Ischemic stroke is the most common cerebrovascular disease, and its diagnosis, treatment, and study relies on non-invasive imaging. Algorithms for stroke lesion segmentation from magnetic resonance imaging (MRI) volumes are intensely researched, but the reported results are largely incomparable due to different datasets and evaluation schemes. We approached this urgent problem of comparability with the Ischemic Stroke Lesion Segmentation (ISLES) challenge organized in conjunction with the MICCAI 2015 conference. In this paper we propose a common evaluation framework, describe the publicly available datasets, and present the results of the two sub-challenges: Sub-Acute Stroke Lesion Segmentation (SISS) and Stroke Perfusion Estimation (SPES). A total of 16 research groups participated with a wide range of state-of-the-art automatic segmentation algorithms. A thorough analysis of the obtained data enables a critical evaluation of the current state-of-the-art, recommendations for further developments, and the identification of remaining challenges. The segmentation of acute perfusion lesions addressed in SPES was found to be feasible. However, algorithms applied to sub-acute lesion segmentation in SISS still lack accuracy. Overall, no algorithmic characteristic of any method was found to perform superior to the others. Instead, the characteristics of stroke lesion appearances, their evolution, and the observed challenges should be studied in detail. The annotated ISLES image datasets continue to be publicly available through an online evaluation system to serve as an ongoing benchmarking resource (www.isles-challenge.org).

The development of in vivo imaging protocols to reliably track transplanted cells or to report on gene expression is critical for treatment monitoring in (pre)clinical cell and gene therapy protocols. Therefore, we evaluated the potential of lentiviral vectors (LVs) and adeno-associated viral vectors (AAVs) to express the magnetic resonance imaging (MRI) reporter gene ferritin in the rodent brain. First, we compared the induction of background MRI contrast for both vector systems in immune-deficient and immune-competent mice. LV injection resulted in hypointense (that is, dark) changes of T 2 /T 2 * (spin-spin relaxation time)-weighted MRI contrast at the injection site, which can be partially explained by an inflammatory response against the vector injection. In contrast to LVs, AAV injection resulted in reduced background contrast. Moreover, AAV-mediated ferritin overexpression resulted in significantly enhanced contrast to background on T 2 *-weighted MRI. Although sensitivity associated with the ferritin reporter remains modest, AAVs seem to be the most promising vector system for in vivo MRI reporter gene imaging. Gene Therapy (2011) INTRODUCTIONThe development of non-invasive imaging methods that can reliably report on therapeutic cell transplantation and/or gene expression is a critical step in the establishment of gene therapy protocols, both for clinical and for research applications. Several molecular imaging modalities are available that enable non-invasive and repeated imaging of gene expression in targeted cells in living organisms, thereby reducing the number of laboratory animals and reducing the inter-animal variability at the preclinical level. Among these are radionuclide imaging techniques such as single-photon emission computed tomography (SPECT) and positron emission tomography (PET), optical imaging methods including fluorescence imaging and bioluminescence imaging (BLI), magnetic resonance imaging (MRI) and spectroscopy, ultrasound and X-ray-based methods (for a review, see the studies by Massoud and Gambhir 1 and Deroose et al. 2 ). Apart from optical imaging methods, molecular imaging technologies using these imaging modalities have the advantage of being translatable to a clinical setting.When comparing imaging modalities, BLI, PET and SPECT provide high sensitivity but low resolution, whereas MRI can reach near-cellular resolution, 3-6 which makes MRI ideally suited to provide information on the location and migration of targeted cells in vivo.

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Protocadherins (Pcdhs), a major subfamily of cadherins, play an important role in specific intercellular interactions in development. These molecules are characterized by their unique extracellular domain (EC) with more than 5 cadherin-like repeats, a transmembrane domain (TM) and a variable cytoplasmic domain. PCNS (Protocadherin in Neural crest and Somites), a novel Pcdh in Xenopus, is initially expressed in the mesoderm during gastrulation, followed by expression in the cranial neural crest (CNC) and somites. PCNS has 65% amino acid identity to Xenopus paraxial protocadherin (PAPC) and 42-49% amino acid identity to Pcdh 8 in human, mouse, and zebrafish genomes. Overexpression of PCNS resulted in gastrulation failure but conferred little if any specific adhesion on ectodermal cells. Loss of function accomplished independently with two non-overlapping antisense morpholino oligonucleotides resulted in failure of CNC migration, leading to severe defects in the craniofacial skeleton. Somites and axial muscles also failed to undergo normal morphogenesis in these embryos. Thus, PCNS has essential functions in these two important developmental processes in Xenopus.

