A considerable proportion of acute ischemic stroke patients treated with endovascular thrombectomy (EVT) are dead or severely disabled at 3 months despite successful reperfusion. Ischemic core ...imaging biomarkers may help to identify patients who are more likely to have a poor outcome after endovascular thrombectomy (EVT) despite successful reperfusion. We studied the association of CT perfusion-(CTP), CT angiography-(CTA), and non-contrast CT-(NCCT) based imaging markers with poor outcome in patients who underwent EVT in daily clinical practice.
We included EVT-treated patients (July 2016-November 2017) with an anterior circulation occlusion from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry with available baseline CTP, CTA, and NCCT. We used multivariable binary and ordinal logistic regression to analyze the association of CTP ischemic core volume, CTA-Collateral Score (CTA-CS), and Alberta Stroke Program Early CT Score (ASPECTS) with poor outcome (modified Rankin Scale score (mRS) 5-6) and likelihood of having a lower score on the mRS at 90 days.
In 201 patients, median core volume was 13 (IQR 5-41) mL. Median ASPECTS was 9 (IQR 8-10). Most patients had grade 2 (83/201; 42%) or grade 3 (28/201; 14%) collaterals. CTP ischemic core volume was associated with poor outcome aOR per 10 mL 1.02 (95%CI 1.01-1.04) and lower likelihood of having a lower score on the mRS at 90 days aOR per 10 mL 0.85 (95% CI 0.78-0.93). In multivariable analysis, neither CTA-CS nor ASPECTS were significantly associated with poor outcome or the likelihood of having a lower mRS.
In our population of patients treated with EVT in daily clinical practice, CTP ischemic core volume is associated with poor outcome and lower likelihood of shift toward better outcome in contrast to either CTA-CS or ASPECTS.
Background Time to reperfusion in patients with ischemic stroke is strongly associated with functional outcome and may differ between hospitals and between patients within hospitals. Improvement in ...time to reperfusion can be guided by between-hospital and within-hospital comparisons and requires insight in specific targets for improvement. We aimed to quantify the variation in door-to-reperfusion time between and within Dutch intervention hospitals and to assess the contribution of different time intervals to this variation. Methods and Results We used data from the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry. The door-to-reperfusion time was subdivided into time intervals, separately for direct patients (door-to-computed tomography, computed tomography-to-computed tomography angiography CTA, CTA-to-groin, and groin-to-reperfusion times) and for transferred patients (door-to-groin and groin-to-reperfusion times). We used linear mixed models to distinguish the variation in door-to-reperfusion time between hospitals and between patients. The proportional change in variance was used to estimate the amount of variance explained by each time interval. We included 2855 patients of 17 hospitals providing endovascular treatment. Of these patients, 44% arrived directly at an endovascular treatment hospital. The between-hospital variation in door-to-reperfusion time was 9%, and the within-hospital variation was 91%. The contribution of case-mix variables on the variation in door-to-reperfusion time was marginal (2%-7%). Of the between-hospital variation, CTA-to-groin time explained 83%, whereas groin-to-reperfusion time explained 15%. Within-hospital variation was mostly explained by CTA-to-groin time (33%) and groin-to-reperfusion time (42%). Similar results were found for transferred patients. Conclusions Door-to-reperfusion time varies between, but even more within, hospitals providing endovascular treatment for ischemic stroke. Quality of stroke care improvements should not only be guided by between-hospital comparisons, but also aim to reduce variation between patients within a hospital, and should specifically focus on CTA-to-groin time and groin-to-reperfusion time.
