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Spinal metastases can be contained in the bone or have epidural spread. Whether the extent of epidural involvement changes tumor response to therapy is unknown. The decision of when to treat disease progression with focal radiation therapy with or without surgery vs. systemic therapy is debated. The present study compared outcomes and local tumor control after stereotactic body radiation therapy (SBRT) between patients with spine metastases localized to the bone (Bilsky 0) vs. patients with mild epidural spread (Bilsky 1). A retrospective analysis of a prospectively maintained database of adult oncological patients who underwent SBRT to the spine at a single, large, tertiary care facility from August 2010 to January 2021 was performed. Patients with Bilsky grades 1a, 1b and 1c were grouped and compared. Approximately half (53.7%) of the 255 patients identified had Bilsky grade 1 epidural disease. Of the 311 spine treatment sites, 86 (27.7%) had a radiosensitive histology, 116 (37.3%) had intermediate radiosensitivity and 109 (35.0%) had a radioresistant histology. Patients with Bilsky grade 1 were more predisposed to receive surgery followed by SBRT compared with those with Bilsky grade 0 (21.0% vs. 6.3%; P=0.0002). Patients with Bilsky grade 0 compression had 92.0% local control at 12 months and 85.8% local control at 24 months; patients with Bilsky grade 1 compression had 85.6% local control at 12 months and 77.6% local control at 24 months. Biologically effective dose and infield progression between patients presenting with Bilsky grade 0 and 1 compression were not statistically different. Local control rates did not differ significantly between Bilsky grade 0 and grade 1 patients following treatment with spinal SBRT. However, patients with grade 1 disease were more likely to receive surgery before SBRT. Overall, evidence indicates that patients may benefit from treatment with SBRT before epidural disease progresses to requiring separation surgery., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Linzey et al.)

Rho guanine nucleotide exchange factor (RGNEF) is a guanine nucleotide exchange factor (GEF) mainly involved in regulating the activity of Rho-family GTPases. It is a bi-functional protein, acting both as a guanine exchange factor and as an RNA-binding protein. RGNEF is known to act as a destabilizing factor of neurofilament light chain RNA (NEFL) and it could potentially contribute to their sequestration in nuclear cytoplasmic inclusions. Most importantly, RGNEF inclusions in the spinal motor neurons of ALS patients have been shown to co-localize with inclusions of TDP-43, the major well-known RNA-binding protein aggregating in the brain and spinal cord of human patients. Therefore, it can be hypothesized that loss-of-function of both proteins following aggregation may contribute to motor neuron death/survival in ALS patients. To further characterize their relationship, we have compared the transcriptomic profiles of neuronal cells depleted of TDP-43 and RGNEF and show that these two factors predominantly act in an antagonistic manner when regulating the expression of axon guidance genes. From a mechanistic point of view, our experiments show that the effect of these genes on the processivity of long introns can explain their mode of action. Taken together, our results show that loss-of-function of factors co-aggregating with TDP-43 can potentially affect the expression of commonly regulated neuronal genes in a very significant manner, potentially acting as disease modifiers. This finding further highlights that neurodegenerative processes at the RNA level are the result of combinatorial interactions between different RNA-binding factors that can be co-aggregated in neuronal cells. A deeper understanding of these complex scenarios may lead to a better understanding of pathogenic mechanisms occurring in patients, where more than one specific protein may be aggregating in their neurons., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

The progressive degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) is accompanied by the formation of a broad array of cytoplasmic and nuclear neuronal inclusions (protein aggregates) largely containing RNA-binding proteins such as TAR DNA-binding protein 43 (TDP-43) or fused in sarcoma/translocated in liposarcoma (FUS/TLS). This process is driven by a liquid-to-solid phase separation generally from proteins in membrane-less organelles giving rise to pathological biomolecular condensates. The formation of these protein aggregates suggests a fundamental alteration in the mRNA expression or the levels of the proteins involved. Considering the role of the epigenome in gene expression, alterations in DNA methylation, histone modifications, chromatin remodeling, non-coding RNAs, and RNA modifications become highly relevant to understanding how this pathological process takes effect. In this review, we explore the evidence that links epigenetic mechanisms with the formation of protein aggregates in ALS. We propose that a greater understanding of the role of the epigenome and how this inter-relates with the formation of pathological LLPS in ALS will provide an attractive therapeutic target., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Noches, Campos-Melo, Droppelmann and Strong.)

