Matrix metalloproteinases (MMPs) are implied in blood-brain barrier degradation and haemorrhagic transformation following ischaemic stroke, but their local relevance in the hyperacute disease phase is unknown. We aimed to examine ultra-early MMP-9 and MMP-2 release into collateral blood vessels, and to assess its prognostic value before therapeutic recanalisation by endovascular thrombectomy (EVT). We report a cross-sectional proof-of-concept study including patients undergoing EVT for large-vessel ischaemic stroke at the University Hospital Würzburg, Germany. We obtained liquid biopsies from the collateral circulation before recanalisation, and systemic control samples. Laboratory workup included quantification of MMP-9 and MMP-2 plasma concentrations by cytometric bead array, immunohistochemical analyses of cellular MMP-9 and MMP-2 expression, and detection of proteolytic activity by gelatine zymography. The clinical impact of MMP concentrations was assessed by stratification according to intracranial haemorrhagic lesions on postinterventional computed tomography (Heidelberg Bleeding Classification, HBC) and early functional outcome (modified Rankin Scale, mRS). We used multivariable logistic regression, receiver-operating-characteristic (ROC) curves, and fixed-level estimates of test accuracy measures to study the prognostic value of MMP-9 concentrations. Between August 3, 2018, and September 16, 2021, 264 matched samples from 132 patients (86 [65.2%] women, 46 [34.8%] men, aged 40-94 years) were obtained. Median (interquartile range, IQR) MMP-9 (279.7 [IQR 126.4-569.6] vs 441 [IQR 223.4-731.5] ng/ml, p < 0.0001) but not MMP-2 concentrations were increased within collateral blood vessels. The median MMP-9 expression level of invading neutrophils was elevated (fluorescence intensity, arbitrary unit: 2276 [IQR 1007-5086] vs 3078 [IQR 1108-7963], p = 0.0018). Gelatine zymography experiments indicated the locally confined proteolytic activity of MMP-9 but not of MMP-2. Pretherapeutic MMP-9 release into stroke-affected brain regions predicted the degree of intracerebral haemorrhages and clinical stroke severity after recanalisation, and independently increased the odds of space-occupying parenchymal haematomas (HBC1c-3a) by 1.54 times, and the odds of severe disability or death (mRS ≥5 at hospital discharge) by 2.33 times per 1000 ng/ml increase. Excessive concentrations of MMP-9 indicated impending parenchymal haematomas and severe disability or death with high specificity. Measurement of MMP-9 within collateral blood vessels is feasible and identifies patients with stroke at risk of major intracerebral haemorrhages and poor outcome before therapeutic recanalisation by EVT, thereby providing evidence of the concept validity of ultra-early local stroke biomarkers. This work was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) and the Interdisciplinary Centre for Clinical Research (IZKF) at the University of Würzburg.

Our aim was to introduce a standardized system for assessing the extent of giant cell arteritis (GCA) on MRI, titled MRVAS (MR Vasculitis Activity score). To obtain a comprehensive view, we used an extensive MRI protocol including cranial vessels and the aorta with its branches. To test reliability, MRI was assessed by 4 readers with different levels of experience. 80 patients with suspected GCA underwent MRI of cranial arteries and the aorta/branches (20 vessel segments). Every vessel was rated dichotomous [inflamed (coded as 1) or not 0], providing a summed score from 0 to 20. Blinded readers (two experienced radiologists [ExR], two inexperienced radiologists [InR]) applied the MRVAS on an individual vessel and an overall level (defined as the highest score of any of the individual vessel scores). To determine interrater agreement, Cohen’s kappa was calculated for pairwise comparison of each reader for individual vessel segments. Intraclass correlation coefficients (ICC) were used for the MRVAS score. Concordance rates were excellent for both sub-cohorts on an individual vessel-based (GCA, ICC, 0.95; and non-GCA, ICC, 0.96) and Overall MRVAS score level (GCA, ICC, 0.96; and non-GCA, ICC, 1.0). Interrater agreement yielded significant concordance (p< 0.001) for all pairs (kappa range 0.78–0.98). No significant differences between ERs and IRs were observed (p= 0.38). The proposed MRVAS score allows standardized scoring of inflammation in GCA and achieved high agreement rates in a prospective setting.

It remains unclear if principal components of the local cerebral stroke immune response can be reliably and reproducibly observed in patients with acute large-vessel-occlusion (LVO) stroke. We prospectively studied a large independent cohort of n = 318 consecutive LVO stroke patients undergoing mechanical thrombectomy during which cerebral blood samples from within the occluded anterior circulation and systemic control samples from the ipsilateral cervical internal carotid artery were obtained. An extensive protocol was applied to homogenize the patient cohort and to standardize the procedural steps of endovascular sample collection, sample processing, and laboratory analyses. N = 58 patients met all inclusion criteria. (1) Mean total leukocyte counts were significantly higher within the occluded ischemic cerebral vasculature (I) vs. intraindividual systemic controls (S): +9.6%, I: 8114/µL ± 529 vs. S: 7406/µL ± 468, p = 0.0125. (2) This increase was driven by neutrophils: +12.1%, I: 7197/µL ± 510 vs. S: 6420/µL ± 438, p = 0.0022. Leukocyte influx was associated with (3) reduced retrograde collateral flow (R² = 0.09696, p = 0.0373) and (4) greater infarct extent (R² = 0.08382, p = 0.032). Despite LVO, leukocytes invade the occluded territory via retrograde collateral pathways early during ischemia, likely compromising cerebral hemodynamics and tissue integrity. This inflammatory response can be reliably observed in human stroke by harvesting immune cells from the occluded cerebral vascular compartment.

