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The optimal treatment for patients with asymptomatic carotid artery stenosis is under debate. Since best medical treatment (BMT) has improved over time, the benefit of carotid endarterectomy (CEA) or carotid artery stenting (CAS) is unclear. Randomised data comparing the effect of CEA and CAS versus BMT alone are absent. We aimed to directly compare CEA plus BMT with CAS plus BMT and both with BMT only.SPACE-2 was a multicentre, randomised, controlled trial at 36 study centres in Austria, Germany, and Switzerland. We enrolled participants aged 50-85 years with asymptomatic carotid artery stenosis at the distal common carotid artery or the extracranial internal carotid artery of at least 70%, according to European Carotid Surgery Trial criteria. Initially designed as a three-arm trial including one group for BMT alone (with a randomised allocation ratio of 2·9:2·9:1), the SPACE-2 study design was amended (due to slow recruitment) to become two substudies with two arms each comparing CEA plus BMT with BMT alone (SPACE-2a) and CAS plus BMT with BMT alone (SPACE-2b); in each case in a 1:1 randomisation. Participants and clinicians were not masked to allocation. The primary efficacy endpoint was the cumulative incidence of any stroke or death from any cause within 30 days or any ipsilateral ischaemic stroke within 5 years. The primary safety endpoint was any stroke or death from any cause within 30 days after CEA or CAS. The primary analysis was by intention-to treat, which included all randomly assigned patients in SPACE-2, SPACE-2a, and SPACE-2b, analysed using meta-analysis of individual patient data. We did two-step hierarchical testing to first show superiority of CEA and CAS to BMT alone then to assess non-inferiority of CAS to CEA. Originally, we planned to recruit 3640 patients; however, the study had to be stopped prematurely due to insufficient recruitment. This report presents the primary analysis at 5-year follow-up. This trial is registered with ISRCTN, number ISRCTN78592017.513 patients across SPACE-2, SPACE-2a, and SPACE-2b were recruited and surveyed between July 9, 2009, and Dec 12, 2019, of whom 203 (40%) were allocated to CEA plus BMT, 197 (38%) to CAS plus BMT, and 113 (22%) to BMT alone. Median follow-up was 59·9 months (IQR 46·6-60·0). The cumulative incidence of any stroke or death from any cause within 30 days or any ipsilateral ischaemic stroke within 5 years (primary efficacy endpoint) was 2·5% (95% CI 1·0-5·8) with CEA plus BMT, 4·4% (2·2-8·6) with CAS plus BMT, and 3·1% (1·0-9·4) with BMT alone. Cox proportional-hazard testing showed no difference in risk for the primary efficacy endpoint for CEA plus BMT versus BMT alone (hazard ratio [HR] 0·93, 95% CI 0·22-3·91; p=0·93) or for CAS plus BMT versus BMT alone (1·55, 0·41-5·85; p=0·52). Superiority of CEA or CAS to BMT was not shown, therefore non-inferiority testing was not done. In both the CEA group and the CAS group, five strokes and no deaths occurred in the 30-day period after the procedure. During the 5-year follow-up period, three ipsilateral strokes occurred in both the CAS plus BMT and BMT alone group, with none in the CEA plus BMT group.CEA plus BMT or CAS plus BMT were not found to be superior to BMT alone regarding risk of any stroke or death within 30 days or ipsilateral stroke during the 5-year observation period. Because of the small sample size, results should be interpreted with caution.German Federal Ministry of Education and Research (BMBF) and German Research Foundation (DFG).

Background and purpose Gadolinium leakage in ocular structures (GLOS) on fluid attenuated inversion recovery images (FLAIR) is a novel imaging marker in acute ischemic stroke and other neurological disorders. Methods In patients with transient neurovascular symptoms who underwent repeated MRI with intravenous contrast agent administration, the presence of acute ischemic lesions on diffusion-weighted images (DWI) as well as the frequency and pattern of blood-brain barrier and blood-retina barrier impairment as demonstrated by the hyperintense acute reperfusion marker (HARM) and GLOS respectively on postcontrast FLAIR were evaluated. Results Overall 28 patients with transient neurovascular symptoms (median age 70.5 years; 18 (64.3%) male) were included. Follow-up MRI was performed within 35 (IQR 21–47) hours after the initial MRI. On DWI, acute ischemic lesions were observed in 22 (78.6%). On contrast-enhanced FLAIR, GLOS was observed in 12 (42.9%) patients: in 1 (3.6%) only in the anterior chamber, and in 11 (39.3%) in the anterior chamber and vitreous body. HARM was observed in 3 (10.7%) patients. In one patient without ischemic lesion on DWI or HARM on FLAIR, GLOS was observed in the anterior chamber and vitreous body. Presence of GLOS was associated with higher age (p = 0.04) and detection of HARM (p = 0.03). Conclusions In patients with transient neurovascular symptoms, GLOS is a frequent finding and associated with HARM on contrast-enhanced FLAIR. As GLOS was observed in one patient without an ischemic lesion or HARM, it might be useful as an additional imaging marker.