The SARS-CoV-2 nucleocapsid protein (N protein) is critical in viral replication by undergoing liquid-liquid phase separation to seed the formation of a ribonucleoprotein (RNP) complex to drive viral genomic RNA (gRNA) translation and in suppressing both stress granules and processing bodies, which is postulated to increase uncoated gRNA availability. The N protein can also form biomolecular condensates with a broad range of host endogenous proteins including RNA binding proteins (RBPs). Amongst these RBPs are proteins that are associated with pathological, neuronal, and glial cytoplasmic inclusions across several adult-onset neurodegenerative disorders, including TAR DNA binding protein 43 kDa (TDP-43) which forms pathological inclusions in over 95% of amyotrophic lateral sclerosis cases. In this study, we demonstrate that the N protein can form biomolecular condensates with TDP-43 and that this is dependent on the N protein C-terminus domain (N-CTD) and the intrinsically disordered C-terminus domain of TDP-43. This process is markedly accelerated in the presence of RNA. In silico modeling suggests that the biomolecular condensate that forms in the presence of RNA is composed of an N protein quadriplex in which the intrinsically disordered TDP-43 C terminus domain is incorporated.

Aggregation of the RNA-binding protein TAR DNA binding protein (TDP-43) is a hallmark of TDP-proteinopathies including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As TDP-43 aggregation and dysregulation are causative of neuronal death, there is a special interest in targeting this protein as a therapeutic approach. Previously, we found that TDP-43 extensively co-aggregated with the dual function protein GEF (guanine exchange factor) and RNA-binding protein rho guanine nucleotide exchange factor (RGNEF) in ALS patients. Here, we show that an N-terminal fragment of RGNEF (NF242) interacts directly with the RNA recognition motifs of TDP-43 competing with RNA and that the IPT/TIG domain of NF242 is essential for this interaction. Genetic expression of NF242 in a fruit fly ALS model overexpressing TDP-43 suppressed the neuropathological phenotype increasing lifespan, abolishing motor defects and preventing neurodegeneration. Intracerebroventricular injections of AAV9/NF242 in a severe TDP-43 murine model (rNLS8) improved lifespan and motor phenotype, and decreased neuroinflammation markers. Our results demonstrate an innovative way to target TDP-43 proteinopathies using a protein fragment with a strong affinity for TDP-43 aggregates and a mechanism that includes competition with RNA sequestration, suggesting a promising therapeutic strategy for TDP-43 proteinopathies such as ALS and FTD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Paraspeckles are nuclear condensates formed by NEAT1_2 lncRNA and different RNA-binding proteins. In general, these membraneless organelles function in the regulation of gene expression and translation and in miRNA processing, and in doing this, they regulate cellular homeostasis and mediate pro-survival in the cell. Despite evidence showing the importance of paraspeckles in the stress response, the dynamics of paraspeckles and their components under conditions of osmotic stress remain unknown. We exposed HEK293T cells to sorbitol and examined NEAT1_2 expression using real-time PCR. Localization and quantification of the main paraspeckle components, NEAT1_2, PSPC1, NONO, and SFPQ, in different cellular compartments was performed using smFISH and immunofluorescence. Our findings showed a significant decrease in total NEAT1_2 expression in cells after osmotic stress. Sorbitol shifted the subcellular localization of NEAT1_2, PSPC1, NONO, and SFPQ from the nucleus to the cytoplasm and decreased the number and size of NEAT1_2 foci in the nucleus. PSPC1 formed immunoreactive cytoplasmic fibrils under conditions of osmotic stress, which slowly disassembled under recovery. Our study deepens the paraspeckle dynamics in response to stress, suggesting a novel role for NEAT1_2 in the cytoplasm in osmotic stress and physiological conditions.

Ethical animal use follows the 3R's: Replacement, Reduction and Refinement. Here, we present the use of simultaneous jugular vein and cisterna magna catheterization via a port system in rats for repeated fluid sampling for 14 consecutive days without loss of catheter patency. This technique allows repeated intra-animal sampling without anesthesia and, if used with pooling samples from a cohort of animals, replaces the need for terminal collections for sufficient sample volumes., (© 2024. The Author(s).)

Introduction: We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases., Methods: Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau)181 and amyloid beta (Aβ) 42/40 were measured using ultra-sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD)., Results: GFAP, NfL, and/or p-tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p-tau181 were highly predictive across diseases, p-tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aβ 42/40 ., Discussion: GFAP, NfL, and p-tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Advances in local and systemic therapies continue to improve overall survival for patients with cancer, increasing the incidence of spine metastases. Up to 15% of patients with solid tumors develop spinal metastases. Spinal metastases can be particularly devastating for quality of life given the potential pain, neurological deficits from spinal cord compression or cauda equina syndrome, spinal instability, and pathological fractures that may result. Stereotactic body radiotherapy (SBRT) with or without adding less invasive surgical techniques for stabilization or separation has gained favor. SBRT uses smaller, more precise treatment volumes, allowing for higher doses per fracture, thus increasing ablative abilities., Methods: We conducted a systematic review using MEDLINE, Embase (Elsevier), and Web of Science to identify all articles investigating the effectiveness of SBRT in providing local disease control, pain control, and relief of spinal cord compression for patients with metastatic disease of the spine., Results: The review yielded 84 articles that met inclusion criteria. The evidence indicates SBRT provides excellent local control and pain control for patients with spine metastesis, and this remains true for patients with spinal cord compression managed with surgical separation followed by postoperative spine SBRT., Conclusion: While not all patients are appropriate candidates for SBRT, carefully considering appropriate frameworks that consider the patient's overall prognosis can guide a multidisciplinary team toward the patients who will benefit the most from this treatment modality., Competing Interests: The authors have no financial or personal conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

