Longitudinal changes of blood-brain barrier and transcytolemmal water exchange permeability in Alzheimer's disease mice: A non-contrast MRI study

Growing evidence suggests that Alzheimer's disease (AD) has been linked with the dysfunction of glymphatic system. Previous studies were primarily cross-sectional and focused on only one specific component, hindering the understanding of overall glymphatic function in AD. We evaluated the longitudinal changes in multiple components of glymphatic system (blood-brain barrier (BBB) and transcytolemmal water exchange (TWE) permeability) in AD mice. Five female wild-type and four 3 × Tg-AD mice from 5 to 13 months of age were scanned monthly using two non-contrast MRI techniques, water-extraction-with-phase-contrast-arterial-spin-tagging (WEPCAST) and diffusion-time-dependent kurtosis imaging (tDKI), yielding BBB and TWE permeability. Immunostaining was used to evaluate tight junction proteins associated with BBB structural integrity, aquaporin 4 (AQP4) related to TWE, and AQP4 perivascular space (PVS) polarization that might represent PVS-parenchyma water exchange. The relationship between glymphatic function and AD pathology, as measured by amyloid beta (Aβ) and tau deposition, was also explored. Our results revealed significantly increased BBB and hippocampal TWE permeability in AD mouse brains, consistent with the histological findings of reduced tight junction proteins and upregulated AQP4, which were correlated with each other and can be predictive of Aβ and tau deposition. Impaired AQP4 PVS polarization was also found in AD mice. In conclusion, water exchange in multiple components of glymphatic system altered in AD mice, and these in vivo MRI findings were validated pathologically, which might affect the waste clearance in the glymphatic neurofluid.