Patient-derived xenograft (PDX) models have emerged as versatile preclinical platforms for investigation of functional pathomechanisms in myelodysplastic syndromes (MDS) and other myeloid neoplasms. However, despite increasingly improved methodology, engraftment efficiencies frequently remain low. Humanized three-dimensional scaffold models (ossicle xenotransplantation models) in immunocompromised mice have recently been found to enable improved engraftment rates of healthy and malignant human hematopoiesis. We therefore interrogated the feasibility of using four different three-dimensional ossicle-based PDX models for application with primary MDS samples. In a fully standardized comparison, we evaluated scaffold materials such as Gelfoam, extracellular matrix (ECM), and human or xenogenous bone substance in comparison to intrafemoral (IF) co-injection of bone marrow (BM)-derived mesenchymal stromal cells (MSCs) and CD34

Despite the proven benefit of stent retrievers, challenges to rapid revascularization of large vessel occlusions (LVO) persist. Current stent retrievers have limited effectiveness for removing organized thrombi. The NeVa device is a novel stent retriever designed with openings in the basket cell structure (“drop zones”) intended to capture organized thrombi within the central scaffold during retrieval. Prospective, multicenter, open label, single arm, FDA-regulated IDE study to evaluate the performance of the NeVa device for recanalizing occluded intracranial vessels including ICA, M1/M2 MCA, and vertebrobasilar arteries, within 8 hours of onset. Primary endpoint was rate of eTICI 2b-3 within 3 NeVa passes, tested for non-inferiority against a performance goal of 72% with a margin of -10%. Additional efficacy endpoints included first pass effect to eTICI 2b-3 (FPE) and 90-day mRS 0-2. Primary safety endpoint was 90-day mortality. (ClinicalTrials.gov NCT04514562) (Site-adjudicated revascularization results are reported here. Final core lab results will be presented at the conference.) From April 1, 2021 to April 28, 2022, 139 subjects were enrolled at 25 centers in the US and Europe. Mean age was 67 ± 13 years; 47% were female. Median NIHSS score was 16 (IQR: 12-20). Occlusions were 14 (10%) ICA, 85 (61%) M1, 38 (27%) M2, 1 (1%) Basilar and 1 (1%) PCA. Mean time to first pass was 19 ± 12 minutes. eTICI 2b-3 within 3 NeVa passes occurred in 87.8% (122/139; CI 81.1%,92.7%; non-inferiority p

Background/aim Sodium (23Na) MR imaging is a noninvasive MRI technique that has been shown to be sensitive to visualize biochemical information about tissue viability, their cell integrity, and cell function in various studies. The aim of this study was to evaluate differences in regional brain 23Na signal intensity between Alzheimer's disease (AD) and healthy controls to preliminarily evaluate the capability of 23Na imaging as a biomarker for AD. Patients and methods A total of 14 patients diagnosed with AD were included: 12 in the state of dementia and 2 with mild cognitive impairment (MCI), and 12 healthy controls (HC); they were all scanned on a 3T clinical scanner with a double tuned 1H/23Na birdcage head coil. After normalizing the signal intensity with that of the vitreous humor, relative tissue sodium concentration (rTSC) was measured after automated segmentation in the hippocampus, amygdala, basal ganglia, white matter (WM) and grey matter (GM) in both cerebral hemispheres. Results Patients with AD showed a significant increase in rTSC in comparison to healthy controls in the following brain regions: WM 13.6%; p=0.007, hippocampus 12.9%; p=0.003, amygdala 18.9%; p=0.0007. Conclusion 23Na-MRI has the potential to be developed as a useful biomarker for the diagnosis of AD.

