title: MRI is a sensitive marker of subtle white matter pathology in hypoperfused mice.
abstract: White matter (WM) abnormalities, possibly resulting from hypoperfusion, are key features of the aging human brain. It is unclear, however, whether in vivo magnetic resonance imaging (MRI) approaches, such as diffusion tensor and magnetization transfer MRI are sufficiently sensitive to detect subtle alterations to WM integrity in mouse models developed to study the aging brain. We therefore investigated the use of diffusion tensor and magnetization transfer MRI to measure structural changes in 4 WM tracts following 1 month of moderate hypoperfusion, which results in diffuse WM pathology in C57Bl/6J mice. Following MRI, brains were processed for evaluation of white and gray matter pathology. Significant reductions in fractional anisotropy were observed in the corpus callosum (p = 0.001) and internal capsule (p = 0.016), and significant decreases in magnetization transfer ratio were observed in the corpus callosum (p = 0.023), fimbria (p = 0.032), internal capsule (p = 0.046) and optic tract (p = 0.047) following hypoperfusion. Hypoperfused mice demonstrated diffuse axonal and myelin pathology which was essentially absent in control mice. Both fractional anisotropy and magnetization transfer ratio correlate with markers of myelin integrity/degradation and not axonal pathology. The study demonstrates that in vivo MRI is a sensitive measure of diffuse, subtle WM changes in the murine brain.
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Centre for Cognitive and Neural Systems, University of Edinburgh, Edinburgh, UK. philip.holland@ed.ac.uk
authors.forename: Philip R
authors.initials: PR
authors.lastname: Holland
authors.forename: Mark E
authors.initials: ME
authors.lastname: Bastin
authors.forename: Maurits A
authors.initials: MA
authors.lastname: Jansen
authors.forename: Gavin D
authors.initials: GD
authors.lastname: Merrifield
authors.forename: Robin B
authors.initials: RB
authors.lastname: Coltman
authors.forename: Fiona
authors.initials: F
authors.lastname: Scott
authors.forename: Hanna
authors.initials: H
authors.lastname: Nowers
authors.forename: Karim
authors.initials: K
authors.lastname: Khallout
authors.forename: Ian
authors.initials: I
authors.lastname: Marshall
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Wardlaw
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Deary
authors.forename: James
authors.initials: J
authors.lastname: McCulloch
authors.forename: Karen
authors.initials: K
authors.lastname: Horsburgh
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000473:pathology*; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods / Q000592:standards*; D008279:Magnetic Resonance Imaging / Q000379:methods / Q000592:standards; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009413:Nerve Fibers, Myelinated / Q000473:pathology*; D012680:Sensitivity and Specificity