DTI reveals whole-brain microstructural changes in the P301L mouse model of tauopathy

Abstract

Introduction: Increased expression of hyperphosphorylated tau and the formation of neurofibrillary tangles are associated with neuronal loss and white matter damage. Using high resolution ex vivo diffusion tensor imaging (DTI), we investigated microstructural changes in the white and grey matter in the P301L mouse model of human tauopathy at 8.5 months-of-age. For unbiased computational analysis, we implemented a pipeline for voxel-based analysis (VBA) and atlas-based analysis (ABA) of DTI mouse brain data. Methods: Hemizygous and homozygous transgenic P301L mice and non-transgenic littermates were used. DTI data were acquired for generation of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD) maps. VBA on the entire brain were performed using SPM8 and SPM Mouse toolbox. Initially, all DTI maps were co-registered with Allen mouse brain atlas to bring them to one common coordinate space. In VBA, co-registered DTI maps were normalized and smoothed in order to perform two-sample t-tests to compare hemizygotes with non-transgenic littermates, homozygotes with non-transgenic littermates, hemizygotes with homozygotes on each DTI parameter map. In ABA, the average values for selected regions-of-interests were computed with co-registered DTI maps and labels in Allen mouse brain atlas. After, the same two-sample t-tests were executed on the estimated average values. Results: We made reconstructed DTI data and VBA and ABA pipeline publicly available. With VBA, we found microstructural changes in the white matter in hemizygous P301L mice compared to non-transgenic littermates. In contrast, more pronounced and brain-wide spread changes were observed in VBA when comparing homozygous P301L mice with non-transgenic littermates. Statistical comparison of DTI metrics in selected brain regions by ABA corroborated findings from VBA. FA was found to be decreased in most brain regions, while MD, RD and AD were increased compared to hemizygotes and non-transgenic littermates. Discussion/Conclusion: High resolution ex vivo DTI demonstrated brain-wide microstructural changes in the P301L mouse model of human tauopathy. The comparison between hemizygous and homozygous P301L mice revealed a gene-dose dependent effect on DTI metrics. The publicly available computational data analysis pipeline can provide a platform for future mechanistic and longitudinal studies.

Arterial spin labeling demonstrates preserved regional cerebral blood flow in the P301L mouse model of tauopathy

“…Mice were studied at 10-12 and 19-21 months-of-age at which they show mid and advanced disease stage pathology such as tau deposition, calcifications and microstructural abnormalities. 15,24,37,38 Model fits were similar between animals of both groups (Supplementary Figure 1). At both disease stages, we did not detect significant differences in rCBF between P301L and non-transgenic littermates in the neocortex, caudate putamen and thalamus (Figure 1(a) and (c)).…”

Visualizing alpha-synuclein and iron deposition in M83 mouse model of Parkinson’s diseasein vivo

“…Two MAPT P301L transgenic mice overexpressing human 2N/4R tau under the neuron-specific Thy1.2 promoter (pR5 line, C57B6. Dg background) [31][32][33], and two respective NTL mice were used. Pelleted food (3437PXL15, CARGILL) and water were provided ad libitum.…”

Non-invasive imaging of tau-targeted probe uptake by whole brain multi-spectral optoacoustic tomography

“…Transgenic MAPT P301L mice overexpressing human 2 N/4R tau under the neuron-specific Thy1.2 promoter (pR5 line, C57B6. Dg background) [26,42,[64][65][66] and wild-type littermates were used (18 months old, n = 10 each group, both genders). For resolution characterization, one female athymic nude mouse (5 weeks old, JanvierLab, France) was used.…”