Data on sepsis in patients with a subarachnoid hemorrhage (SAH) are scarce. We assessed the impact of different sepsis criteria on the outcome in an SAH cohort. Adult patients admitted to our ICU with a spontaneous SAH between 11/2014 and 11/2018 were retrospectively included. In patients developing an infection, different criteria for sepsis diagnosis (Sepsis-1, Sepsis-3_original, Sepsis-3_modified accounting for SAH-specific therapy, alternative sepsis criteria compiled of consensus conferences) were applied and their impact on functional outcome using the modified Rankin Scale (mRS) on hospital discharge and in-hospital mortality was evaluated. Of 270 SAH patients, 129 (48%) developed an infection. Depending on the underlying criteria, the incidence of sepsis and septic shock ranged between 21–46% and 9–39%. In multivariate logistic regression, the Sepsis-1 criteria were not associated with the outcome. The Sepsis-3 criteria were not associated with the functional outcome, but in shock with mortality. Alternative sepsis criteria were associated with mortality for sepsis and in shock with mortality and the functional outcome. While Sepsis-1 criteria were irrelevant for the outcome in SAH patients, septic shock, according to the Sepsis-3 criteria, adversely impacted survival. This impact was higher for the modified Sepsis-3 criteria, accounting for SAH-specific treatment. Modified Sepsis-3 and alternative sepsis criteria diagnosed septic conditions of a higher relevance for outcomes in patients with an SAH.

Background The appropriate management of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) remains uncertain. We aimed to evaluate the effect of implementing a standardized protocol for detection and management of DCI after aSAH on cerebral infarction and functional outcome. Methods We studied two cohorts of aSAH patients, one before (pre-implementation cohort: January 2012 to August 2014) and one after (post-implementation cohort: January 2016 to July 2018) implementation of a multidisciplinary approach, with standardized neurological and radiological assessment and risk-based medical treatment of DCI. We assessed the presence of new hypodensities on CT within 6 weeks after aSAH and categorized cerebral infarction into overall and DCI-related infarctions (hypodensities not within 48 h after IA repair and not attributable to aneurysm occlusion or intraparenchymal hematoma). Functional outcome was assessed at 3 months using the extended Glasgow outcome scale (eGOS), dichotomized into unfavorable (eGOS: 1–5) and favorable (eGOS: 6–8). We calculated odds ratios (OR) with corresponding 95% confidence intervals (CI’s), and adjusted for age, WFNS grade, Fisher score, and treatment modality (aOR). Results In the post-implementation (n = 158) versus the pre-implementation (n = 143) cohort the rates for overall cerebral infarction were 29.1% vs 46.9% (aOR: 0.41 [0.24–0.69]), for DCI-related cerebral infarction 17.7% vs. 31.5% (aOR: 0.41 [0.23–0.76]), and for unfavorable functional outcome at 3 months 37.3% vs. 53.8% (aOR: 0.30 [0.17–0.54]). For patients with DCI, the rates for unfavorable functional outcomes at 3 months in the post-implementation versus the pre-implementation cohort were 42.3% vs. 77.8% (aOR: 0.1 [0.03–0.27]). Conclusions A multidisciplinary approach with more frequent and standardized neurological assessment, standardized CT and CT perfusion monitoring, as well as tailored application of induced hypertension and invasive rescue therapy strategies, is associated with a significant reduction of cerebral infarction and unfavorable functional outcome after aneurysmal aSAH.

Background/Aim: Various neurological disorders are associated with lesions predominantly or exclusively affecting the splenium of the corpus callosum (CC), such as Marchiafava-Bignami syndrome (MBS), reversible splenium lesion (RSL), and ischemic stroke (IS). The spectrum of symptoms is broad and clinical presentations may be indistinguishable. Therefore, we aimed to investigate the additional value of diffusion-weighted imaging (DWI) findings of splenial lesions in patients with MBS, RSL, and IS. Patients and Methods: Overall, 23 patients (4 patients with MBS, 10 patients with RSL, and 9 patients with isolated IS in the splenium) were identified from a magnetic resonance imaging report database and analyzed with focus on lesion localization, shape, and size on DWI, as well as relative apparent diffusion coefficient (ADC). Results: A focal hyperintensity in the splenium was observed on DWI in all patients. In MBS symmetrical boomerang-shaped lesions, in RSL central oval or round lesions, and in IS eccentric irregular lesions in the splenium were found. The median lesion size in MBS [6.25 (IQR=2.04-8.62) ml] was significantly larger than that in RSL [0.38 (IQR=0.09-0.92) ml, p=0.01], and in IS [0.09 (IQR=0.05-0.94) ml; p=0.01]. Regarding relative ADC values, no significant differences between MBS [0.32 (IQR=0.19-0.62)], RSL [0.22 (IQR=0.14-0.30)], and IS [0.27 (IQR=0.20-1.19)] were found. Conclusion: Diffusion restricted lesions in the splenium of the CC are best classified by localization, shape, and size, whereas relative ADC values are of limited value for differentiation of different neurological disorders.

