Genetically Encoded and Modular SubCellular Organelle Probes (GEM-SCOPe) reveal lysosomal and mitochondrial dysfunction driven by PRKN knockout.

Cellular processes including lysosomal and mitochondrial dysfunction are implicated in the development of many diseases. Quantitative visualization of mitochondria and lysosoesl is crucial to understand how these organelles are dysregulated during disease. To address a gap in live-imaging tools, we developed GEM-SCOPe (Genetically Encoded and Modular SubCellular Organelle Probes), a modular toolbox of fluorescent markers designed to inform on localization, distribution, turnover, and oxidative stress of specific organelles. We expressed GEM-SCOPe in differentiated astrocytes and neurons from a human pluripotent stem cell PRKN-knockout model of Parkinson's disease and identified disease-associated changes in proliferation, lysosomal distribution, mitochondrial transport and turnover, and reactive oxygen species. We demonstrate GEM-SCOPe is a powerful panel that provide critical insight into the subcellular mechanisms underlying Parkinson's disease in human cells. GEM-SCOPe can be expanded upon and applied to a diversity of cellular models to glean an understanding of the mechanisms that promote disease onset and progression.

Endovascular Versus Medical Management in Distal Medium Vessel Occlusion Stroke: The DUSK Study.

BACKGROUND: Endovascular treatment (EVT) is part of the usual care for proximal vessel occlusion strokes. However, the safety and effectiveness of EVT for distal medium vessel occlusions remain unclear. We sought to compare the clinical outcomes of EVT to medical management (MM) for isolated distal medium vessel occlusions. METHODS: This is a retrospective analysis of prospectively collected data from seven comprehensive stroke centers. Patients were included if they had isolated distal medium vessel occlusion strokes due to middle cerebral artery M3/M4, anterior cerebral artery A2/A3, or posterior cerebral artery P1/P2 segments. Patients treated with EVT or MM were compared with multivariable logistic regression and inverse probability of treatment weighting. The primary outcome was the shift in the degree of disability as measured by the modified Rankin Scale (mRS) at 90 days. Secondary outcomes included 90-day good (mRS score, 0-2) and excellent (mRS score, 0-1) outcomes. Safety measures included symptomatic intracranial hemorrhage and 90-day mortality. RESULTS: A total of 321 patients were included in the analysis (EVT, 179; MM, 142; 40.8% treated with intravenous thrombolysis). In the inverse probability of treatment weighting model, there were no significant differences between EVT and MM in terms of the overall degree of disability (mRS ordinal shift; adjusted odds ratio [aOR], 1.25 [95% CI, 0.95-1.64]; P=0.110), rates of good (mRS score, 0-2; aOR, 1.32 [95% CI, 0.97-1.80]; P=0.075) and excellent (aOR, 1.32 [95% CI, 0.94-1.85]; P=0.098) outcomes, or mortality (aOR, 1.20 [95% CI, 0.78-1.85]; P=0.395) at 90 days. The multivariable regression model showed similar findings. Moreover, there was no difference between EVT and MM in rates of symptomatic intracranial hemorrhage in the multivariable regression model (aOR, 0.57 [95% CI, 0.21-1.58]; P=0.277), but the inverse probability of treatment weighting model showed a lower likelihood of symptomatic intracranial hemorrhage (aOR, 0.46 [95% CI, 0.24-0.85]; P=0.013) in the EVT group. CONCLUSIONS: This multicenter study failed to demonstrate any significant outcome differences among patients with isolated distal medium vessel occlusions treated with EVT versus MM. These findings reinforce clinical equipoise. Randomized clinical trials are ongoing and will provide more definite evidence.

Reconstruction of the Blood-Brain Barrier In Vitro to Model and Therapeutically Target Neurological Disease.

