Contrast-enhanced magnetic resonance microangiography reveals remodeling of the cerebral microvasculature in transgenic ArcAß mice.

Amyloid-ß (Aß) deposition in the cerebral vasculature is accompanied by remodeling which has a profound influence on vascular integrity and function. In the current study we have quantitatively assessed the age-dependent changes of the cortical vasculature in the arcAß model of cerebral amyloidosis. To estimate the density of the cortical microvasculature in vivo, we used contrast-enhanced magnetic resonance microangiography (CE-µMRA). Three-dimensional gradient echo datasets with 60 µm isotropic resolution were acquired in 4- and 24-month-old arcAß mice and compared with wild-type (wt) control mice of the same age before and after administration of superparamagnetic iron oxide nanoparticles. After segmentation of the cortical vasculature from difference images, an automated algorithm was applied for assessing the number and size distribution of intracortical vessels. With CE-µMRA, cerebral arteries and veins with a diameter of less than the nominal pixel resolution (60 µm) can be visualized. A significant age-dependent reduction in the number of functional intracortical microvessels (radii of 20-80 µm) has been observed in 24-month-old arcAß mice compared with age-matched wt mice, whereas there was no difference between transgenic and wt mice of 4 months of age. Immunohistochemistry demonstrated strong fibrinogen and Aß deposition in small- and medium-sized vessels, but not in large cerebral arteries, of 24-month-old arcAß mice. The reduced density of transcortical vessels may thus be attributed to impaired perfusion and vascular occlusion caused by deposition of Aß and fibrin. The study demonstrated that remodeling of the cerebrovasculature can be monitored noninvasively with CE-µMRA in mice.

Vascular response to acetazolamide decreases as a function of age in the arcA beta mouse model of cerebral amyloidosis.

Deposition of beta-amyloid along cerebral vessels is found in most patients suffering from Alzheimer's disease. The effects of cerebral amyloid angiopathy (CAA) on the function of cerebral blood vessels were analyzed applying cerebral blood volume (CBV)-based fMRI to transgenic arcA beta mice. In a cortical brain region of interest (ROI), displaying high CAA, arcA beta mice older than 16 months showed reduced response to the vasodilatory substance acetazolamide compared to age-matched wild-type animals, both with regard to rate (vascular reactivity) and extent of vasodilation (maximal vasodilation). In a subcortical ROI, displaying little CAA, no genotype-specific decrease was observed, but maximal vasodilation decreased with age in arcA beta and wild-types. These findings indicate that vascular beta-amyloid deposits reduce the capacity of cerebral blood vessels to dilate upon demand, supporting the hypothesis that vascular beta-amyloid contributes to hypoperfusion and neurological deficits observed in AD and CAA. High diagnostic accuracy of the combined readouts in detecting vascular dysfunction in arcA beta mice was found.

Detecting amyloid-ß plaques in Alzheimer's disease.

One of the major neuropathological changes characteristic of Alzheimer's disease (AD) is deposits of beta-amyloid plaques and neurofibrillary tangles in neocortical and subcortical regions of the AD brain. The histochemical detection of these lesions in postmortem brain tissue is necessary for definitive diagnosis of AD. Methods for their in vivo detection would greatly aid the diagnosis of AD in early stages when neuronal loss and related functional impairment are still limited and would also open the opportunity for effective therapeutic interventions. Magnetic resonance imaging (MRI) theoretically provides the spatial resolution needed to resolve amyloid-ß plaques. Although currently limited for clinical applications due to unfavorable long acquisition times, MRI has been used to visualize Aß plaques in AD mouse models. The ability to detect amyloid-positive brain lesions in vivo using non-invasive imaging would allow to track disease progression and to monitor the efficacy of potential therapies in disease-modifying studies using transgenic models resembling AD pathology. Here, we provide MRI protocols for in vivo (mouse) and ex vivo (AD tissue samples) amyloid plaque imaging and the procedure for correlating these with thioflavin-S and iron-staining histology. Current challenges and limitations are discussed.