BackgroundFilament perforation is a widely-used method to induce subarachnoid hemorrhage (SAH) in mice. Whereas the perforation site has been assumed to be in the branching of middle cerebral artery (MCA) and anterior cerebral artery (ACA), we recently observed more proximal perforations.MethodsFilament perforation was performed in CD1- (n = 10) and C57Bl/6N-mice (n = 9) ex vivo. The filament was left in place and the perforation site was microscopically assessed. Digital subtraction angiography (DSA) was performed in CD1- (n = 9) and C57Bl/6J-mice (n = 29) and anatomical differences of the internal carotid artery (ICA) were determined.ResultsWhereas in C57Bl/6N-mice perforation occurred in the proximal intracranial ICA in 89% (n = 8), in CD1-mice the perforation site was in the proximal ICA in 50% (n = 5), in the branching between MCA and ACA in 40% (n = 4), and in the proximal ACA in 10% (n = 1). DSA revealed a stronger angulation (pweight/angle= 0.757) and CD1-mice (r = -0.468, pweight/angle= 0.242).ConclusionFilament perforation in mice occurs not only at the hitherto presumed branching between MCA and ACA, but seems to depend on mouse strain and anatomy as the proximal intracranial ICA may also be perforated frequently.

IgG4‐related disease (IgG4‐RD) is a fibroinflammatory disorder signified by aberrant infiltration of IgG4‐restricted plasma cells into a variety of organs. Clinical presentation is heterogeneous, and pathophysiological mechanisms of IgG4‐RD remain elusive. There are very few cases of IgG4‐RD with isolated central nervous system manifestation. By leveraging single‐cell sequencing of the cerebrospinal fluid (CSF) of a patient with an inflammatory intracranial pseudotumor, we provide novel insights into the immunopathophysiology of IgG4‐RD. Our data illustrate an IgG4‐RD‐associated polyclonal T‐cell response in the CSF and an oligoclonal T‐cell response in the parenchymal lesions, the latter being the result of a multifaceted cell–cell interaction between immune cell subsets and pathogenic B cells. We demonstrate that CD8+ T effector memory cells might drive and sustain autoimmunity via macrophage migration inhibitory factor (MIF)‐CD74 signaling to immature B cells and CC‐chemokine ligand 5 (CCL5)‐mediated recruitment of cytotoxic CD4+ T cells. These findings highlight the central role of T cells in sustaining IgG4‐RD and open novel avenues for targeted therapies., This translational study demonstrates the potential of single‐cell profiling technologies to support clinicians in the diagnosis of rare autoimmune disorders while shedding new light into potential molecular pathomechanisms of intercellular communication in IgG4‐related disease.

Summary Background Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. Methods ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. Findings Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86–1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91–1·32; p=0·21). Interpretation Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable. Funding UK Medical Research Council and Health Technology Assessment Programme.

Longitudinal in vivo imaging studies characterizing subarachnoid hemorrhage (SAH)-induced large artery vasospasm (LAV) in mice are lacking. We developed a SAH-scoring system to assess SAH severity in mice using micro CT and longitudinally analysed LAV by intravenous digital subtraction angiography (i.v. DSA). Thirty female C57Bl/6J-mice (7 sham, 23 SAH) were implanted with central venous ports for repetitive contrast agent administration. SAH was induced by filament perforation. LAV was assessed up to 14 days after induction of SAH by i.v. DSA. SAH-score and neuroscore showed a highly significant positive correlation (rsp = 0.803, p sp = −0.71, p max = 30.5%, p max = 21.2%, p = 0.014), middle cerebral (Δmax = 28.16%, p max = 23.49%, p Pe = −0.54, p = 0.04). Arterial diameter of the left MCA correlated negatively with cerebral perfusion on day 3 (rPe = −0.72, p = 0.005). In addition, pseudoaneurysms arising from the filament perforation site were visualized in three mice using i.v. DSA. Thus, micro-CT and DSA are valuable tools to assess SAH severity and to longitudinally monitor LAV in living mice.

