Brain calcifications are common in aged individuals, but the mechanisms underlying their formation are unclear. Zarb et al. show that in primary familial brain calcification, a neuropsychiatric disorder featuring bilateral vessel-associated calcifications in the basal ganglia, vessel calcification is accompanied by an osteogenic environment which elicits a neurotoxic astrocyte response.

Amyloid-␤ (A␤) 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 arcA␤ model of cerebral amyloidosis. To estimate the density of the cortical microvasculature in vivo, we used contrast-enhanced magnetic resonance microangiography (CE-MRA). Three-dimensional gradient echo datasets with 60 m isotropic resolution were acquired in 4-and 24-month-old arcA␤ 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-MRA, cerebral arteries and veins with a diameter of less than the nominal pixel resolution (60 m) can be visualized. A significant age-dependent reduction in the number of functional intracortical microvessels (radii of 20 -80 m) has been observed in 24-month-old arcA␤ 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 A␤ deposition in small-and medium-sized vessels, but not in large cerebral arteries, of 24-monthold arcA␤ mice. The reduced density of transcortical vessels may thus be attributed to impaired perfusion and vascular occlusion caused by deposition of A␤ and fibrin. The study demonstrated that remodeling of the cerebrovasculature can be monitored noninvasively with CE-MRA in mice.

Cerebral microbleeds (CMBs) are findings in patients with neurological disorders such as cerebral amyloid angiopathy and Alzheimer's disease, and are indicative of an underlying vascular pathology. A diagnosis of CMBs requires an imaging method that is capable of detecting iron-containing lesions with high sensitivity and spatial accuracy in the presence of potentially confounding tissue abnormalities. In this study, we investigated the feasibility of quantitative magnetic susceptibility mapping (QSM), a novel technique based on gradient-recalled echo (GRE) phase data, for the detection of CMBs in the arcAβ mouse, a mouse model of cerebral amyloidosis. Quantitative susceptibility maps were generated from phase data acquired with a high-resolution T(2)(*)-weighted GRE sequence at 9.4 T. We examined the influence of different regularization parameters on susceptibility computation; a proper adjustment of the regularization parameter minimizes streaking artifacts and preserves fine structures. In the present study, it is shown that QSM provides increased detection sensitivity of CMBs and improved contrast when compared with GRE magnitude imaging. Furthermore, QSM corrects for the blooming effect observed in magnitude and phase images and depicts both the localization and spatial extent of CMBs with high accuracy. Therefore, QSM may become an important tool for diagnosing CMBs in neurological diseases.

Impairment of brain functional connectivity (FC) is thought to be an early event occurring in diseases with cerebral amyloidosis, such asAlzheimer's disease. Regions sustaining altered functional networks have been shown to colocalize with regions marked with amyloid plaques burden suggesting a strong link between FC and amyloidosis. Whether the decline in FC precedes amyloid plaque deposition or is a consequence thereof is currently unknown. The sequence of events during early stages of the disease is difficult to capture in humans due to the difficulties in providing an early diagnosis and also in view of the heterogeneity among patients. Transgenic mouse lines overexpressing amyloid precursor proteins develop cerebral amyloidosis and constitute an attractive model system for studying the relationship between plaque and functional changes. In this study, ArcA␤ transgenic and wild-type mice were imaged using resting-state fMRI methods across their life-span in a cross-sectional design to analyze changes in FC in relation to the pathology. Transgenic mice show compromised development of FC during the first months of postnatal life compared with wild-type animals, resulting in functional impairments that affect in particular the sensory-motor cortex already in preplaque stage. These functional alterations were accompanied by structural changes as reflected by reduced fractional anisotropy values, as derived from diffusion tensor imaging. Our results suggest cerebral amyloidosis in mice is preceded by impairment of neuronal networks and white matter structures. FC analysis in mice is an attractive tool for studying the implications of impaired neuronal networks in models of cerebral amyloid pathology.

Light in the near-infrared (NIR) region between 700-900 nm can penetrate deep into living tissue, thereby offering a unique opportunity to use near-infrared fluorescence (NIRF) imaging techniques to detect and visualize fluorescent probes in-vivo. In the past few years, many novel NIR fluorescent probes have been designed, synthesized and studied in a variety of disease conditions. Recent research has focused primarily on the class of cyanines dyes as non-specific agents and as part of specific NIR fluorescent probes. The publications reviewed herein discuss the characteristics of cyanine dyes and their conjugates and present examples for the application of these probes for imaging vascular pathophysiology.

Matrix metalloproteinases (MMPs) have been implicated in the pathophysiology of cerebral ischemia. In this study, we explored whether MMP activity can be visualized by noninvasive nearinfrared fluorescence (NIRF) imaging using an MMP-activatable probe in a mouse model of stroke. C57Bl6 mice were subjected to transient middle cerebral artery occlusion (MCAO) or sham operation. Noninvasive NIRF imaging was performed 24 h after probe injection, and target-tobackground ratios (TBRs) between the two hemispheres were determined. TBRs were significantly higher in MCAO mice injected with the MMP-activatable probe than in sham-operated mice and in MCAO mice that were injected with the nonactivatable probe as controls. Treatment with an MMP inhibitor resulted in significantly lower TBRs and lesion volumes compared to injection of vehicle. To test the contribution of MMP-9 to the fluorescence signal, MMP9-deficient (MMP9 À/À ) mice and wild-type controls were subjected to MCAO of different durations to attain comparable lesion volumes. TBRs were significantly lower in MMP9 À/À mice, suggesting a substantial contribution of MMP-9 activity to the signal. Our study shows that MMP activity after cerebral ischemia can be imaged noninvasively with NIRF using an MMP-activatable probe, which might be a useful tool to study MMP activity in the pathophysiology of the disease.

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The effect of cerebral amyloidosis on cerebral hemodynamics was investigated with photoacoustic tomography (PAT) and magnetic resonance imaging (MRI). First, the sensitivity and robustness of PAT for deriving metrics of vascular and tissue oxygenation in the murine brain was assessed in wild-type mice with a hyperoxia-normoxia challenge. Secondly, cerebral oxygenation was assessed in young and aged arcAβ mice and wild-type controls with PAT, while cerebral blood flow (CBF) was determined by perfusion MRI. The investigations revealed that PAT can sensitively and robustly detect physiological changes in vascular and tissue oxygenation. An advanced stage of cerebral amyloidosis in arcAβ mice is accompanied by a decreases in cortical CBF and the cerebral metabolic rate of oxygen (CMRO2), as oxygen extraction fraction (OEF) has been found unaffected. Thus, PAT constitutes a robust non-invasive tool for deriving metrics of tissue oxygenation, extraction and metabolism in the mouse brain under physiological and disease states.