Longitudinal changes in the US emergency department use of advanced neuroimaging in the mechanical thrombectomy era.

PURPOSE: To describe ED neuroimaging trends across the time-period spanning the early adoption of endovascular therapy for acute stroke (2013-2018). MATERIALS AND METHODS: We performed a retrospective, cross-sectional study of ED visits using the 2013-2018 National Emergency Department Sample, a 20% sample of ED encounters in the United States. Neuroimaging use was determined by Common Procedural Terminology (CPT) code for non-contrast head CT (NCCT), CT angiography head (CTA), CT perfusion (CTP), and MRI brain (MRI) in non-admitted ED patients. Data was analyzed according to sampling weights and imaging rates were calculated per 100,000 ED visits. Multivariate logistic regression analysis was performed to identify hospital-level factors associated with imaging utilization. RESULTS: Study population comprised 571,935,906 weighted adult ED encounters. Image utilization increased between 2013 and 2018 for all modalities studied, although more pronounced in CTA (80.24/100,000 ED visits to 448.26/100,000 ED visits (p < 0.001)) and CTP (1.75/100,000 ED visits to 28.04/100,000 ED visits p < 0.001)). Regression analysis revealed that teaching hospitals were associated with higher odds of high CTA utilization (OR 1.88 for 2018, p < 0.05), while low-volume EDs and public hospitals showed the reverse (OR 0.39 in 2018, p < 0.05). CONCLUSIONS: We identified substantial increases in overall neuroimaging use in a national sample of non-admitted emergency department encounters between 2013 and 2018 with variability in utilization according to both patient and hospital properties. Further investigation into the appropriateness of this imaging is required to ensure that access to acute stroke treatment is balanced against the timing and cost of over-imaging.

Prehospital Stroke Care Part 2: On-Scene Evaluation and Management by Emergency Medical Services Practitioners.

The prehospital phase is a critical component of delivering high-quality acute stroke care. This topical review discusses the current state of prehospital acute stroke screening and transport, as well as new and emerging advances in prehospital diagnosis and treatment of acute stroke. Topics include prehospital stroke screening, stroke severity screening, emerging technologies to aid in the identification and diagnosis of acute stroke in the prehospital setting, prenotification of receiving emergency departments, decision support for destination determination, and the capabilities and opportunities for prehospital stroke treatment in mobile stroke units. Further evidence-based guideline development and implementation of new technologies are critical for ongoing improvements in prehospital stroke care.

TGFß signaling in the brain increases with aging and signals to astrocytes and innate immune cells in the weeks after stroke.

BACKGROUND: TGFß is both neuroprotective and a key immune system modulator and is likely to be an important target for future stroke therapy. The precise function of increased TGF-ß1 after stroke is unknown and its pleiotropic nature means that it may convey a neuroprotective signal, orchestrate glial scarring or function as an important immune system regulator. We therefore investigated the time course and cell-specificity of TGFß signaling after stroke, and whether its signaling pattern is altered by gender and aging. METHODS: We performed distal middle cerebral artery occlusion strokes on 5 and 18 month old TGFß reporter mice to get a readout of TGFß responses after stroke in real time. To determine which cell type is the source of increased TGFß production after stroke, brain sections were stained with an anti-TGFß antibody, colocalized with markers for reactive astrocytes, neurons, and activated microglia. To determine which cells are responding to TGFß after stroke, brain sections were double-labelled with anti-pSmad2, a marker of TGFß signaling, and markers of neurons, oligodendrocytes, endothelial cells, astrocytes and microglia. RESULTS: TGFß signaling increased 2 fold after stroke, beginning on day 1 and peaking on day 7. This pattern of increase was preserved in old animals and absolute TGFß signaling in the brain increased with age. Activated microglia and macrophages were the predominant source of increased TGFß after stroke and astrocytes and activated microglia and macrophages demonstrated dramatic upregulation of TGFß signaling after stroke. TGFß signaling in neurons and oligodendrocytes did not undergo marked changes. CONCLUSIONS: We found that TGFß signaling increases with age and that astrocytes and activated microglia and macrophages are the main cell types that undergo increased TGFß signaling in response to post-stroke increases in TGFß. Therefore increased TGFß after stroke likely regulates glial scar formation and the immune response to stroke.

LSP5-2157 a new inhibitor of vesicular glutamate transporters.

Vesicular glutamate transporters (VGLUT1-3) mediate the uptake of glutamate into synaptic vesicles. VGLUTs are pivotal actors of excitatory transmission and of almost all brain functions. Their implication in various pathologies has been clearly documented. Despite their functional importance, the pharmacology of VGLUTs is limited to a few dyes such as Trypan Blue, Rose Bengal or Brilliant Yellow type. Here, we report the design and evaluation of new potent analogs based on Trypan Blue scaffold. Our best compound, named LSP5-2157, has an EC50 of 50 nM on glutamate vesicular uptake. Using a 3D homology model of VGLUT1 and docking experiments, we determined its putative binding subdomains within vesicular glutamate transporters and validated the structural requirement for VGLUT inhibition. To better estimate the specificity and potency of LSP5-2157, we also investigated its ability to block glutamatergic transmission in autaptic hippocampal cells. Neither glutamate receptors nor GABAergic transmission or transmission machinery were affected by LSP5-2157. Low doses of compound reversibly reduce glutamatergic neurotransmission in hippocampal autpases. LSP5-2157 had a low and depressing effect on synaptic efficacy in hippocampal slice. Furthermore, LSP5-2157 had no effect on NMDA-R- mediated fEPSP but reduce synaptic plasticity induced by 3 trains of 100 Hz. Finally, LSP5-2157 had the capacity to inhibit VGLUT3-dependent auditory synaptic transmission in the guinea pig cochlea. In this model, it abolished the compound action potential of auditory nerve at high concentration showing the limited permeation of LSP5-2157 in an in-vivo model. In summary, the new ligand LSP5-2157, has a high affinity and specificity for VGLUTs and shows some permeability in isolated neuron, tissue preparations or in vivo in the auditory system. These findings broaden the field of VGLUTs inhibitors and open the way to their use to assess glutamatergic functions in vitro and in vivo.