Longitudinal Assessment of Amyloid Pathology in Transgenic ArcAβ Mice Using Multi-Parametric Magnetic Resonance Imaging

Abstract

Magnetic resonance imaging (MRI) can be used to monitor pathological changes in Alzheimer's disease (AD). The objective of this longitudinal study was to assess the effects of progressive amyloid-related pathology on multiple MRI parameters in transgenic arcAβ mice, a mouse model of cerebral amyloidosis. Diffusion-weighted imaging (DWI), T1-mapping and quantitative susceptibility mapping (QSM), a novel MRI based technique, were applied to monitor structural alterations and changes in tissue composition imposed by the pathology over time. Vascular function and integrity was studied by assessing blood-brain barrier integrity with dynamic contrast-enhanced MRI and cerebral microbleed (CMB) load with susceptibility weighted imaging and QSM. A linear mixed effects model was built for each MRI parameter to incorporate effects within and between groups (i.e. genotype) and to account for changes unrelated to the disease pathology. Linear mixed effects modelling revealed a strong association of all investigated MRI parameters with age. DWI and QSM in addition revealed differences between arcAβ and wt mice over time. CMBs became apparent in arcAβ mice with 9 month of age; and the CMB load reflected disease stage. This study demonstrates the benefits of linear mixed effects modelling of longitudinal imaging data. Moreover, the diagnostic utility of QSM and assessment of CMB load should be exploited further in studies of AD.

Quantitative susceptibility mapping (QSM) with an extended physical model for MRI frequency contrast in the brain: a proof‐of‐concept of quantitative susceptibility and residual (QUASAR) mapping

“…Susceptibility map reconstruction issues similar to those observed in the present work with the traditional physical model (Figures and ) may be found also in published rodent work by other authors. For example, susceptibility contrast was absent from the frontal horn of the lateral ventricles on all in vivo images presented by O'Callaghan et al (Figures and therein), Ziser et al (Figures and therein) and Vaas et al (Figure therein), as well as studies to which we have contributed …”

Age and sex related differences in subcortical brain iron concentrations among healthy adults

“…Aging per se unfolds over time and to the best of our knowledge, inference about age associations of estimates of human brain iron, rely solely on cross sectional studies, while longitudinal studies have been performed only in rodents (Klohs et al, 2013). Cross-sectional design relies on age-related differences between persons that are captured in a snapshot frozen in time, and cannot measure the true dynamic trajectories within a person.…”

Can MRI T1 be used to detect early changes in 5xFAD Alzheimer’s mouse brain?

“…Despite focusing our attention on the lower cortex and corpus callosum, T 1 values were not significantly different between 5-month-old 5xFAD and WT mice. Other studies have found no T 1 differences between AD and WT mice, for example, in PS/APP mice 16–23 months old [34], and in ArcAβ mice, which have similar T 1 values to WT mice irrespective of age [35]. It is not known, however, if the lack of T 1 change in those studies is due to the size and placement of ROIs or the use of different AD transgenic models.…”