We present four different protocols of varying complexity for the isolation of cell culture-derived extracellular vesicles (EVs)/exosome-enriched fractions with the objective of providing researchers with easily conducted methods that can be adapted for many different uses in various laboratory settings and locations. These protocols are primarily based on polymer precipitation, filtration and/or ultracentrifugation, as well as size-exclusion chromatography (SEC) and include: (i) polyethylene glycol and sodium chloride supplementation of the conditioned medium followed by low-speed centrifugation; (ii) ultracentrifugation of conditioned medium; (iii) filtration of conditioned media through a 100-kDa exclusion filter; and (iv) isolation using a standard commercial kit. These techniques can be followed by further purification by ultracentrifugation, sucrose density gradient centrifugation, or SEC if needed and the equipment is available. HEK293 and SH-SY5Y cell cultures were used to generate conditioned medium containing exosomes. This medium was then depleted of cells and debris, filtered through a 0.2-µM filter, and supplemented with protease and RNAse inhibitors prior to exosomal isolation. The purified EVs can be used immediately or stably stored at 4°C (up to a week for imaging or using intact EVS downstream) or at -80°C for extended periods and then used for biochemical study. Our aim is not to compare these methodologies but to present them with descriptors so that researchers can choose the "best method" for their work under their individual conditions., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press.)

The utilization of biocompatible drug delivery systems with extended drug release capabilities is highly advantageous in cancer therapy, as they can mitigate adverse effects. To establish such a biocompatible system with prolonged drug release behavior, researchers developed an innovative drug carrier. In this study, a sustainable approach was employed to synthesize a new zinc-based metal-organic framework (Zn-MOF) through the reaction between synthesized Schiff base ligands and zinc ions. Comprehensive analyses, including FT-IR, XRD, SEM, BET surface area, and TGA techniques, were employed to thoroughly characterize the frameworks. Following comprehensive characterization, curcumin (CUR) was loaded onto the Zn-MOF, resulting in CUR entrapment efficiency and loading capacity of 79.23 % and 26.11 %, respectively. In vitro evaluations of CUR release from CUR@MOF exhibited controlled release patterns, releasing 78.9 % and 50.0 % of CUR at pH 5.0 and pH 7.4, respectively. To mitigate initial burst release, a coating of the biopolymer sodium alginate (SA) was applied to CUR@Zn-MOF. In vitro CUR release tests indicated that SA/CUR@Zn-MOF outperformed pristine CUR@Zn-MOF. The release of CUR conformed to the Korsmeyer-Peppas model, displaying non-Fickian diffusion. Furthermore, an in vitro cytotoxicity study clearly demonstrated the potent anti-tumor activity of the synthesized CUR@Zn-MOF attributed to its controlled release of CUR. This led to the induction of apoptotic effects and cell death across HeLa, HEK293, and SH-SY5Y cell lines. These findings strongly suggest that the developed pH-sensitive carriers hold remarkable potential as targeted vehicles for drug delivery in cancer therapy., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Crown Copyright © 2023. Published by Elsevier B.V. All rights reserved.)