The Apidima 2 fossil cranium from South Peloponnese is one of the most important hominin specimens from Southeast Europe. Nevertheless, there has been continuous controversy as to whether it represents a so-called Preneandertal/Homo heidelbergensis such as, for example, the Petralona cranium from Northern Greece or a more derived Neandertal. Recent absolute dating evidence alone cannot clarify the issue because both classifications would be possible during the respective Middle Pleistocene time span. Since only limited data were available on the cranium, there have been repeated claims for the need of a broader comparative study of the hominin. The present article presents a CT-based virtual reconstruction including corrections of postmortem fractures and deformation as well as detailed metrical and morphological analyses of the specimen. Endocranial capacity could be estimated for the first time based on virtual reconstruction. Our multivariate analyses of metric data from the face and vault revealed close affinities to early and later Neandertals, especially showing the derived facial morphometrics. In addition, comparative analyses of Apidima 2 were done for many derived Neandertal features. Here again, a significant number of Neandertal features could be found in the Apidima cranium but no conditions common in Preneandertals. In agreement with a later Middle Pleistocene age Apidima is currently the earliest evidence of a hominin in Europe with such a derived Neandertal facial morphology. The place of Apidima in the complex process of Neandertal evolution as well as its taxonomic classification are discussed as well. Anat Rec, 303:1374-1392, 2020. © 2019 American Association for Anatomy.

Gadolinium leakage in ocular structures (GLOS) on fluid-attenuated inversion recovery images (FLAIR) is a novel imaging marker in acute ischemic stroke. The present study sought to investigate the frequency and pattern of blood-retina barrier impairment in acute ischemic stroke due to internal carotid artery (ICA) stenosis or occlusion as demonstrated by GLOS. From a magnetic resonance imaging (MRI) report database patients were identified with acute ischemic stroke due to ICA stenosis/occlusion who underwent repeated MRI with intravenous contrast agent administration and FLAIR and MR angiography (MRA). On FLAIR the presence of GLOS was noted in the vitreous body. Overall 51 patients with a median age of 70 years (interquartile range, IQR 63–77 years) were included. Of these, 22 (43.1%) patients had an ICA stenosis and 29 (56.9%) an ICA occlusion. On contrast-enhanced FLAIR, GLOS was observed in 29 (56.9%) patients: in 7 (13.7%) unilateral, in 15 (68.2%) bilateral asymmetrical and in 7 (31.8%) bilateral symmetrical. In unilateral asymmetrical GLOS, more pronounced enhancement was always found ipsilateral to ICA stenosis/occlusion. In 4 (5.9%) patients with asymmetrical GLOS a pre-existing signal increase in the vitreous body was found on native FLAIR. The presence of GLOS was associated with an impaired collateralization through the circle of Willis (p

Gliomatosis cerebri (GC) is a rare growth pattern of glioblastoma whose diffuse nature is reflected by unspecific, relatively uniform findings on conventional MRI. In the present study we sought to evaluate the additional value of diffusion (DWI) and perfusion weighted (PWI) MRI for a more detailed characterization. We analyzed the MRI findings in patients with histologically proven glioblastoma with GC growth pattern with a specific emphasis on T2 lesion pattern, volume, relative apparent diffusion coefficient (rACD), and relative cerebral blood volume (rCBV) and compared these to age-/gender-matched patients with localized glioblastoma. Overall, 16 patients (median age 59.5 years, 4 male) were included in the study. Of these, 8 patients had a glioblastoma with GC growth pattern, and 8 a classical localized growth pattern. While the median rADC (1.27 [IQR 1.12–1.41]) within the T2 lesion was significant lower in glioblastoma with GC growth pattern compared to localized glioblastoma (1.74 [IQR 1.45–1.96]; p = 0.003), the median T2 lesion volume and rCBV within the T2 lesion did not differ significantly. Furthermore, six patients with glioblastoma with GC growth pattern showed focal areas with significantly reduced rADC (p = 0.043), and/or increased rCBV (p = 0.028). Lower rADC in glioblastoma with GC growth pattern might reflect the diffuse tumor cell infiltration whereas focal areas with decreased rADC and/or increased rCBV probably indicate high tumor cell density and/or abnormal tumor vessels which may be useful for biopsy guidance.

