title: Age-related decline in white matter integrity in a mouse model of tauopathy: an in vivo diffusion tensor magnetic resonance imaging study.
abstract: Elevated expression of human hyperphosphorylated tau is associated with neuronal loss and white matter (WM) pathology in Alzheimer's disease (AD) and related neurodegenerative disorders. Using in vivo diffusion tensor magnetic resonance imaging (DT-MRI) at 11.1 Tesla we measured age-related alterations in WM diffusion anisotropy indices in a mouse model of human tauopathy (rTg4510) and nontransgenic (nonTg) control mice at the age of 2.5, 4.5, and 8 months. Similar to previous DT-MRI studies in AD subjects, 8-month-old rTg4510 mice showed lower fractional anisotropy (FA) values in WM structures than nonTg. The low WM FA in rTg4510 mice was observed in the genu and splenium of the corpus callosum, anterior commissure, fimbria, and internal capsule and was associated with a higher radial diffusivity than nonTg. Interestingly, rTg4510 mice showed lower estimates for the mode of anisotropy than controls at 2.5 months suggesting that changes in this diffusivity metric are detectable at an early stage preceding severe tauopathy. Immunogold electron microscopy partly supports our diffusion tensor imaging findings. At the age of 4 months, rTg4510 mice show axonal tau inclusions and unmyelinated processes. At later ages (12 months and 14 months) we observed inclusions in myelin sheath, axons, and unmyelinated processes, and a "disorganized" pattern of myelinated fiber arrangement with enlarged inter-axonal spaces in rTg4510 but not in nonTg mice. Our data support a role for the progression of tau pathology in reduced WM integrity measured by DT-MRI. Further in vivo DT-MRI studies in the rTg4510 mouse should help better discern the detailed mechanisms of reduced FA and anisotropy mode, and the specific role of tau during neurodegeneration.
authors.affiliation: Department of Neuroscience, University of Florida, Gainesville, FL, USA; Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, FL, USA; Center for Translational Research on Neurodegenerative Disease (CTRND), University of Florida, Gainesville, FL, USA; Molecular Imaging Center, National Institute on Radiological Sciences, Chiba, Japan.
authors.forename: Naruhiko
authors.initials: N
authors.lastname: Sahara
authors.affiliation: Department of Psychiatry, University of Florida, Gainesville, FL, USA.
authors.forename: Pablo D
authors.initials: PD
authors.lastname: Perez
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Wen-Lang
authors.initials: WL
authors.lastname: Lin
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Center for Translational Research on Neurodegenerative Disease (CTRND), University of Florida, Gainesville, FL, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Advanced Magnetic Resonance Imaging and Spectroscopy Facility (AMRIS), University of Florida, Gainesville, FL, USA.
authors.forename: Huadong
authors.initials: H
authors.lastname: Zeng
authors.affiliation: Department of Neuroscience, University of Florida, Gainesville, FL, USA; Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, FL, USA; Center for Translational Research on Neurodegenerative Disease (CTRND), University of Florida, Gainesville, FL, USA.
authors.forename: Jada
authors.initials: J
authors.lastname: Lewis
authors.affiliation: Department of Psychiatry, University of Florida, Gainesville, FL, USA; Department of Neuroscience, University of Florida, Gainesville, FL, USA; Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, FL, USA. Electronic address: febo@ufl.edu.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Febo
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology*; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000818:Animals; D016880:Anisotropy; D003337:Corpus Callosum / Q000378:metabolism / Q000473:pathology*; D056324:Diffusion Tensor Imaging / Q000379:methods*; D004195:Disease Models, Animal; D051379:Mice; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology; D024801:Tauopathies / Q000378:metabolism / Q000473:pathology*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016875:tau Proteins
keywords: Alzheimer's disease; Diffusion tensor MRI; Electron microscopy; FTDP-17; Neurodegenerative disease; Tauopathy; Ultrastructure; White matter integrity; rTg4510