TY - JOUR
T1 - Age-related decline in white matter integrity in a mouse model of tauopathy
T2 - An invivo diffusion tensor magnetic resonance imaging study
AU - Sahara, Naruhiko
AU - Perez, Pablo D.
AU - Lin, Wen Lang
AU - Dickson, Dennis W.
AU - Ren, Yan
AU - Zeng, Huadong
AU - Lewis, Jada
AU - Febo, Marcelo
N1 - Funding Information:
MF is supported by National Institutes of Health grant DA019946 and a seed grants from the McKnight Brain Institute and from the University of Florida College of Medicine . NS is supported by National Institutes of Health grant NS067127 , by the Thomas H. Maren Junior Investigator Fund from University of Florida . NS and JL are supported by the Center for Translational Research in Neurodegenerative Disease and the Department of Neuroscience . The authors thank the Advanced Magnetic Resonance Imaging and Spectroscopy (AMRIS) Facility for their continued support.
PY - 2014/6
Y1 - 2014/6
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - Diffusion tensor MRI
KW - Electron microscopy
KW - FTDP-17
KW - Neurodegenerative disease
KW - RTg4510
KW - Tauopathy
KW - Ultrastructure
KW - White matter integrity
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UR - http://www.scopus.com/inward/citedby.url?scp=84903365866&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2013.12.009
DO - 10.1016/j.neurobiolaging.2013.12.009
M3 - Article
C2 - 24411290
AN - SCOPUS:84903365866
SN - 0197-4580
VL - 35
SP - 1364
EP - 1374
JO - Neurobiology of aging
JF - Neurobiology of aging
IS - 6
ER -