BackgroundRandomised controlled trials with perfusion selection have shown benefit of endovascular treatment (EVT) for ischaemic stroke between 6 and 24 hours after symptom onset or time last seen ...well. However, outcomes after EVT in these late window patients without perfusion imaging are largely unknown. We assessed their characteristics and outcomes in routine clinical practice.MethodsThe Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands Registry, a prospective, multicentre study in the Netherlands, included patients with an anterior circulation occlusion who underwent EVT between 2014 and 2017. CT perfusion was no standard imaging modality. We used adjusted ordinal logistic regression analysis to compare patients treated within versus beyond 6.5 hours after propensity score matching on age, prestroke modified Rankin Scale (mRS), National Institutes of Health Stroke Scale, Alberta Stroke Programme Early CT Score (ASPECTS), collateral status, location of occlusion and treatment with intravenous thrombolysis. Outcomes included 3-month mRS score, functional independence (defined as mRS 0–2), and death.ResultsOf 3264 patients who underwent EVT, 106 (3.2%) were treated beyond 6.5 hours (median 8.5, IQR 6.9–10.6), of whom 93 (87.7%) had unknown time of stroke onset. CT perfusion was not performed in 87/106 (80.2%) late window patients. Late window patients were younger (mean 67 vs 70 years, p<0.04) and had slightly lower ASPECTS (median 8 vs 9, p<0.01), but better collateral status (collateral score 2–3: 68.3% vs 57.7%, p=0.03). No differences were observed in proportions of functional independence (43.3% vs 40.5%, p=0.57) or death (24.0% vs 28.9%, p=0.28). After matching, outcomes remained similar (adjusted common OR for 1 point improvement in mRS 1.04, 95% CI 0.56 to 1.93).ConclusionsWithout the use of CT perfusion selection criteria, EVT in the 6.5–24-hour time window was not associated with poorer outcome in selected patients with favourable clinical and CT/CT angiography characteristics. randomised controlled trials with lenient inclusion criteria are needed to identify more patients who can benefit from EVT in the late window.
SummaryA main neurogenic niche in the adult human brain is the subventricular zone (SVZ). Recent data suggest that the progenitors that are born in the human SVZ migrate via the rostral migratory ...stream (RMS) towards the olfactory bulb (OB), similar to what has been observed in other mammals. A subpopulation of astrocytes in the SVZ specifically expresses an assembly-compromised isoform of the intermediate filament protein glial fibrillary acidic protein (GFAP-d). To further define the phenotype of these GFAP-d expressing cells and to determine whether these cells are present throughout the human subventricular neurogenic system, we analysed SVZ, RMS and OB sections of 14 aged brain donors (ages 74-93). GFAP-d was expressed in the SVZ along the ventricle, in the RMS and in the OB. The GFAP-d cells in the SVZ co-expressed the neural stem cell (NSC) marker nestin and the cell proliferation markers proliferating cell nuclear antigen (PCNA) and Mcm2. Furthermore, BrdU retention was found in GFAP-d positive cells in the SVZ. In the RMS, GFAP-d was expressed in the glial net surrounding the neuroblasts. In the OB, GFAP-d positive cells co-expressed PCNA. We also showed that GFAP-d cells are present in neurosphere cultures that were derived from SVZ precursors, isolated postmortem from four brain donors (ages 63-91). Taken together, our findings show that GFAP-d is expressed in an astrocytic subpopulation in the SVZ, the RMS and the OB. Importantly, we provide the first evidence that GFAP-d is specifically expressed in longterm quiescent cells in the human SVZ, which are reminiscent of NSCs.
Glucosylceramide synthase (GCS) is an important target for clinical drug development for the treatment of lysosomal storage disorders and a promising target for combating type 2 diabetes. Iminosugars ...are useful leads for the development of GCS inhibitors; however, the effective iminosugar type GCS inhibitors reported have some unwanted cross-reactivity toward other glyco-processing enzymes. In particular, iminosugar type GCS inhibitors often also inhibit to some extent human acid glucosylceramidase (GBA1) and the nonlysosomal glucosylceramidase (GBA2), the two enzymes known to process glucosylceramide. Of these, GBA1 itself is a potential drug target for the treatment of the lysosomal storage disorder, Gaucher disease, and selective GBA1 inhibitors are sought after as potential chemical chaperones. The physiological importance of GBA2 in glucosylceramide processing in relation to disease states is less clear, and here, selective inhibitors can be of use as chemical knockout entities. In this communication, we report our identification of a highly potent and selective N-alkylated l-ido-configured iminosugar. In particular, the selectivity of 27 for GCS over GBA1 is striking.
