Alternative structural MRI approaches are based on the quantitative assessment of MRI parameters determining image contrast. For instance, the occurrence of microstructural changes in brain parenchyma due to plaque and tangle formation should translate into locally altered MRI relaxation times. High-field MRI has been used to investigate brain regional changes of MR relaxation times in two different murine AD models . The transverse relaxation time T2 was significantly reduced in various brain regions (hippocampus, cingulate, and retrosplenial cortex) of PSAPP mice  as compared to nontransgenic animals. No significant differences were observed between T2-values measured in PS mice , which do not display deposition of solid A|3-containing plaques, and control animals. These results indicate that T2 might constitute a sensitive marker of parenchymal abnormalities due to massive deposition of insoluble A|3. No significant changes have been found in the longitudinal relaxation time Tj.
A similar hypothesis has been pursuit by analyzing the water apparent diffusion coefficient (ADC) in brain parenchyma. Extracellular deposition of A|3 plaques impinges restrictions to interstitial fluid diffusion reflected by a reduction of the tissue ADC. In fact, in 24-month-old APP23 mice significantly decreased ADC values were observed in cortical regions that displayed high amounts of insoluble A|3 plaques as compared to wildtype animals. In 6-month-old animals, no difference was observed between transgenic and control mice .
Damage and dysfunction in AD is not only confined to gray matter but occurs also in white matter. White matter degeneration has been studied using diffusion-tensor (DT) MRI in APP overexpressing mice, in which APP was expressed under the control of the platelet-derived growth factor promoter (PDAPP line). Due to the fact that water diffusion is restricted by cellular membranes perpendicular to the fiber axis and is essentially free along the nerve fibers, high values of diffusion anisotropy reflect integrity of corresponding white matter tracts. DT anisotropy was significantly reduced in 15-month-old PDAPP mice with established pathology as compared to that of age-matched control mice, while no difference in DTI parameters was observed between the young, 3-month-old, PDAPP and control mice .
A final structural readout that has been proposed is the analysis of the cerebro-arterial systems. AD-related vasculopathy also affects lager vessels including the principal feeding arteries of the brain . MR angiography (MRA) studies in APP23 mice confirmed this fact. Flow voids were detected at the internal carotid artery of 11-month-old APP23 mice. At the age of 20 months, more pronounced and additional flow disturbances were observed in large arteries at the Circle of Willis.
Vascular corrosion casts obtained from the same mice revealed that vessel elimination and/or deformation had taken place at the sites where flow voids were detected by MRA [80,81].
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