Phosphorylated microtubule-associated protein tau (tau) aggregates are a pathological hallmark of various neurodegenerative diseases, including chronic traumatic encephalopathy and amyotrophic lateral sclerosis with cognitive impairment. While there are many residues phosphorylated on tau, phosphorylation of threonine 175 (pThr 175 tau) has been shown to initiate fibril formation in vitro and is present in pathological tau aggregates in vivo . Given this, preventing Thr 175 tau phosphorylation presents a potential approach to reduce fibril formation; however, the kinase(s) acting on Thr 175 are not yet fully defined. Using a single controlled cortical impact rodent model of traumatic brain injury (TBI), which rapidly induces Thr 175 tau phosphorylation, we observed an upregulation and alteration in subcellular localization of leucine-rich repeat kinase 2 (LRRK2), a kinase that has been implicated in tau phosphorylation. LRRK2 upregulation was evident by one-day post-injury and persisted to day 10. The most notable changes were observed in microglia at the site of injury in the cortex. To determine if the appearance of pThr 175 tau was causally related to the upregulation of LRRK2 expression, we examined the ability of LRRK2 to phosphorylate Thr 175 in vitro by co-transfecting 2N4R human WT-tau with either LRRK2-WT, constitutively-active LRRK2-G2019S or inactive LRRK2-3XKD. We found no significant difference in the level of pThr 175 tau between the overexpression of LRRK2-WT, -G2019S or -3XKD, suggesting LRRK2 does not phosphorylate tau at Thr 175 . Further, downstream events known to follow Thr 175 phosphorylation and known to be associated with pathological tau fibril formation (pSer 9 -GSK3β and pThr 231 tau induction) also remained unchanged. We conclude that while LRRK2 expression is altered in TBI, it does not contribute directly to pThr 175 tau generation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Donison, Hintermayer, Subramaniam, Santandrea, Volkening and Strong.)

Background: The outcomes for patients with metastatic renal cell carcinoma (RCC) to the spine who underwent stereotactic body radiotherapy (SBRT) through a multidisciplinary spine oncology program are not well described. We sought to describe the clinical course and local control rates at 1 and 2 years for these patients., Methods: A retrospective analysis of a prospectively maintained database of adult oncologic patients receiving SBRT to the spine through a multidisciplinary spine oncology program at a single institution from 2010 to 2021 was performed. Patients with a pathologic diagnosis of RCC were included., Results: A total of 75 spinal sites were treated in 60 patients. Of the 60 patients, 75.0% were men, and the mean patient age was 59.2 ± 11.3 years. At 1 year after treatment, 6 of the 60 patients were lost to follow-up. Of the remaining 54 patients, 18 were censored by death and 7 treatment sites showed local recurrence, for 37 of 44 treatment sites with local control (87.8%). At 2 years, 1 additional local recurrence had developed, 15 patients were censored by death, and no additional patients had been lost to follow-up, resulting in 28 of 36 treatment sites with local control (83.2%). None of the patients who had undergone repeat SBRT had local recurrence at 1 or 2 years. For those with local recurrence, the average time from treatment to progression was 6.6 ± 6.5 months., Conclusions: In this cohort, one of the largest reported studies of spine SBRT for metastatic RCC, local control was high at 1 and 2 years. Our findings support the role of coordinated, algorithmic treatment for these patients., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: As cancer therapies have improved, spinal metastases are increasingly common. Resulting complications have a significant impact on patient's quality of life. Optimal methods of surveillance and avoidance of neurologic deficits are understudied. This study compares the clinical course of patients who initially presented to the emergency department (ED) versus a multidisciplinary spine oncology clinic and who underwent stereotactic body radiation therapy (SBRT) secondary to progression/presentation of metastatic spine disease., Methods: We performed a retrospective analysis of a prospectively maintained database of adult oncologic patients who underwent spinal SBRT at a single hospital from 2010 to 2021. Descriptive statistics and survival analyses were performed., Results: We identified 498 spinal radiographic treatment sites in 390 patients. Of these patients, 118 (30.3%) presented to the ED. Patients presenting to the ED compared to the clinic had significantly more severe spinal compression (52.5% vs. 11.7%; p < 0.0001), severe pain (28.8% vs. 10.3%; p < 0.0001), weakness (24.5% vs. 4.5%; p < 0.0001), and difficulty walking (24.5% vs. 4.5%; p < 0.0001). Patients who presented to the ED compared to the clinic were significantly more likely to have surgical intervention followed by SBRT (55.4% vs. 15.3%; p < 0.0001) compared to SBRT alone. Patients who presented to the ED compared to the clinic had a significantly quicker interval to distant spine progression (5.1 ± 6.5 vs. 9.1 ± 10.2 months; p = 0.004), systemic progression (5.1 ± 7.2 vs. 9.2 ± 10.7 months; p < 0.0001), and worse overall survival (9.3 ± 10.0 vs. 14.3 ± 13.7 months; p = 0.002)., Conclusion: The establishment of multidisciplinary spine oncology clinics is an opportunity to potentially allow for earlier, more data-driven treatment of their spinal metastatic disease., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Referential signaling, a complex form of communication in which specific signals are associated with external referents, was once thought to be limited to primates. Recent research has documented referential signaling in several other cooperative taxa, predominantly in kin-based societies. Here, we show that greater anis, communally nesting birds that breed in nonkin groups, give one type of alarm call in response to aerial threats (flying raptors) and another to more general threats (nonaerial predators). Observational data show that anis give these calls in response to different classes of threats, and playback experiments in the field confirmed that the alarm calls alone are sufficient to elicit appropriate behavioral responses even in the absence of an actual threat. Genetic data on a subset of groups confirmed that breeding groups are composed of nonkin, suggesting that referential alarm calls are often given in situations when no genetic relatives are present. These results suggest that complex referential communication can occur in social groups composed of nonrelatives, despite the absence of kin-selected fitness benefits.

