125IAmyloid1-40 26. Brain Bulk FlowAQP4 deletionAquaporins amyloid clearance Brain reduces125IAmyloid1-40 27. Diagnostic test of glymphatic function based on MRIJCI, 2013 28. Diagnostic test of glymphatic function based on MRIWhen is the glymphatic most active?JCI, 2013 29. Does arousal regulate glymphatic activity? 30. Does arousal regulate glymphatic activity? 31. Does arousal regulate glymphatic activity? 32. Does arousal regulate glymphatic activity? 33. In vivo imaging of tracer influx in the awake stateCascade blue IV CSF tracer 34. In vivo imaging of tracer influx in K/X anesthesiaCascade blue IV CSF tracer 35. In vivo imaging of tracer influx in sleep vs awakeCSF tracerCSF tracer 36. In vivo imaging of tracer influx in awake vs K/X anesthesia200 m200 m 200 mCSF tracer - awake CSF tracer - anesthesia 37. In vivo imaging of tracer influx in sleep vs awakeC S F 200 m200 m 200 mt r a c eCSF tracer - awake r CSF tracer - sleep 38. In vivo imaging of tracer influx in sleep vs awake vs anesthesia 39. In vivo imaging of tracer influx in awake vs following exposure to norepinephrine receptor antagonists 40. In vivo imaging of tracer influx in awake and following exposure to norepinephrine receptor antagonists200 m200 m200 m 41. In vivo imaging of tracer influx in awake and following exposure to norepinephrine receptor antagonists200 m200 m200 m 42. In vivo imaging of tracer influx in awake and following exposure to norepinephrine receptor antagonists200 m200 m200 m 43. Is glymphatic clearance reduced in the awake state? 44. Glymphatic clearance is reduced in the awake stateAmyloid*; p