The blood-brain barrier (BBB) is a key physiological component of the central nervous system (CNS), maintaining nutrients, clearing waste, and protecting the brain from pathogens. The inherent barrier properties of the BBB pose a challenge for therapeutic drug delivery into the CNS to treat neurological diseases. Impaired BBB function has been related to neurological disease. Cerebral amyloid angiopathy (CAA), the deposition of amyloid in the cerebral vasculature leading to a compromised BBB, is a co-morbidity in most cases of Alzheimer's disease (AD), suggesting that BBB dysfunction or breakdown may be involved in neurodegeneration. Due to limited access to human BBB tissue, the mechanisms that contribute to proper BBB function and BBB degeneration remain unknown. To address these limitations, we have developed a human pluripotent stem cell-derived BBB (iBBB) by incorporating endothelial cells, pericytes, and astrocytes in a 3D matrix. The iBBB self-assembles to recapitulate the anatomy and cellular interactions present in the BBB. Seeding iBBBs with amyloid captures key aspects of CAA. Additionally, the iBBB offers a flexible platform to modulate genetic and environmental factors implicated in cerebrovascular disease and neurodegeneration, to investigate how genetics and lifestyle affect disease risk. Finally, the iBBB can be used for drug screening and medicinal chemistry studies to optimize therapeutic delivery to the CNS. In this protocol, we describe the differentiation of the three types of cells (endothelial cells, pericytes, and astrocytes) arising from human pluripotent stem cells, how to assemble the differentiated cells into the iBBB, and how to model CAA in vitro using exogenous amyloid. This model overcomes the challenge of studying live human brain tissue with a system that has both biological fidelity and experimental flexibility, and enables the interrogation of the human BBB and its role in neurodegeneration.

Initial experience with minimally invasive endoscopic evacuation of intracerebral hemorrhage in the setting of radiographic herniation.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) can rapidly result in cerebral herniation, leading to poor neurologic outcomes or mortality. To date, neither decompressive hemicraniectomy (DH) nor hematoma evacuation have been conclusively shown to improve outcomes for comatose ICH patients presenting with cerebral herniation, with these patients largely excluded from clinical trials. Here we present the outcomes of a series of patients presenting with ICH and radiographic herniation who underwent emergent minimally invasive (MIS) ICH evacuation. METHODS: We reviewed our prospectively collected registry of patients undergoing MIS ICH evacuation at a single institution from 01/01/2017 to 10/01/2021. We selected all consecutive patients with Glasgow coma scale (GCS) ≤ 8 and radiographic herniation for this case series. Clinical and radiographic variables were collected, including admission GCS score, preoperative and postoperative hematoma volumes, National Institute of Health stroke scale (NIHSS) scores, and modified Rankin scale (mRS) scores at last follow-up. RESULTS: Of 176 patients with spontaneous supratentorial ICH who underwent minimally invasive endoscopic evacuation during the study time period, a total of 9 patients presented with GCS ≤ 8 and evidence of radiographic herniation. Among these patients, the mean age was 62 ± 12 years, the median GCS at presentation was 5 [IQR 4-6], the mean preoperative hematoma volume was 94 ± 44 mL, the mean time from ictus to evacuation was 12 ± 5 h, and the mean postoperative hematoma volume was 11 ± 16 mL, for a median evacuation percentage of 97% [83-99]. Three patients (33%) died, four (44%) survived with mRS 5 and two (22%) with mRS 4. Patients had a median NIHSS improvement of 5 compared to their initial NIHSS. Age was very strongly correlate to improvements in NIHSS (r2 = 0.90). CONCLUSION: Data from this initial experience suggest emergent MIS hematoma evacuation in the setting of ICH with radiographic herniation is feasible and technically effective. Further randomized studies are required to determine if such an intervention offers overall benefits to patients and their families.

Dysphagia after ischemic and hemorrhagic stroke: A propensity-matched 20-year analysis of the national inpatient sample.

OBJECTIVE: Dysphagia is a common symptom of acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH), but little is known surrounding national trends of this post-stroke condition. Hence, this study aimed to identify the risk factors for dysphagia following AIS and ICH and evaluate in-hospital outcomes in these patients. METHODS: The 2000-2019 Nationwide Inpatient Sample was queried for patients admitted with AIS (ICD9 433, 43401, 43411, 43491, ICD-10 I63) and ICH (ICD9 431, 432.9, ICD-10 I61, I62.9). Univariate analysis with t-tests or chi-square performed as appropriate. A 1:1 nearest neighbor propensity score matched cohort was generated. Variables with standardized mean differences >0.1 were used in multivariable regression to generate adjusted odds ratios (AOR)/ß-coefficients for the presence of dysphagia on outcomes. RESULTS: Of 10,415,286 patients with AIS, 956,662 (9.2%) had in-hospital dysphagia. Total of 2,000,868 patients with ICH were identified; 203,511 (10.2%) had in-hospital dysphagia. Patients with dysphagia after AIS were less likely to experience in-hospital mortality (OR 0.61;95%CI: 0.60-0.63) or be discharged home (AOR 0.51;95%CI: 0.51-0.52), had increased length of stay (Beta-coefficient = 0.43 days; 95%CI: 0.36-0.50), and had increased hospital charges ($14411.96;95%CI: 13565.68-15257.44) (all p < 0.001). Patients with dysphagia after ICH were less likely to experience in-hospital mortality (AOR 0.39;95%CI: 0.37-0.4), less likely to be discharged home (AOR 0.59,95%CI:0.57-0.61), have longer hospital stay (Beta-coefficient = 1.99 days;95%CI: 1.78-2.21), and increased hospital charges ($28251.93; 95%CI: $25594.57-30909.28)(all p < 0.001). CONCLUSION: This is the first study to report on national trends in patients with dysphagia after AIS and ICH. These patients had longer hospital LOS, worse functional outcomes at discharge, and higher hospital costs.

