Age-related decline in white matter integrity in a mouse model of tauopathy: An invivo diffusion tensor magnetic resonance imaging study

Naruhiko Sahara, Pablo D. Perez, Wen Lang Lin, Dennis W. Dickson, Yan Ren, Huadong Zeng, Jada Lewis, Marcelo Febo

Research output: Contribution to journalArticle

29 Scopus citations

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 invivo 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 2.5months 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 invivo 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.

Original languageEnglish (US)
Pages (from-to)1364-1374
Number of pages11
JournalNeurobiology of aging
Volume35
Issue number6
DOIs
StatePublished - Jun 2014

Keywords

  • Alzheimer's disease
  • Diffusion tensor MRI
  • Electron microscopy
  • FTDP-17
  • Neurodegenerative disease
  • RTg4510
  • Tauopathy
  • Ultrastructure
  • White matter integrity

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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