No abstract

95%-CI = 95% confidence interval, COVID-19 = coronavirus disease 2019, FLAIR = fluidattenuated inversion recovery, PCR = polymerase-chain-reaction, rCBF = relative cerebral blood flow, SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2, SWI = susceptibility-weighted imaging.

BACKGROUND AND PURPOSE:CTA is becoming the frontline modality to reveal aneurysms in patients with SAH. However, in about 20% of SAH patients no aneurysm is found. In these cases, intra-arterial DSA is still performed. Our aim was to evaluate whether negative findings on CTA can reliably exclude aneurysms in patients with acute SAH.

A B S T R A C TBackground and aims: Unstable carotid atherosclerosis causes stroke, but methods to identify patients and lesions at risk are lacking. We recently found enrichment of genes associated with calcification in carotid plaques from asymptomatic patients. Here, we hypothesized that calcification represents a stabilising feature of plaques and investigated how macro-calcification, as estimated by computed tomography (CT), correlates with gene expression profiles in lesions. Methods: Plaque calcification was measured in pre-operative CT angiographies. Plaques were sorted into high-and lowcalcified, profiled with microarrays, followed by bioinformatic analyses. Immunohistochemistry and qPCR were performed to evaluate the findings in plaques and arteries with medial calcification from chronic kidney disease patients. Results: Smooth muscle cell (SMC) markers were upregulated in high-calcified plaques and calcified plaques from symptomatic patients, whereas macrophage markers were downregulated. The most enriched processes in high-calcified plaques were related to SMCs and extracellular matrix (ECM) organization, while inflammation, lipid transport and chemokine signaling were repressed. These findings were confirmed in arteries with high medial calcification. Proteoglycan 4 (PRG4) was identified as the most upregulated gene in association with plaque calcification and found in the ECM, SMA+ and CD68+/TRAP + cells. Conclusions: Macro-calcification in carotid lesions correlated with a transcriptional profile typical for stable plaques, with altered SMC phenotype and ECM composition and repressed inflammation. PRG4, previously not described in atherosclerosis, was enriched in the calcified ECM and localized to activated macrophages and smooth muscle-like cells. This study strengthens the notion that assessment of calcification may aid evaluation of plaque phenotype and stroke risk.

Background Imatinib, a tyrosine kinase inhibitor, has been shown to restore blood–brain barrier integrity and reduce infarct size, haemorrhagic transformation and cerebral oedema in stroke models treated with tissue plasminogen activator. We evaluated the safety of imatinib, based on clinical and neuroradiological data, and its potential influence on neurological and functional outcomes. Methods A Phase II randomised trial was performed in patients with acute ischaemic stroke treated with intravenous thrombolysis. A total of 60 patients were randomly assigned to four groups [3 (active) : 1 (control)]; the active treatment groups received oral imatinib for 6 days at three dose levels (400, 600 and 800 mg). Primary outcome was any adverse event; secondary outcomes were haemorrhagic transformation, cerebral oedema, neurological severity on the National Institutes of Health Stroke Scale (NIHSS) at 7 days and at 3 months and functional outcomes on the modified Rankin scale (mRS). Results Four serious adverse events were reported, which resulted in three deaths (one in the control group and two in the 400 mg dose group; one patient in the latter group did not receive active treatment and the other received two doses). Non-serious adverse events were mostly mild, resulting in full recovery. Imatinib ameliorated neurological outcomes with an improvement of 0.6 NIHSS points per 100 mg imatinib (P = 0.02). For the 800 mg group, the mean unadjusted and adjusted NIHSS improvements were 4 (P = 0.037) and 5 points (P = 0.012), respectively, versus controls. Functional independence (mRS 0–2) increased by 18% versus controls (61 vs. 79; P = 0.296). Conclusion This Phase II study showed that imatinib is safe and tolerable, and may reduce neurological disability in patients treated with intravenous thrombolysis after ischaemic stroke. A confirmatory randomised trial is currently underway.