Progressive deterioration of social cognition and emotion processing are core symptoms of the behavioral variant of frontotemporal dementia (bvFTD). Here we investigate whether bvFTD is also associated with impaired recognition of static (Experiment 1) and dynamic (Experiment 2) bodily expressions. In addition, we compared body expression processing with processing of static (Experiment 3) and dynamic (Experiment 4) facial expressions, as well as with face identity processing (Experiment 5). The results reveal that bvFTD is associated with impaired recognition of static and dynamic bodily and facial expressions, while identity processing was intact. No differential impairments were observed regarding motion (static vs. dynamic) or category (body vs. face). Within the bvFTD group, we observed a significant partial correlation between body and face expression recognition, when controlling for performance on the identity task. Voxel-Based Morphometry (VBM) analysis revealed that body emotion recognition was positively associated with gray matter volume in a region of the inferior frontal gyrus (pars orbitalis/triangularis). The results are in line with a supramodal emotion recognition deficit in bvFTD.

Multiple sclerosis is a devastating demyelinating disease of the central nervous system (CNS) in which endogenous remyelination, and thus recovery, often fails. Although the cuprizone mouse model allowed elucidation of many molecular factors governing remyelination, currently very little is known about the spatial origin of the oligodendrocyte progenitor cells that initiate remyelination in this model. Therefore, we here investigated in this model whether subventricular zone (SVZ) neural stem/progenitor cells (NSPCs) contribute to remyelination of the splenium following cuprizone-induced demyelination. Experimentally, from the day of in situ NSPC labeling, C57BL/6J mice were fed a 0.2% cuprizone diet during a 4-week period and then left to recover on a normal diet for 8weeks. Two in situ labeling strategies were employed: (i) NSPCs were labeled by intraventricular injection of micron-sized iron oxide particles and then followed up longitudinally by means of magnetic resonance imaging (MRI), and (ii) SVZ NSPCs were transduced with a lentiviral vector encoding the eGFP and Luciferase reporter proteins for longitudinal monitoring by means of in vivo bioluminescence imaging (BLI). In contrast to preceding suggestions, no migration of SVZ NSPC towards the demyelinated splenium was observed using both MRI and BLI, and further validated by histological analysis, thereby demonstrating that SVZ NSPCs are unable to contribute directly to remyelination of the splenium in the cuprizone model. Interestingly, using longitudinal BLI analysis and confirmed by histological analysis, an increased migration of SVZ NSPC-derived neuroblasts towards the olfactory bulb was observed following cuprizone treatment, indicative for a potential link between CNS inflammation and increased neurogenesis.

Prenatal irradiation is known to perturb brain development. Epidemiological studies revealed that radiation exposure during weeks 8–15 of pregnancy was associated with an increased occurrence of mental disability and microcephaly. Such neurological deficits were reproduced in animal models, in which rodent behavioral testing is an often used tool to evaluate radiation-induced defective brain functionality. However, up to now, animal studies suggested a threshold dose of around 0.30 Gray (Gy) below which no behavioral alterations can be observed, while human studies hinted at late defects after exposure to doses as low as 0.10 Gy. Here, we acutely irradiated pregnant mice at embryonic day 11 with doses ranging from 0.10 to 1.00 Gy. A thorough investigation of the dose-response relationship of altered brain function and architecture following in utero irradiation was achieved using a behavioral test battery and volumetric 3D T2-weighted magnetic resonance imaging (MRI). We found dose-dependent changes in cage activity, social behavior, anxiety-related exploration, and spatio-cognitive performance. Although behavioral alterations in low-dose exposed animals were mild, we did unveil that both emotionality and higher cognitive abilities were affected in mice exposed to ≥0.10 Gy. Microcephaly was apparent from 0.33 Gy onwards and accompanied by deviations in regional brain volumes as compared to controls. Of note, total brain volume and the relative volume of the ventricles, frontal and posterior cerebral cortex, cerebellum, and striatum were most strongly correlated to altered behavioral parameters. Taken together, we present conclusive evidence for persistent low-dose effects after prenatal irradiation in mice and provide a better understanding of the correlation between their brain size and performance in behavioral tests.

The transcription factor AP2 (TFAP2) has an important role in regulating gene expression in both epidermis and neural crest cells. In order to further characterize these functions we have used a hormone inducible TFAP2α fusion protein in a Xenopus animal cap assay to identify downstream targets of this factor. The most common pattern comprised genes predominantly expressed in the epidermis. A second group was expressed at high levels in the neural crest, but all of these were also expressed in the epidermis as well as in other tissues in which TFAP2α has not been detected, suggesting modular control involving both TFAP2-dependent and TFAP2-independent components. In addition, a few strongly induced genes did not overlap at all in expression pattern with that of TFAP2α in the early embryo, and were also activated precociously in the experimentally manipulated ectoderm, and thus likely represent inappropriate regulatory interactions. A final group was identified that were repressed by TFAP2α and were expressed in the neural plate. These results provide further support for the importance of TFAP2α in ectoderm development, and also highlight the molecular linkage between the epidermis and neural crest in the Xenopus embryo.