Trends and In-Hospital Outcomes in Patients with Vocal Fold Paralysis after Ischemic and Intracerebral Hemorrhagic Stroke: A Propensity Matched 20-Year Analysis of the Nationwide Inpatient Sample.

OBJECTIVE: Laryngeal manifestations of stroke have been sparsely described in the literature, specifically vocal fold paralysis (VFP). This study aimed to identify the prevalence, characteristics, and in-hospital outcomes of patients presenting with VFP after acute ischemic stroke (AIS) and intracranial hemorrhage (ICH). METHODS: A query of the 2000-2019 Nationwide Inpatient Sample was performed for patients admitted with AIS (International Classification of Diseases, Ninth Revision 433, 43,401, 43,411, 43,491, International Classification of Diseases, Tenth Revision I63) and ICH (International Classification of Diseases, Ninth Revision 431, 432.9, International Classification of Diseases, Tenth Revision I61, I62.9). Demographics, comorbidities, and outcomes were identified. Univariate analysis with t-tests or χ2 performed as appropriate. A 1:1 nearest neighbor propensity score matched cohort was generated. Variables with standardized mean differences > 0.1 used in multivariable regression to generate adjusted odds ratios (AOR)/ß-coefficients for VFP on outcomes. Significance was set at an alpha level of < 0.001. All analysis were performed in R version 4.1.3. RESULTS: A total of 10,415,286 patients with AIS were included; 11,328 (0.1%) had VFP. Of 2,000,868 patients with ICH 2132 (0.1%) had in-hospital VFP. Multivariable analysis revealed that patients with VFP after AIS were less likely to be discharged home (AOR 0.32; 95% confidence interval {CI}: 0.18-0.57; P < 0.001) and elevated total hospital charges (ß coefficient = 59,684.6; 95% CI = 18,365.12-101,004.07; P = 0.005). Patients with VFP after ICH were less likely to experience in-hospital mortality (AOR 0.53; 95% CI: 0.34-0.79; P = 0.002) with longer hospital stays (1.99 days; 95% CI: 1.78-2.21; P < 0.001) and elevated total hospital charges (ß coefficient = 53,905.35; 95% CI = 16,352.84-91,457.85; P = 0.005).. CONCLUSIONS: VFP in patients with ischemic stroke and ICH; although an infrequent complication is associated with functional impairment, longer hospital stay, and higher charges.

External Ventricular Drain Training in Medical Students Improves Procedural Accuracy and Attitudes Toward Virtual Reality.

OBJECTIVE: Neurosurgery residents face a learning curve at the beginning of residency. Virtual reality (VR) training may alleviate challenges through an accessible, reusable, anatomical model. METHODS: Medical students performed external ventricular drain placements in VR to characterize the learning curve from novice to proficient. Distance from catheter to foramen of Monro and location with respect to ventricle were recorded. Changes in attitudes toward VR were assessed. Neurosurgery residents performed external ventricular drain placements to validate proficiency benchmarks. Resident and student impressions of the VR model were compared. RESULTS: Twenty-one students with no neurosurgical experience and 8 neurosurgery residents participated. Student performance improved significantly from trial 1 to 3 (15 mm [12.1-20.70] vs. 9.7 [5.8-15.3], P = 0.02). Student attitudes regarding VR utility improved significantly posttrial. The distance to foramen of Monro was significantly shorter for residents than for students in trial 1 (9.05 [8.25-10.73] vs. 15 [12.1-20.70], P = 0.007) and trial 2 (7.45 [6.43-8.3] vs. 19.5 [10.9-27.6], P = 0.002). By trial 3 there was no significant difference (10.1 [8.63-10.95 vs. 9.7 [5.8-15.3], P = 0.62). Residents and students provided similarly positive feedback for VR in resident curricula, patient consent, preoperative practice and planning. Residents provided more neutral-to-negative feedback regarding skill development, model fidelity, instrument movement, and haptic feedback. CONCLUSIONS: Students showed significant improvement in procedural efficacy which may simulate resident experiential learning. Improvements in fidelity are needed before VR can become a preferred training technique in neurosurgery.