As the world continues to experience the effects of SARS-CoV-2, there is evidence to suggest that the sequelae of viral infection (the post-COVID-19 condition; PCC) at both an individual and population level will be significant and long-lasting. The history of pandemics or epidemics in the last 100 years caused by members of the RNA virus family, of which coronaviruses are a member, provides ample evidence of the acute neurological effects. However, except for the H1N1 influenza pandemic of 1918/1919 (the Spanish flu) with its associated encephalitis lethargica, there is little information on long-term neurological sequelae. COVID-19 is the first pandemic that has occurred in a setting of an aging population, especially in several high-income countries. Its survivors are at the greatest risk for developing neurodegenerative conditions as they age, rendering the current pandemic a unique paradigm not previously witnessed. The SARS-CoV-2 virus, among the largest of the RNA viruses, is a single-stranded RNA that encodes for 29 proteins that include the spike protein that contains the key domains required for ACE2 binding, and a complex array of nonstructural proteins (NSPs) and accessory proteins that ensure the escape of the virus from the innate immune response, allowing for its efficient replication, translation, and exocytosis as a fully functional virion. Increasingly, these proteins are also recognized as potentially contributing to biochemical and molecular processes underlying neurodegeneration. In addition to directly being taken up by brain endothelium, the virus or key protein constituents can be transported to neurons, astrocytes, and microglia by extracellular vesicles and can accelerate pathological fibril formation. The SARS-CoV-2 nucleocapsid protein is intrinsically disordered and can participate in liquid condensate formation, including as pathological heteropolymers with neurodegenerative disease-associated RNA-binding proteins such as TDP-43, FUS, and hnRNP1A. As the SARS-CoV-2 virus continues to mutate under the immune pressure exerted by highly efficacious vaccines, it is evolving into a virus with greater transmissibility but less severity compared with the original strain. The potential of its lingering impact on the nervous system thus has the potential to represent an ongoing legacy of an even greater global health challenge than acute infection., (© 2022 The Author. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Introduction: Understanding synergies between neurodegenerative and cerebrovascular pathologies that modify dementia presentation represents an important knowledge gap., Methods: This multi-site, longitudinal, observational cohort study recruited participants across prevalent neurodegenerative diseases and cerebrovascular disease and assessed participants comprehensively across modalities. We describe univariate and multivariate baseline features of the cohort and summarize recruitment, data collection, and curation processes., Results: We enrolled 520 participants across five neurodegenerative and cerebrovascular diseases. Median age was 69 years, median Montreal Cognitive Assessment score was 25, median independence in activities of daily living was 100% for basic and 93% for instrumental activities. Spousal study partners predominated; participants were often male, White, and more educated. Milder disease stages predominated, yet cohorts reflect clinical presentation., Discussion: Data will be shared with the global scientific community. Within-disease and disease-agnostic approaches are expected to identify markers of severity, progression, and therapy targets. Sampling characteristics also provide guidance for future study design., (© 2022 the Alzheimer's Association.)

The gap between the tremendous burden of neurological disease requiring surgical management and the limited capacity for neurosurgical care has fueled the growth of the global neurosurgical movement. It is estimated that an additional 23 300 neurosurgeons are needed to meet the burden posed by essential cases across the globe. Initiatives to increase neurosurgical capacity through systems strengthening and workforce development are key elements in correcting this deficit. Building on the growing interest in global health among neurosurgical trainees, we propose the integration of targeted public health education into neurosurgical training, in both high-income countries and low- and middle-income countries. This effort will ensure that graduates possess the fundamental skillsets and experience necessary to participate in and lead capacity-building efforts in the developing countries. This additional public health training can also help neurosurgical residents to achieve the core competencies outlined by accreditation boards, such as the Accreditation Committee on Graduate Medical Education in the United States. In this narrative review, we describe the global burden of neurosurgical disease, establish the need and role for the global neurosurgeon, and discuss pathways for implementing targeted global public health education in the field of neurosurgery., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

