Diffuse white matter loss in a transgenic rat model of cerebral amyloid angiopathy

Abstract

Diffuse white matter (WM) disease is highly prevalent in elderly with cerebral small vessel disease (cSVD). In humans, cSVD such as cerebral amyloid angiopathy (CAA) often coexists with Alzheimer’s disease imposing a significant impediment for characterizing their distinct effects on WM. Here we studied the burden of age-related CAA pathology on WM disease in a novel transgenic rat model of CAA type 1 (rTg-DI). A cohort of rTg-DI and wild-type rats was scanned longitudinally using MRI for characterization of morphometry, cerebral microbleeds (CMB) and WM integrity. In rTg-DI rats, a distinct pattern of WM loss was observed at 9 M and 11 M. MRI also revealed manifestation of small CMB in thalamus at 6 M, which preceded WM loss and progressively enlarged until the moribund disease stage. Histology revealed myelin loss in the corpus callosum and thalamic CMB in all rTg-DI rats, the latter of which manifested in close proximity to occluded and calcified microvessels. The quantitation of CAA load in rTg-DI rats revealed that the most extensive microvascular Aβ deposition occurred in the thalamus. For the first time using in vivo MRI, we show that CAA type 1 pathology alone is associated with a distinct pattern of WM loss.

Disparate volumetric fluid shifts across cerebral tissue compartments with two different anesthetics

“…During MRI, the anesthetized rat was placed in the supine position onto a custom-built 3D-printed animal holder with physiological monitors attached. 3D PDW sequence: 3D PDW images were acquired using a fast low angle shot (FLASH) sequence with the following parameters [ 39 ]: repetition time (TR) = 50 ms; echo time (TE) = 4 ms; flip angle (FA) = 7°; number of signal averages (NA) = 4; spatial resolution = 0.23 × 0.23 × 0.23 mm; acquisition time = 27 min. T2* sequence: immediately following the 3D PDW scan, a multi-gradient echo (MGE) sequence with 16 evenly spaced echo times was performed using the following parameters: TR/TE/FA = 60 ms/2 ~ 32 ms/15°; NA = 2; spatial resolution = 0.23 × 0.23 × 0.23 mm; acquisition time = 16 min).…”

“…Voxel-based morphometry (VBM) was implemented using the SPM12 software package ( https://www.fil.ion.ucl.ac.uk/spm ) described previously [ 39 , 42 ]. PDW images were first corrected for B1 inhomogeneity, followed by spatial registration and tissue segmentation into three tissue compartments: grey matter (GM), white matter (WM), and CSF.…”

“…T2* differences between the two anesthetic groups were also characterized by voxel-wise analysis [ 39 ]. 3D T2* maps were first calculated from the 3D MGE image intensities by assuming mono-exponential signal decay between the detected signals and the echo times using the following formula: S(TE) = S 0 e −TE/T2* , where S 0 , TE, and T2* represent the PDW signal, echo time and the transverse relaxation time, respectively.…”

“…Sample size for the crossover study design using MRI based morphometry between the two anesthetics was determined based on previous experience [ 39 ]. A linear mixed-model with a heterogeneous variance covariance matrix for repeated measures over time was used to analyze the impact of the multiple scan sessions and type of anesthetic on each physiological parameter and body weight within the same rat with fixed effects of ‘time’ (MRI sequence), group (anesthetic) and the interaction between time and group.…”

“…During MRI, the anesthetized rat was placed in the supine position onto a custom-built 3D-printed animal holder with physiological monitors attached. 3D PDW sequence: 3D PDW images were acquired using a fast low angle shot (FLASH) sequence with the following parameters [39]: repetition time (TR) = 50 ms; echo time (TE) = 4 ms; flip angle (FA) = 7°; number of signal averages (NA) = 4; spatial resolution = 0.23 × 0.23 × 0.23 mm; Fig. 1 Experimental design of the study and overview of computational analysis.…”