Cells of the monocyte macrophage lineage form multinucleated giant cells (GCs) by fusion, which may express some cell cycle markers. By using a comprehensive marker set, here we looked for potential replication activities in GCs, and investigated whether these have diagnostic or clinical relevance in giant cell tumor of bone (GCTB). GC rich regions of 10 primary and 10 first recurrence GCTB cases were tested using immunohistochemistry in tissue microarrays. The nuclear positivity rate of the general proliferation marker, replication licensing, G1/S-phase, S/G2/M-phase, mitosis promoter, and cyclin dependent kinase (CDK) inhibitor reactions was analyzed in GCs. Concerning Ki67, moderate SP6 reaction was seen in many GC nuclei, while B56 and Mib1 positivity was rare, but the latter could be linked to more aggressive (p = 0.012) phenotype. Regular MCM6 reaction, as opposed to uncommon MCM2, suggested an initial DNA unwinding. Early replication course in GCs was also supported by widely detecting CDK4 and cyclin E, for the first time, and confirming cyclin D1 upregulation. However, post-G1-phase markers CDK2, cyclin A, geminin, topoisomerase-2a, aurora kinase A, and phospho-histone H3 were rare or missing. These were likely silenced by upregulated CDK inhibitors p15INK4b, p16INK4a, p27KIP1, p53 through its effector p21WAF1 and possibly cyclin G1, consistent with the prevention of DNA replication. In conclusion, the upregulation of known and several novel cell cycle progression markers detected here clearly verify early replication activities in GCs, which are controlled by cell cycle arresting CDK inhibitors at G1 phase, and support the functional maturation of GCs in GCTB.

Background Crossed cerebellar diaschisis (CCD) is a phenomenon with depressed metabolism and hypoperfusion in the cerebellum. Using arterial spin-labelling perfusion weighted magnetic resonance imaging (ASL PWI), we investigated the frequency of CCD in patients with Alzheimer's disease (AD) and differences between patients with and without CCD. Patients and methods In patients with AD who underwent a standardized magnetic resonance imaging including ASL PWI cerebral blood flow was evaluated in the cerebellum, and brain segmentation/volumetry was performed using mdbrain (mediaire GmbH, Berlin, Germany) and FSL FIRST (Functional Magnetic Resonance Imaging of the Brain Software Library). Results In total, 65 patients were included, and 22 (33.8%) patients were assessed as being CCD-positive. Patients with CCD had a significantly smaller whole brain volume (862.8±49.9 vs. 893.7±62.7 ml, p=0.049) as well as white matter volume (352.9±28.0 vs. 374.3±30.7, p=0.008) in comparison to patients without CCD. Conclusion It was possible to detect CCD by ASL PWI in approximately one-third of patients with AD and was associated with smaller whole brain and white matter volume.

Computer-assisted reporting (CAR) tools were suggested to improve radiology report quality by context-sensitively recommending key imaging biomarkers. However, studies evaluating machine learning (ML) algorithms on cross-lingual ontological (RadLex) mappings for developing embedded CAR algorithms are lacking. Therefore, we compared ML algorithms developed on human expert-annotated features against those developed on fully automated cross-lingual (German to English) RadLex mappings using 206 CT reports of suspected stroke. Target label was whether the Alberta Stroke Programme Early CT Score (ASPECTS) should have been provided (yes/no:154/52). We focused on probabilistic outputs of ML-algorithms including tree-based methods, elastic net, support vector machines (SVMs) and fastText (linear classifier), which were evaluated in the same 5 × fivefold nested cross-validation framework. This allowed for model stacking and classifier rankings. Performance was evaluated using calibration metrics (AUC, brier score, log loss) and -plots. Contextual ML-based assistance recommending ASPECTS was feasible. SVMs showed the highest accuracies both on human-extracted- (87%) and RadLex features (findings:82.5%; impressions:85.4%). FastText achieved the highest accuracy (89.3%) and AUC (92%) on impressions. Boosted trees fitted on findings had the best calibration profile. Our approach provides guidance for choosing ML classifiers for CAR tools in fully automated and language-agnostic fashion using bag-of-RadLex terms on limited expert-labelled training data.