Background: It is unknown whether technological advancement of stent-retriever devices influences typical observational indicators of safety or effectiveness. Methods: Observational retrospective study of APERIO® (AP) vs. new generation APERIO® Hybrid (APH) (Acandis®, Pforzheim, Germany) stent-retriever device (01/2019–09/2020) for mechanical thrombectomy (MT) in large vessel occlusion (LVO) stroke. Primary effectiveness endpoint was successful recanalization eTICI (expanded Thrombolysis In Cerebral Ischemia) ≥ 2b67, primary safety endpoint was occurrence of hemorrhagic complications after MT. Secondary outcome measures were time from groin puncture to first pass and successful reperfusion, and the total number of passes needed to achieve the final recanalization result. Results: A total of 298 patients with LVO stroke who were treated by MT matched the inclusion criteria: 148 patients (49.7%) treated with AP vs. 150 patients (50.3%) treated with new generation APH. Successful recanalization was not statistically different between both groups: 75.7% for AP vs. 79.3% for APH; p = 0.450. Postinterventional hemorrhagic complications and particularly subarachnoid hemorrhage as the entity possibly associated with stent-retriever device type was significantly less frequent in the group treated with the APH: 29.7% for AP and 16.0% for APH; p = 0.005; however, rates of symptomatic hemorrhage with clinical deterioration and in domo mortality were not statistically different. Neither the median number of stent-retriever passages needed to achieve final recanalization, time from groin puncture to first pass, time from groin puncture to final recanalization nor the number of cases in which successful recanalization could only be achieved by using a different stent-retriever as bail-out device differed between both groups. Conclusion: In the specific example of the APERIO® stent-retriever device, we observed that further technological developments of the new generation device were not associated with disadvantages with respect to typical observational indicators of safety or effectiveness.

Purpose: Disturbances of blood gas and ion homeostasis including regional hypoxia and massive sodium (Na⁺)/potassium (K⁺) shifts are a hallmark of experimental cerebral ischemia but have not been sufficiently investigated for their relevance in stroke patients. Methods: We report a prospective observational study on 366 stroke patients who underwent endovascular thrombectomy (EVT) for large-vessel occlusion (LVO) of the anterior circulation (18 December 2018–31 August 2020). Intraprocedural blood gas samples (1 ml) from within cerebral collateral arteries (ischemic) and matched systemic control samples were obtained according to a prespecified protocol in 51 patients. Results: We observed a significant reduction in cerebral oxygen partial pressure (−4.29%, p_aO_2ischemic = 185.3 mm Hg vs. p_aO_2systemic = 193.6 mm Hg; p = 0.035) and K⁺ concentrations (−5.49%, K⁺_ischemic = 3.44 mmol/L vs. K⁺_systemic = 3.64 mmol/L; p = 0.0083). The cerebral Na⁺:K⁺ ratio was significantly increased and negatively correlated with baseline tissue integrity (r = −0.32, p = 0.031). Correspondingly, cerebral Na⁺ concentrations were most strongly correlated with infarct progression after recanalization (r = 0.42, p = 0.0033). We found more alkaline cerebral pH values (+0.14%, pH_ischemic = 7.38 vs. pH_systemic = 7.37; p = 0.0019), with a time-dependent shift towards more acidotic conditions (r = −0.36, p = 0.055). Conclusion: These findings suggest that stroke-induced changes in oxygen supply, ion composition and acid-base balance occur and dynamically progress within penumbral areas during human cerebral ischemia and are related to acute tissue damage.

Background: Diagnosis of Giant Cell Arteritis (GCA) and Polymyalgia rheumatica (PMR) may be challenging as many patients present with non-specific symptoms. Superficial cranial arteries are predilection sites of inflammatory affection. Ultrasound is typically the diagnostic tool of first choice supplementary to clinical and laboratory examination. Inflammation of temporal arteries can be detected sonographically with high reliability. However, due to the vessel’s course and location, occipital arteries evade sonographic detectability. Objective: The aim of our study was to evaluate the infestation pattern of superficial cranial arteries in GCA and PMR patients with special focus on the occipital arteries. Methods: 90 treatment-naïve patients with clinically and/or histologically proven GCA and/or PMR (51 GCA, 20 PMR, 10 GCA-PMR) were included in the study. All patients underwent contrast-enhanced, fat-suppressed, high-resolution black blood 2D T1-weighted spin echo imaging at 3T MRI. Images were read by three different readers independently. Temporal and occipital arteries were assessed regarding vasculitic affection. Circumferential mural hyperenhancement and thickening of the vessel wall ≥ 600 μm was considered positive for vasculitis. Results: 9/90 (10%) of all patients revealed inflammatory changes of the occipital artery only. Prevalence of isolated inflammatory affection of occipital artery was even higher in the GCA subgroup with 7/51 (14%) patients. Conclusion: 14% of GCA patients and 10% of GCA-PMR patients present with signs of inflammation of the occipital artery only. Since the occipital artery is not accessible to routine ultrasound examination, MRI renders incremental value in the diagnosis of GCA and PMR patients.