T1? MRI AS A MARKER FOR NEUROFIBRILLARY TANGLES IN A MOUSE MODEL OF AD

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. AD mouse models mimicking, either the amyloid-beta or hyperphosphorylated tau pathologies, the post-mortem diagnostic markers of Alzheimer's disease (AD), have been characterized using biochemical and histological techniques. However, the only MRI characterization reported on transgenic mouse models of AD have studied the amyloid-beta pathology. A relaxometry study of the T1¿ relaxation time in human AD patients showed a difference of 8% in the T1¿ relaxation times of white matter and 5% in gray matter of the medial temporal lobe. It is hypothesized that the T1¿ relaxation time constant is also sensitive to the pathologic biochemical changes resulting from pathology due to tau protein that leads to intracellular neurofibrillary tangles (NFTs). To test this hypothesis, we are currently studying a cohort of transgenic (Tg) tau mice expressing the P301S mutation in a human tau isoform, and age-matched wild-type (WT) mice with T1¿ MRI. All animal studies were approved by the IACUC. Tg animals were bred from the PS19 line of the P301S model. MRI was performed on a 9.4T small-bore scanner by Varian on mice aged 13-15 months. Four T1¿-weighted images were obtained, at spin-locking times of TSL=1, 20, 30, 40ms for quantifying T1¿ relaxation time constant. The four MRI contrasts were exponentially fit on a pixel-by-pixel basis to create a color-coded parametric map of the T1¿ at each pixel. ROIs of the hippocampus and cortex were manually drawn on T1¿-weighted images at TSL=1ms, and masks were applied to the corresponding slices in the T1¿ maps to measure the mean T1¿ relaxation times. Immunohistochemistry was performed on the PS19 mice after harvesting the brain in order to verify the extent of tau pathology. An antibody for phosphorylated tau stained brown and a counter-stain with hematoxylin were used to visualize neuronal nuclei.