The fundamental origin of amyotrophic lateral sclerosis (ALS) has remained an enigma since its earliest description as a relentlessly progressive degeneration with prominent neuromuscular manifestations that are associated with upper and lower motor neuron dysfunction. Although this remains the hallmark of ALS, a significant proportion of patients will also demonstrate one or more features of frontotemporal dysfunction, including a frontotemporal dementia (FTD). Understanding whether these 2 seemingly disparate syndromes are simply reflective of the co-occurrence of 2 distinct pathologic processes or the clinical manifestations of a common pathophysiologic derangement involving the brain more widely has gripped contemporary ALS researchers. Supporting a commonality of causation, both ALS and FTD show an alteration in the metabolism of TAR DNA-binding protein 43, marked by a shift in nucleocytoplasmic localization alongside a broad range of neuronal cytoplasmic inclusions consisting of pathologic aggregates of RNA-binding proteins. Similarly, several disease-associated or disease-modifying genetic variants that are shared between the 2 disorders suggest shared underlying mechanisms. In both, a prominent glial response has been postulated to contribute to non-cell-autonomous spread. A more contemporary hypothesis, however, suggests that syndromes of cortical and subcortical dysfunction are driven by impairments in discrete neural networks. This postulates that such networks, including networks subserving motor or cognitive function, possess unique and selective vulnerabilities to either single molecular toxicities or combinations thereof. The co-occurrence of one or more network dysfunctions in ALS and FTD is thus a reflection not of unique neuroanatomic correlates but rather of shared molecular vulnerabilities. The basis of such shared vulnerabilities becomes the fulcrum around which the next advances in our understanding of ALS and its possible therapy will develop., (© 2022 American Academy of Neurology.)

Objective: Changes to neurosurgical practices during the coronavirus disease 2019 (COVID-19) pandemic have not been thoroughly analyzed. We report the effects of operative restrictions imposed under variable local COVID-19 infection rates and health care policies using a retrospective multicenter cohort study and highlight shifts in operative volumes and subspecialty practice., Methods: Seven academic neurosurgery departments' neurosurgical case logs were collected; procedures in April 2020 (COVID-19 surge) and April 2019 (historical control) were analyzed overall and by 6 subspecialties. Patient acuity, surgical scheduling policies, and local surge levels were assessed., Results: Operative volume during the COVID-19 surge decreased 58.5% from the previous year (602 vs. 1449, P = 0.001). COVID-19 infection rates within departments' counties correlated with decreased operative volume (r = 0.695, P = 0.04) and increased patient categorical acuity (P = 0.001). Spine procedure volume decreased by 63.9% (220 vs. 609, P = 0.002), for a significantly smaller proportion of overall practice during the COVID-19 surge (36.5%) versus the control period (42.0%) (P = 0.02). Vascular volume decreased by 39.5% (72 vs. 119, P = 0.01) but increased as a percentage of caseload (8.2% in 2019 vs. 12.0% in 2020, P = 0.04). Neuro-oncology procedure volume decreased by 45.5% (174 vs. 318, P = 0.04) but maintained a consistent proportion of all neurosurgeries (28.9% in 2020 vs. 21.9% in 2019, P = 0.09). Functional neurosurgery volume, which declined by 81.4% (41 vs. 220, P = 0.008), represented only 6.8% of cases during the pandemic versus 15.2% in 2019 (P = 0.02)., Conclusions: Operative restrictions during the COVID-19 surge led to distinct shifts in neurosurgical practice, and local infective burden played a significant role in operative volume and patient acuity., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Retropleural, retrodiaphragmatic, and retroperitoneal approaches are utilized to access difficult thoracolumbar junction (T10-L2) pathology. The authors present a 58-year-old man with chronic low-back pain who failed years of conservative therapy. Preoperative radiographs demonstrated significant levoconvex scoliosis with coronal and sagittal imbalance. He underwent a retrodiaphragmatic/retroperitoneal approach for T12-L1, L1-2, L2-3, and L3-4 interbody release and fusion in conjunction with second-stage facet osteotomies, L4-5 TLIF, and T10-iliac posterior instrumented fusion. This video focuses on the retrodiaphragmatic approach assisted by 3D navigation. The video can be found here: https://stream.cadmore.media/r10.3171/2022.3.FOCVID2215., Competing Interests: Disclosures Dr. Park reported personal fees from Globus, NuVasive, DePuy Synthes, and Accelus; and grants from DePuy Synthes, Cerapedics, SI-BONE, and ISSG, outside the submitted work.Dr. Park reported personal fees from Globus, NuVasive, DePuy Synthes, and Accelus; and grants from DePuy Synthes, Cerapedics, SI-BONE, and ISSG, outside the submitted work., (© 2022, The Authors.)

