title: Impairment of paravascular clearance pathways in the aging brain.
abstract: OBJECTIVE
  In the brain, protein waste removal is partly performed by paravascular pathways that facilitate convective exchange of water and soluble contents between cerebrospinal fluid (CSF) and interstitial fluid (ISF). Several lines of evidence suggest that bulk flow drainage via the glymphatic system is driven by cerebrovascular pulsation, and is dependent on astroglial water channels that line paravascular CSF pathways. The objective of this study was to evaluate whether the efficiency of CSF-ISF exchange and interstitial solute clearance is impaired in the aging brain.
  
  
  METHODS
  CSF-ISF exchange was evaluated by in vivo and ex vivo fluorescence microscopy and interstitial solute clearance was evaluated by radiotracer clearance assays in young (2-3 months), middle-aged (10-12 months), and old (18-20 months) wild-type mice. The relationship between age-related changes in the expression of the astrocytic water channel aquaporin-4 (AQP4) and changes in glymphatic pathway function was evaluated by immunofluorescence.
  
  
  RESULTS
  Advancing age was associated with a dramatic decline in the efficiency of exchange between the subarachnoid CSF and the brain parenchyma. Relative to the young, clearance of intraparenchymally injected amyloid-β was impaired by 40% in the old mice. A 27% reduction in the vessel wall pulsatility of intracortical arterioles and widespread loss of perivascular AQP4 polarization along the penetrating arteries accompanied the decline in CSF-ISF exchange.
  
  
  CONCLUSIONS
  We propose that impaired glymphatic clearance contributes to cognitive decline among the elderly and may represent a novel therapeutic target for the treatment of neurodegenerative diseases associated with accumulation of misfolded protein aggregates.
authors.affiliation: Center for Translational Neuromedicine, University of Rochester School of Medicine, Rochester, NY.
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Kress
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Iliff
authors.forename: Maosheng
authors.initials: M
authors.lastname: Xia
authors.forename: Minghuan
authors.initials: M
authors.lastname: Wang
authors.forename: Helen S
authors.initials: HS
authors.lastname: Wei
authors.forename: Douglas
authors.initials: D
authors.lastname: Zeppenfeld
authors.forename: Lulu
authors.initials: L
authors.lastname: Xie
authors.forename: Hongyi
authors.initials: H
authors.lastname: Kang
authors.forename: Qiwu
authors.initials: Q
authors.lastname: Xu
authors.forename: Jason A
authors.initials: JA
authors.lastname: Liew
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Plog
authors.forename: Fengfei
authors.initials: F
authors.lastname: Ding
authors.forename: Rashid
authors.initials: R
authors.lastname: Deane
authors.forename: Maiken
authors.initials: M
authors.lastname: Nedergaard
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000502:physiology*; D005260:Female; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D036641:Microscopy, Fluorescence, Multiphoton / Q000379:methods; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology
chemical_list: C496031:Aqp4 protein, mouse; D051401:Aquaporin 4