Magnetic Resonance Q Mapping Reveals a Decrease in Microvessel Density in the arcAβ Mouse Model of Cerebral Amyloidosis

Alterations in density and morphology of the cerebral microvasculature have been reported to occur in Alzheimer's disease patients and animal models of the disease. In this study we compared magnetic resonance imaging (MRI) techniques for their utility to detect age-dependent changes of the cerebral vasculature in the arcAβ mouse model of cerebral amyloidosis. Dynamic susceptibility contrast (DSC)-MRI was performed by tracking the passage of a superparamagnetic iron oxide nanoparticle in the brain with dynamic gradient echo planar imaging (EPI). From this measurements relative cerebral blood volume [rCBV(DSC)] and relative cerebral blood flow (rCBF) were estimated. For the same animal maps of the relaxation shift index Q were computed from high resolution gradient echo and spin echo data that were acquired before and after superparamagnetic iron oxide (SPIO) nanoparticle injection. Q-values were used to derive estimates of microvessel density. The change in the relaxation rates ΔR∗2 obtained from pre- and post-contrast gradient echo data was used for the alternative determination of rCBV [rCBV(ΔR∗2)]. Linear mixed effects modeling found no significant association between rCBV(DSC), rCBV(ΔR∗2), rCBF, and Q with genotype in 13-month old mice [compared to age- matched non-transgenic littermates (NTLs)] for any of the evaluated brain regions. In 24-month old mice there was a significant association for rCBV(DSC) with genotype in the cerebral cortex, and for rCBV(ΔR∗2) in the cerebral cortex and cerebellum. For rCBF there was a significant association in the cerebellum but not in other brain regions. Q-values in the olfactory bulb, cerebral cortex, striatum, hippocampus, and cerebellum in 24-month old mice were significantly associated with genotype. In those regions Q-values were reduced between 11 and 26% in arcAβ mice compared to age-matched NTLs. Vessel staining with CD31 immunohistochemistry confirmed a reduction of microvessel density in the old arcAβ mice. We further demonstrated a region- specific association between parenchymal and vascular deposition of β-amyloid and decreased vascular density, without a correlation with the amount of Aβ deposition. We found that Q mapping was more suitable than the hemodynamic read-outs to detect amyloid-related degeneration of the cerebral microvasculature

Longitudinal resting-state functional magnetic resonance imaging in a mouse model of metastatic bone cancer reveals distinct functional reorganizations along a developing chronic pain state

Functional neuroimaging has emerged as attractive option for characterizing pain states complementing behavioral readouts or clinical assessment. In particular, resting-state functional magnetic resonance imaging (rs-fMRI) enables monitoring of functional adaptations across the brain, for example, in response to chronic nociceptive input. We have used rs-fMRI in a mouse model of chronic pain from breast cancer-derived tibial bone metastases to identify pain-induced alterations in functional connectivity. Combined assessment of behavioral readouts allowed for defining a trajectory as model function for extracting pain-specific functional connectivity changes from the fMRI data reflective of a chronic pain state. Cingulate and prefrontal cortices as well as the ventral striatum were identified as predominantly affected regions, in line with findings from clinical and preclinical studies. Inhibition of the peripheral bone remodeling processes by antiosteolytic therapy led to a reduction of pain-induced network alterations, emphasizing the specificity of the functional readouts for a developing chronic pain state

Prospective Administration of Anti-NGF Treatment Effectively Suppresses Functional Connectivity Alterations Following Cancer-Induced Bone Pain in Mice

Cancer-induced bone pain is abundant among advanced stage cancer patients and arises from a primary tumor in the bone or skeletal metastasis of common cancer types such as breast, lung or prostate cancer. Recently, antibodies targeting nerve growth factor (NGF) have been shown to effectively relieve neuropathic and inflammatory pain states in mice and in humans. While efficacy has been shown in mice on a behavioral level, effectiveness in preventing pain-induced functional rearrangements in the central nervous system has not been shown. Therefore we assessed longitudinal whole-brain functional connectivity using resting-state fMRI in a mouse model of cancer-induced bone pain. We found functional connectivity between major hubs of ascending and descending pain pathways such as the periaqueductal gray, amygdala, thalamus as well as cortical somatosensory regions to be affected by a developing cancer pain state. These changes could be successfully prevented through prospective administration of a monoclonal anti-NGF antibody (mAb911). This indicates efficacy of anti-NGF treatment to prevent pain-induced adaptations in brain functional networks following persistent nociceptive input from cancer-induced bone pain. Additionally, it highlights the suitability of resting-state fMRI readouts as an indicator of treatment response on the basis of longitudinal functional network changes

An in vivo wound healing model for the characterization of the angiogenic process and its modulation by pharmacological interventions

Angiogenesis during wound healing is essential for tissue repair and also affected during cancer treatment by anti-angiogenic drugs. Here, we introduce a minimally invasive wound healing model in the mouse ear to assess angiogenesis with high spatiotemporal resolution in a longitudinal manner in vivo using two-photon microscopy in mice expressing GCaMP2 in arterial endothelial cells. The development of vascular sprouts occurred in a highly orchestrated manner within a time window of 8 days following wounding. Novel sprouts developed exclusively from the distal stump of the transsected arteries, growing towards the proximal arterial stump. This was in line with the incidence of Ca2+ transients in the arterial endothelial cells, most probably a result of VEGF stimulation, which were more numerous on the distal part. Functional analysis revealed perfusion across the wound site via arterial sprouts developed between days 6 and 8 following the incision. At day 8, proximal and distal arteries were structurally and functionally connected, though only 2/3 of all sprouts detected were actually perfused. Treatment with the FDA approved drug, sunitinib, the preclinical drug AZD4547, as well as with the combination of the two agents had significant effects on both structural and functional readouts of neo-angiogenesis. The simplicity and high reproducibility of the model makes it an attractive tool for elucidating migratory activity, phenotype and functionality of endothelial cells during angiogenesis and for evaluating specific anti-angiogenic drug interventions.ISSN:2045-232