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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.
Highlights
Alzheimer’s disease (AD) has a complex pathophysiology with pathomorphological hallmarks of the disease being the misfolding of amyloid-b (Ab) protein and hyperphosphorylation of the tau protein
We found that factors unrelated to the disease pathology have a strong effect on all Magnetic resonance imaging (MRI) parameters and that linear mixed effects (LME) modelling can account for these factors
Each scan session consisted of two sets of measurements using MRI systems of different field strength: anatomical reference data, Diffusion-weighted imaging (DWI), T1-mapping and dynamic contrast-enhanced MRI (DCE-MRI) data were acquired at 4.7 T, whereas anatomical reference and gradient recalled echo (GRE) data were collected at 9.4 T for computing GRE magnitude images, susceptibility weighted imaging (SWI) and quantitative susceptibility mapping (QSM); taking advantage of the increased signal-to-noise ratio at the higher magnetic field strength
Summary
Alzheimer’s disease (AD) has a complex pathophysiology with pathomorphological hallmarks of the disease being the misfolding of amyloid-b (Ab) protein and hyperphosphorylation of the tau protein These pathological changes are associated with the aggregation of Ab plaques, neurofibrillary tangles, neuronal degeneration and neuroinflammation [1]. Transgenic mouse models have been engineered to investigate the pathophysiology of AD [4,5], where several mouse lines express the mutant genes for human amyloid precursor protein (APP) and presenilin, responsible for the proteolytic processing of APP. These transgenic mice develop Ab aggregates (senile plaques) in the brain parenchyma in an age-dependent manner. Despite the fact that transgenic mouse models do not completely replicate AD, they have become indispensible for studying disease mechanism and drug discovery
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