Characterization of length of stay after minimally invasive endoscopic intracerebral hemorrhage evacuation.

BACKGROUND: Minimally invasive evacuation may help ameliorate outcomes after intracerebral hemorrhage (ICH). However, hospital length of stay (LOS) post-evacuation is often long and costly. OBJECTIVE: To examine factors associated with LOS in a large cohort of patients who underwent minimally invasive endoscopic evacuation. METHODS: Patients presenting to a large health system with spontaneous supratentorial ICH qualified for minimally invasive endoscopic evacuation if they met the following inclusion criteria: age ≥18, premorbid modified Rankin Scale (mRS) score ≤3, hematoma volume ≥15 mL, and presenting National Institutes of Health Stroke Scale (NIHSS) score ≥6. Demographic, clinical, radiographic, and operative characteristics were included in a multivariate logistic regression for hospital and ICU LOS dichotomized into short and prolonged stay at 14 and 7 days, respectively. RESULTS: Among 226 patients who underwent minimally invasive endoscopic evacuation, the median intensive care unit and hospital LOS were 8 (4-15) days and 16 (9-27) days, respectively. A greater extent of functional impairment on presentation (OR per NIHSS point 1.10 (95% CI 1.04 to 1.17), P=0.007), concurrent intraventricular hemorrhage (OR=2.46 (1.25 to 4.86), P=0.02), and deep origin (OR=per point 2.42 (1.21 to 4.83), P=0.01) were associated with prolonged hospital LOS. A longer delay from ictus to evacuation (OR per hour 1.02 (1.01 to 1.04), P=0.007) and longer procedure time (OR per hour 1.91 (1.26 to 2.89), P=0.002) were associated with prolonged ICU LOS. Prolonged hospital and ICU LOS were in turn longitudinally associated with a lower rate of discharge to acute rehabilitation (40% vs 70%, P<0.0001) and worse 6-month mRS outcomes (5 (4-6) vs 3 (2-4), P<0.0001). CONCLUSIONS: We present factors associated with prolonged LOS, which in turn was associated with poor long-term outcomes. Factors associated with LOS may help to inform patient and clinician expectations of recovery, guide protocols for clinical trials, and select suitable populations for minimally invasive endoscopic evacuation.

Vagal Nerve Stimulation: A Bibliometric Analysis of Current Research Trends.

BACKGROUND: Vagal nerve stimulation (VNS) has become established as an effective tool for the management of various neurologic disorders. Consequently, a growing number of VNS studies have been published over the past four decades. This study presents a bibliometric analysis investigating the current trends in VNS literature. MATERIALS AND METHODS: Using the Web of Science collection data base, a search was performed to identify literature that discussed applications of VNS from 2000 to 2021. Analysis and visualization of the included literature were completed with VOSviewer. RESULTS: A total of 2895 publications were identified. The number of articles published in this area has increased over the past two decades, with the most citations (7098) occurring in 2021 and the most publications (270) in 2020. The h-index, i-10, and i-100 were 97, 994, and 91, respectively, with 17.0 citations per publication on average. The highest-producing country and institution of VNS literature were the United States and the University of Texas, respectively. The most productive journal was Epilepsia. Epilepsy was the predominant focus of VNS research, with the keyword "epilepsy" having the greatest total link strength (749) in the keyword analysis. The keyword analysis also revealed two major avenues of VNS research: 1) the mechanisms by which VNS modulates neural circuitry, and 2) therapeutic applications of VNS in a variety of diseases beyond neurology. It also showed a significant prevalence of noninvasive VNS research. Although epilepsy research appears more linked to implanted VNS, headache and depression specialists were more closely associated with noninvasive VNS. CONCLUSION: VNS may serve as a promising intervention for rehabilitation beyond neurologic applications, with an expanding base of literature over the past two decades. Although epilepsy researchers have produced most current literature, other fields have begun to explore VNS as a potential treatment, likely owing to the rise of noninvasive forms of VNS.

Exosome-Based Therapy for Ischemic Stroke: A Bibliometric Analysis of Current Trends and Future Directions.