Introduction: Glioblastoma (GBM) is a devastating disease with poor overall survival. Despite the common occurrence of GBM among primary brain tumors, metastatic disease is rare. Our goal was to perform a systematic literature review on GBM with osseous metastases and understand the rate of metastasis to the vertebral column as compared to the remainder of the skeleton, and how this histology would fit into our current paradigm of treatment for bone metastases., Methods: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-compliant literature search was performed using the PubMed database from 1952 to 2021. Search terms included "GBM", "glioblastoma", "high-grade glioma", "bone metastasis", and "bone metastases"., Results: Of 659 studies initially identified, 67 articles were included in the current review. From these 67 articles, a total of 92 distinct patient case presentations of metastatic glioblastoma to bone were identified. Of these cases, 58 (63%) involved the vertebral column while the remainder involved lesions within the skull, sternum, rib cage, and appendicular skeleton., Conclusion: Metastatic dissemination of GBM to bone occurs. While the true incidence is unknown, workup for metastatic disease, especially involving the spinal column, is warranted in symptomatic patients. Lastly, management of patients with GBM vertebral column metastases can follow the International Spine Oncology Consortium two-step multidisciplinary algorithm for the management of spinal metastases., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Roughly 400,000 people in the U.S. are living with bone metastases, the vast majority occurring in the spine. Metastases to the spine result in fractures, pain, paralysis, and significant health care costs. This predilection for cancer to metastasize to the bone is seen across most cancer histologies, with the greatest incidence seen in prostate, breast, and lung cancer. The molecular process involved in this predilection for axial versus appendicular skeleton is not fully understood, although it is likely that a combination of tumor and local micro-environmental factors plays a role. Immune cells are an important constituent of the bone marrow microenvironment and many of these cells have been shown to play a significant role in tumor growth and progression in soft tissue and bone disease. With this in mind, we sought to examine the differences in immune landscape between axial and appendicular bones in the normal noncancerous setting in order to obtain an understanding of these landscapes. To accomplish this, we utilized mass cytometry by time-of-flight (CyTOF) to examine differences in the immune cell landscapes between the long bone and vertebral body bone marrow from patient clinical samples and C57BL/6J mice. We demonstrate significant differences between immune populations in both murine and human marrow with a predominance of myeloid progenitor cells in the spine. Additionally, cytokine analysis revealed differences in concentrations favoring a more myeloid enriched population of cells in the vertebral body bone marrow. These differences could have clinical implications with respect to the distribution and permissive growth of bone metastases., Competing Interests: The authors have declared that no competing interests exist.

Background: Syringomyelia has a long-established association with pediatric scoliosis, but few data exist on the relationship of syringomyelia to pediatric kyphotic deformities., Observations: This report reviewed a unique case of rapid and sustained regression of syringomyelia in a 13-year-old girl after surgical correction of iatrogenic kyphotic deformity., Lessons: In cases of syringomyelia associated with acquired spinal deformity, treatment of deformity to resolve an associated subarachnoid block should be considered because it may obviate the need for direct treatment of syrinx.

Objective: In the era of modern medicine with an armamentarium full of state-of-the art technologies at our disposal, the incidence of wrong-level spinal surgery remains problematic. In particular, the thoracic spine presents a challenge for accurate localization due partly to body habitus, anatomical variations, and radiographic artifact from the ribs and scapula. The present review aims to assess and describe thoracic spine localization techniques., Methods: The authors performed a literature search using the PubMed database from 1990 to 2020, compliant with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A total of 27 articles were included in this qualitative review., Results: A number of pre- and intraoperative strategies have been devised and employed to facilitate correct-level localization. Some of the more well-described approaches include fiducial metallic markers (screw or gold), metallic coils, polymethylmethacrylate, methylene blue, marking wire, use of intraoperative neuronavigation, intraoperative localization techniques (including using a needle, temperature probe, fluoroscopy, MRI, and ultrasonography), and skin marking., Conclusions: While a number of techniques exist to accurately localize lesions in the thoracic spine, each has its advantages and disadvantages. Ultimately, the localization technique deployed by the spine surgeon will be patient-specific but often based on surgeon preference.