Background and purpose To date, treatment response to stereotactic radiosurgery (SRS) in brain metastases (BM) can only be determined by MRI evaluation of contrast-enhancing lesions in a long-time follow-up. Sodium MRI has been a subject of immense interest in imaging research as the measure of tissue sodium concentration (TSC) can give valuable quantitative information on cell viability. We aimed to analyze the longitudinal changes of TSC in BM measured with 23 Na MRI before and after SRS for assessment of early local tumor effects. Methods Seven patients with a total of 12 previously untreated BM underwent SRS with 22 Gy. In addition to a standard MRI protocol including dynamic susceptibility-weighted contrast-enhanced perfusion, a 23 Na MRI was performed at three time points: (I) 2 days before, (II) 5 days, and (III) 40 days after SRS. Nine BMs were evaluated. The absolute TSC in the BM, the respective peritumoral edemas, and the normal-appearing corresponding contralateral brain area were assessed and the relative TSC were correlated to the changes in BM longest axial diameters. Results TSC was elevated in nine BM at baseline before SRS with a mean of 73.4 ± 12.3 mM. A further increase in TSC was observed 5 days after SRS in all the nine BM with a mean of 86.9 ± 13 mM. Eight of nine BM showed a mean 60.6 ± 13.3% decrease in the longest axial diameter 40 days after SRS; at this time point, the TSC also had decreased to a mean 65.1 ± 7.9 mM. In contrast, one of the nine BM had a 13.4% increase in the largest axial diameter at time point III. The TSC of this BM showed a further TSC increase of 80.1 mM 40 days after SRS. Conclusion Changes in TSC using 23 Na MRI shows the possible capability to detect radiobiological changes in BM after SRS.

Within the bone marrow microenvironment, endothelial cells (EC) exert important functions. Arterial EC support hematopoiesis while H-type capillaries induce bone formation. Here, we show that BM sinusoidal EC (BM-SEC) actively control erythropoiesis. Mice with stabilized β-catenin in BM-SEC (Ctnnb1OE-SEC) generated by using a BM-SEC-restricted Cre mouse line (Stab2-iCreF3) develop fatal anemia. While activation of Wnt-signaling in BM-SEC causes an increase in erythroblast subsets (PII–PIV), mature erythroid cells (PV) are reduced indicating impairment of terminal erythroid differentiation/reticulocyte maturation. Transplantation of Ctnnb1OE-SEC hematopoietic stem cells into wildtype recipients confirms lethal anemia to be caused by cell-extrinsic, endothelial-mediated effects. Ctnnb1OE-SEC BM-SEC reveal aberrant sinusoidal differentiation with altered EC gene expression and perisinusoidal ECM deposition and angiocrine dysregulation with de novo endothelial expression of FGF23 and DKK2, elevated in anemia and involved in vascular stabilization, respectively. Our study demonstrates that BM-SEC play an important role in the bone marrow microenvironment in health and disease., Niche crosstalk with Haematopoietic cells underlies normal haematopoiesis and myeloid disorders. Here the authors report a Stabilin2-Cre driver mouse with Cre-activity restricted to bone marrow sinusoidal endothelial cells, and that Stabilin2-Cre driven overactivation of b-catenin leads to erythroid differentiation defects and anaemia.

Background/Aim: Sodium ((23)Na) MR imaging is a noninvasive MRI technique that has been shown to be sensitive to visualize biochemical information about tissue viability, their cell integrity, and cell function in various studies. The aim of this study was to evaluate differences in regional brain (23)Na signal intensity between Alzheimer’s disease (AD) and healthy controls to preliminarily evaluate the capability of (23)Na imaging as a biomarker for AD. Patients and Methods: A total of 14 patients diagnosed with AD were included: 12 in the state of dementia and 2 with mild cognitive impairment (MCI), and 12 healthy controls (HC); they were all scanned on a 3T clinical scanner with a double tuned (1)H/(23)Na birdcage head coil. After normalizing the signal intensity with that of the vitreous humor, relative tissue sodium concentration (rTSC) was measured after automated segmentation in the hippocampus, amygdala, basal ganglia, white matter (WM) and grey matter (GM) in both cerebral hemispheres. Results: Patients with AD showed a significant increase in rTSC in comparison to healthy controls in the following brain regions: WM 13.6%; p=0.007, hippocampus 12.9%; p=0.003, amygdala 18.9%; p=0.0007. Conclusion: (23)Na-MRI has the potential to be developed as a useful biomarker for the diagnosis of AD.