BACKGROUND: Stroke is a leading cause of mortality and disability worldwide. Exosomes, or small extracellular vesicles with signaling properties, have recently been identified as novel mechanisms for stroke treatment. This study aims to use bibliometric techniques to identify current research trends and future directions of exosome-based stroke therapy. METHODS: The Web of Science Core Collection was searched using terms that included "exosome" and all stroke types. Bibliometric data, including authors, publication years, citations, countries/regions, institutions, journals, and Keywords Plus, were extracted directly from the Web of Science Core Collection. Keywords were mapped using VOSviewer. RESULTS: From 2010 to 2021, 424 documents were identified with a total of 12,708 citations. The number of publications increased yearly from 2012 to 2021, the majority of which were research and review articles. China and the United States produced the most publications with Henry Ford Hospital and Oakland University serving as the 2 most highly published research institutions. Documents were published most frequently in the journal Stroke. Keywords Plus analyses revealed 3 main research areas: exosomes as pathogenic mediators, biomarkers, and treatments of stroke. Ischemic stroke was the most prevalent type of stroke included in these studies. CONCLUSIONS: Using bibliometric techniques, this study identified a current and growing interest in the research of exosomes in stroke, particularly in their pathogenic, biomarker, and potential minimally invasive therapeutic properties. Given the high prevalence of ischemic stroke in the current literature, further characterization of exosomes in other stroke types, such as intracerebral hemorrhage, emerges as a future direction for this field of research.

Prehospital Stroke Detection Devices: A Bibliometric Analysis of Current Trends.

BACKGROUND: Stroke represents the second highest disease burden worldwide. It is well documented that rapid stroke identification and treatment are associated with improved outcomes. In particular, prehospital stroke detection (PSD) devices have emerged as possible tools to facilitate more rapid and accurate stroke triage. Bibliometric analyses offer a powerful tool to characterize the entire field from an interdisciplinary perspective. This bibliometric analysis aims to analyze current themes and identify future trends within the PSD space. METHODS: The Web of Science collection database was surveyed for PSD literature. Search terms focused on stroke diagnostic techniques, clinical indicators for ischemia/hemorrhage, and prehospital timing. Subsequently, VOSviewer was used for visual mapping analyses. RESULTS: A total of 237 documents were identified between 1995 and 2021 from 1190 different authors. Publication volume has increased greatly in recent years. Publications were spread across 156 journals with the largest journal, Stroke, contributing just 7 studies over 26 years. Keywords analysis showed that stroke, near-infrared spectroscopy, and electroencephalography were the most common keywords. CONCLUSIONS: Novel PSD devices are promising tools for the early detection and characterization of stroke. This study identifies recent increased attention to PSD technology, a trend that will likely continue in the coming years. Devices using near-infrared spectroscopy, ultrasonography, microwave, and electroencephalography represent the central areas of future PSD research. The multidisciplinary, and therefore fractured, nature of the PSD space requires those interested in the field to maintain active search habits across multiple journals to remain up to date on PSD innovations.

Accuracy of artificial intelligence for the detection of intracranial hemorrhage and chronic cerebral microbleeds: a systematic review and pooled analysis.

BACKGROUND: Artificial intelligence (AI)-driven software has been developed and become commercially available within the past few years for the detection of intracranial hemorrhage (ICH) and chronic cerebral microbleeds (CMBs). However, there is currently no systematic review that summarizes all of these tools or provides pooled estimates of their performance. METHODS: In this PROSPERO-registered, PRISMA compliant systematic review, we sought to compile and review all MEDLINE and EMBASE published studies that have developed and/or tested AI algorithms for ICH detection on non-contrast CT scans (NCCTs) or MRI scans and CMBs detection on MRI scans. RESULTS: In total, 40 studies described AI algorithms for ICH detection in NCCTs/MRIs and 19 for CMBs detection in MRIs. The overall sensitivity, specificity, and accuracy were 92.06%, 93.54%, and 93.46%, respectively, for ICH detection and 91.6%, 93.9%, and 92.7% for CMBs detection. Some of the challenges encountered in the development of these algorithms include the laborious work of creating large, labeled and balanced datasets, the volumetric nature of the imaging examinations, the fine tuning of the algorithms, and the reduction in false positives. CONCLUSIONS: Numerous AI-driven software tools have been developed over the last decade. On average, they are characterized by high performance and expert-level accuracy for the diagnosis of ICH and CMBs. As a result, implementing these tools in clinical practice may improve workflow and act as a failsafe for the detection of such lesions. REGISTRATION-URL: https://www.crd.york.ac.uk/prospero/ Unique Identifier: CRD42021246848.