Maria Fatima Falangola1,2, Xingju Nie1,2, Emilie T. McKinnon1,2,3, Joseph A. Helpern1,2,3,4, and Jens H. Jensen1,2,4
1Department of Neuroscience, Medical University of South Carolina, Charleston, SC, United States, 2Center for Biomedical Imaging, Medical University of South Carolina, Charleston, SC, United States, 3Department of Neurology, Medical University of South Carolina, Charleston, SC, United States, 4Department of Radiology and Radiological Science, Medical University of South Carolina, Charleston, SC, United States
Synopsis
The triple transgenic mouse model (3xTg)
of Alzheimer’s disease (AD) exhibits both Aβ and tau pathology. Interestingly,
the first detectable pathological features in this model are alterations in
overall myelination patterns leading to white matte disruption as early as 2
months of age. Here we investigated the sensitivity of diffusion MRI (dMRI) to
detect brain changes in young 3xTg mice. Our results indicate that dMRI is able
to capture brain microstructural alterations associated with the hippocampus-fimbria-fornix
circuit in 2 months-old 3xTg-AD mice, thus demonstrating dMRI as a viable tool
for studying abnormal pathology in this AD mouse model.
INTRODUCTION
The 3xTg-AD mouse model has been used
extensively as a model of AD1,2 and develops both Aβ and
neurofibrillary tangles (NFTs) in a temporal and spatial pattern that is
similar to human AD pathology3,4. Interestingly, abnormal myelination
patterns with changes in oligodendrocyte and myelin marker expression are early
pathological features described in this model even before amyloid and
tau-related pathologies are observed, particularly in sub-regions of the hippocampus
and the entorhinal cortex5,6. Additionally, significant volumetric
differences have been reported for the 3xTg-AD mice in the hippocampal complex
and fimbria7. Thus, the goal of this study was to investigate the
sensitivity of diffusion MRI (dMRI) to capture brain microstructural alterations
associated with the hippocampus and fimbria-fornix circuit in 2 months-old
3xTg-AD mice.METHODS
Female
3xTg (TG, n = 14) and age-matched normosomic littermates (NC, n = 8) mice were
studied at 2 months of age. In vivo
MRI experiments were performed on a 7T Bruker MRI system (PARAVISION 5.1). A
2-shot SE-EPI dMRI sequence was used for a diffusional kurtosis imaging (DKI) acquisition8.
Sequence parameters: TR/TE=3750/32.6ms, δ/Δ=5/18ms, slice thickness =0.7 mm, 15
slices with no gap, data matrix=128×128, image resolution=156×156μm2,
2 signal acquisitions, 10 b-value=0 images, followed by 30 diffusion encoding
gradient directions with 4 b-values for each gradient direction (0.5, 1, 1.5, 2
ms/μm2) and fat suppression flip angle=105°. Total acquisition
time=33 minutes. Mean diffusivity (MD), axial diffusivity (D‖),
radial diffusivity (D┴), fractional anisotropy (FA), mean kurtosis (MK), axial kurtosis
(K‖), radial kurtosis (K┴), and kurtosis fractional
anisotropy (KFA) were all derived from the DKI dataset (Figure 1) using
Diffusional Kurtosis Estimator software (DKE;
http://www.nitrc.org/projects/dke)9. Regions of interest (ROIs) at
the level of the dorsal (DH) and ventral (VH) hippocampus, fimbria (Fi) and fornix
(Fx) were manually drawn in the average b-value=0 images, and verified on the
FA maps to ensure correct anatomical location, using ImageJ (http://rsb.info.nih.gov/)
(Figure 2). The average regional value for each dMRI metric was obtained from
the voxels within each ROI. To minimize the effect of cerebrospinal fluid (CSF)
contamination, all voxels with MD ˃1.5 μm2/ms were excluded from the
ROIs prior to parameter quantification. Two-tailed paired t-tests were
performed to assess differences in the ROI measurements between the two groups. RESULTS
Table 1
shows the group means, standard deviations and p-values for all the diffusion
metrics in each ROI. Each ROI was analyzed separately, using all the dMRI
metrics, and we considered the results statistically
significant at p < 0.05 (uncorrected). For the 3xTg
group, in the dorsal hippocampus
(Figure 3), MD, D‖ and D┴ were all significantly increased (Figure 3), and
K‖ was significantly reduced. In the ventral hippocampus (Figure 4),
MD, D‖ and D┴ were significantly increased, with no changes in kurtosis
metrics. In the fimbria (Figure 5), FA and KFA were significantly decreased, D┴ was significantly increased,
and K┴ was significantly reduced. No statistically significant dMRI
changes were observed in the fornix.
DISCUSSION & CONCLUSION
Our results indicate that dMRI is able to
capture brain pathology in young 3xTg mice. Although preliminary, these results
correlate well with previously described morphological changes, where abnormal oligodendrocyte and myelin marker
expression are noticeable in the hippocampus of 2 months old 3xTg mice5,6. The
hippocampus of 2 months old 3xTg-AD mice had an overall increase of diffusivity
metrics (MD, D‖ and D┴) and a decrease in FA and K‖,
which could be explained by the ultrastructural changes in myelin sheath
integrity and the decline in the total number of myelinated processes demonstrated
in this model6. Additionally,
significant volumetric differences in the hippocampal complex and fimbria have
been reported in young 3xTg-AD mice7, which
may also be related to our results. The fimbria and fornix of hippocampus form
a complex system of afferent and efferent nerve fibers closely related
functionally and structurally with the hippocampal formation and other brain
parts, and it is clearly involved in AD pathology10-12. This study
is the first application of dMRI to 2 month old 3xTg-AD mice, and it
illustrates the sensitivity of dMRI metrics for detecting early pathological features, even
before the presence of Aβ and tau pathology.Acknowledgements
This work was supported by the National
Institutes of Health (1RF1AG057602-01) and The Litwin Foundation. References
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