Goal: Insufficient data is available about safety and efficacy of endovascular treatment (EVT) in patients with minor stroke symptoms because these patients were excluded from most randomized trials. ...We aimed to compare characteristics, functional outcome, and complications in patients with minor ischemic stroke National Institutes of Health Stroke Scale score ≤5 (NIHSS score ≤5) and moderate to severe ischemic stroke (NIHSS score ≥6) due to intracranial proximal artery occlusion of the anterior circulation who underwent EVT. Materials and Methods: We report patients with an anterior circulation occlusion who were included between March 2014 and June 2016 in the multicenter randomized clinical trial of EVT of acute ischemic stroke in the Netherlands Registry, a prospective, multicenter, observational study for stroke centers that perform EVT in the Netherlands. Minor ischemic stroke was defined as baseline NIHSS score of 5 or less. Primary outcome is the modified Rankin Scale (mRS) score at 90 days. Secondary outcomes include symptomatic intracranial hemorrhage (sICH) and mortality. Findings: Seventy-one (5.5%) patients had a NIHSS score of 5 or less. Functional independence (mRS 0-2 at 90 days) was reached in 75% of these patients, compared to 40% of patients with NIHSS score of 6 or more. sICH occurred in 4% of patients, of which 1% occurred peri-interventionally. Death occurred in 6% of patients. Conclusions: Patients with minor ischemic stroke with an intracranial proximal arterial occlusion of the anterior circulation who underwent EVT have a high chance of favorable outcome and appear to have low occurrence of treatment-related sICH. Therefore, our results encourage the use of EVT for minor ischemic stroke in the absence of effect estimates from controlled studies.
Adult neurogenesis has been shown to be upregulated following a wide variety of brain injury paradigms. During the first weeks of postnatal life there is around 50 fold more neurogenesis occurring ...than in the adult CNS, yet little is known regarding the effect of neonatal brain injury on this developmental proliferation. We have investigated the effect of a global perinatal birth asphyxia on postnatal proliferation at 2, 5, 8, 11, 15, 21 and 28 days after birth (injury) using a
3H-thymidine tracer study. We found a specific upregulation of proliferation at 5 days after the injury within the injured hippocampus only, with an associated increase in hippocampal mass and without any changes in GFAP content at any timepoint. Perinatal asphyxia did not alter proliferation within the cerebellum, sub ventricular zone, olfactory bulb, cervical or thoracic spinal cord. Similarly, no changes in corticosterone levels were induced by the injury. Since there were no changes in GFAP content we hypothesize that this increased proliferation is likely neurogenetic, similar to what is seen in the adult brain following injury. Further we show that the dramatic increase in corticosterone at the end of the stress hyporesponsive period is not responsible for the equally dramatic decrease in postnatal proliferation within the CNS.
Parkinson's disease (PD) as a progressive neurodegenerative disorder arises from multiple genetic and environmental factors. However, underlying pathological mechanisms remain poorly understood. ...Using multiplexed single-cell transcriptomics, we analyze human neural precursor cells (hNPCs) from sporadic PD (sPD) patients. Alterations in gene expression appear in pathways related to primary cilia (PC). Accordingly, in these hiPSC-derived hNPCs and neurons, we observe a shortening of PC. Additionally, we detect a shortening of PC in PINK1-deficient human cellular and mouse models of familial PD. Furthermore, in sPD models, the shortening of PC is accompanied by increased Sonic Hedgehog (SHH) signal transduction. Inhibition of this pathway rescues the alterations in PC morphology and mitochondrial dysfunction. Thus, increased SHH activity due to ciliary dysfunction may be required for the development of pathoetiological phenotypes observed in sPD like mitochondrial dysfunction. Inhibiting overactive SHH signaling may be a potential neuroprotective therapy for sPD. Here, the authors reveal using single-cell RNA sequencing that Parkinson's disease (PD) patient-derived neuronal cells show altered primary cilia morphology and signaling suggesting cilia dysfunction may underlie PD pathogenesis.
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