Background and Purpose— We investigated the frequency and pattern of blood-brain barrier, as well as blood-retina barrier, impairment in acute lacunar infarction as demonstrated by hyperintense acute reperfusion marker and gadolinium leakage in ocular structures (GLOS), respectively, on fluid-attenuated inversion recovery images. Methods— Acute lacunar infarction patients who underwent repeated magnetic resonance imaging after intravenous contrast agent administration were identified and the presence of GLOS in the anterior chamber and vitreous body and hyperintense acute reperfusion marker noted on fluid-attenuated inversion recovery. Results— Overall, 24 acute lacunar infarction patients (median age 64.5 years; interquartile range, 54–78 years) were included. On contrast-enhanced fluid-attenuated inversion recovery, GLOS was observed in 11 (45.8%) patients: in 4 (16.7%) in the anterior chamber only and in 7 (29.2%) in the anterior chamber and vitreous body. In all patients, GLOS was bilateral and symmetrical. In patients with GLOS in the anterior chamber only, the time between initial and follow-up magnetic resonance imaging was significantly shorter (7.5 [interquartile range, 4.25–11.5] hours) compared with patients with GLOS in the anterior chamber and vitreous body (28 [interquartile range, 10–43] hours; P =0.047). Hyperintense acute reperfusion marker could not be demonstrated in any of the patients. Conclusions— In acute lacunar infarction patients, unlike hyperintense acute reperfusion marker, GLOS is a frequent finding and shows a similar temporal evolution like in larger ischemic stroke.

Background and Purpose— Cerebral microbleeds (cMBs) have previously been linked with especially high incidence in Asian patients with moyamoya together with high tendency to bleed. This, presumably, is characteristic of patients with moyamoya. Herein, we, therefore, investigate retrospectively the frequency, location, and longitudinal course of cMBs in a large German cohort. Methods— We included all patients with moyamoya who underwent standard magnetic resonance imaging, including T2*-weighted images, in our department between 1998 and 2015. Two independent readers evaluated magnetic resonance imaging scans to determine the occurrence of cMBs according to the Brain Observer Microbleed Scale. Demographics, initial symptoms leading to hospitalization, and associated diseases were obtained by chart review. Results— Overall, there was a total of 242 T2* studies of 101 included moyamoya patients available with a strong female predominance (69.3%). Eight patients (7.9%) were ≤18 years of age. We detected 25 cMBs within 13 patients (12.9%). One patient Conclusions— Although the frequency of cMBs herein is much higher than the expected age-specific incidence, it is still much lower compared with previous reports on cMBs in moyamoya patients of Asian descent. These results might reflect another ethnic-specific difference in patients diagnosed with moyamoya.

Occlusion or significant stenosis of the internal carotid artery (ICA) in the cervical segment is commonly associated with a poststenotic decrease in the downstream blood flow and perfusion. Fluid attenuated inversion recovery (FLAIR) vascular hyperintensities (FVH) are a phenomenon that represents slow arterial blood flow. In this study, we investigated the frequency and extent of FVH in the distal ICA in patients with proximal ICA stenosis. We analyzed the magnetic resonance imaging (MRI) findings in 51 patients with a total of 60 cervical ICA stenoses with special focus on the frequency and extent of FVH in the area of the petrous segment of the ICA on FLAIR images and correlated these with Doppler/duplex sonography results. In 46 (76.7%) patients with ICA stenosis, FVH could be detected in the petrous segment of the ICA: in 19 (41.3%) patients a thin hyperintense rim near the vessel wall (grade 1), in 24 (52.2%) patients a strong hyperintense rim near the vessel wall (grade 2), and in 3 (6.5%) patients a hyperintense filling of the entire lumen (grade 3) was observed. The extent of FVH in the ICA in the petrous segment showed a high negative correlation with the poststenotic flow velocity (Spearman correlation, R = –0.75, p