Background: Single-position prone lateral interbody fusion is a recently introduced technical modification of the minimally invasive retroperitoneal transpsoas approach for lateral lumbar interbody fusion (LLIF). Several technical descriptions of single-position prone LLIF have been published with traditional fluoroscopy for guidance. However, there has been no investigation of either three-dimensional computed tomography-based navigation for prone LLIF or integration with robotic assistance platforms with the prone lateral technique. This study evaluated the feasibility and safety of spinal navigation and robotic assistance for single-position prone LLIF., Methods: Retrospective review of medical records and a prospectively acquired database for a single center was performed to examine immediate and 30-day clinical and radiographic outcomes for consecutive patients undergoing single-position prone LLIF with spinal navigation and/or robotic assistance., Results: Nine patients were treated, 4 women and 5 men. Mean age was 65.4 years (range, 46-75 years), and body mass index was 30.2 kg/m 2 (range, 24-38 kg/m 2 ). The most common surgical indication was adjacent segment disease (44.4%), followed by pseudarthrosis (22.2%), spondylolisthesis (11.1%), degenerative disc disease (11.1%), and recurrent stenosis (11.1%). Postoperative approach-related complications included pain-limited bilateral hip flexor weakness (4/5) and pain-limited left knee extension weakness (4/5) in 1 patient (11.1%) and right lateral thigh numbness and dysesthesia in 1 patient (11.1%). All cages were placed within quarters 2-3, signifying the middle portion of the disc space. There were no instances of misguidance by navigation., Conclusions: Integration of spinal navigation and robotic assistance appears feasible, accurate, and safe as an alternative to fluoroscopic guidance for single-position LLIF., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), can be clinically heterogeneous which may be explained by the co-inheritance of multiple genetic variants that modify the clinical course. In this study we examine variants in three genes in a family with one individual presenting with ALS and lipodystrophy. Sequencing revealed a p.Gly602Ser variant in LMNA, and two additional variants, one each in SETX (g.intron10-13delCTT) and FUS (p.Gly167&#95;Gly168del). These latter genes have been linked to ALS. All family members were genotyped and each variant, and each combination of variants detected, were functionally evaluated in vitro regarding effects on cell survival, expression patterns and cellular phenotype. Muscle biopsy retrieved from the individual with ALS showed leakage of chromatin from the nucleus, a phenotype that was recapitulated in vitro with expression of all three variants simultaneously. Individually expressed variants gave cellular phenotypes there were unremarkable. Interestingly the FUS variant appears to be protective against the effects of the SETX and the LMNA variants on cell viability and may indicate loss of interaction of FUS with SETX and/or R-loops. We conclude that these findings support genetic modifications as an explanation of the clinical heterogeneity observed in human disease.

Schwannomas are typically benign tumors that arise from the sheaths of nerves in the peripheral nervous system. In the spine, schwannomas usually arise from spinal nerve roots and are therefore extramedullary in nature. Surgical resection-achieving a gross total resection, is the main treatment modality and is typically curative for patients with sporadic tumors. In this video, we present the case of a 38-yr-old male with worsening left leg radiculopathy, found to have a lumbar schwannoma. Preoperative imaging demonstrated that the tumor was at the level of L4-L5. A laminectomy at this level was performed with gross total resection of the tumor. The key points of the video include use of intraoperative fluoroscopy to confirm surgical level and help plan surgical exposure, use of ultrasound for intradural tumor localization, and advocating for maximum safe resection using neurostimulation. The patient tolerated the surgery well without any complications. He was discharged home with no additional therapy needed. Appropriate patient consent was obtained., (© Congress of Neurological Surgeons 2021.)

Stress granules (SGs) are phase-separated, membraneless, cytoplasmic ribonucleoprotein (RNP) assemblies whose primary function is to promote cell survival by condensing translationally stalled mRNAs, ribosomal components, translation initiation factors, and RNA-binding proteins (RBPs). While the protein composition and the function of proteins in the compartmentalization and the dynamics of assembly and disassembly of SGs has been a matter of study for several years, the role of RNA in these structures had remained largely unknown. RNA species are, however, not passive members of RNA granules in that RNA by itself can form homo and heterotypic interactions with other RNA molecules leading to phase separation and nucleation of RNA granules. RNA can also function as molecular scaffolds recruiting multivalent RBPs and their interactors to form higher-order structures. With the development of SG purification techniques coupled to RNA-seq, the transcriptomic landscape of SGs is becoming increasingly understood, revealing the enormous potential of RNA to guide the assembly and disassembly of these transient organelles. SGs are not only formed under acute stress conditions but also in response to different diseases such as viral infections, cancer, and neurodegeneration. Importantly, these granules are increasingly being recognized as potential precursors of pathological aggregates in neurodegenerative diseases. In this review, we examine the current evidence in support of RNA playing a significant role in the formation of SGs and explore the concept of SGs as therapeutic targets., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Campos-Melo, Hawley, Droppelmann and Strong.)

Nonunion of a type II odontoid fracture after the placement of an anterior odontoid screw can occur despite careful patient selection. Countervailing factors to successful fusion include the vascular watershed zone between the odontoid process and body of C2 as well as the relatively low surface area available for fusion. Patient-specific factors include osteoporosis, advanced age, and poor fracture fragment apposition. Cervical 1-2 posterior instrumented fusion is indicated for symptomatic nonunion. The technique leverages the larger posterolateral surface area for fusion and does not rely on bony growth in a watershed zone. Although loss of up to half of cervical rotation is expected after C1-2 arthrodesis, this may be better tolerated in the elderly, who may have lower physical demands than younger patients. In this video, we discuss the case of a 75-yr-old woman presenting with intractable mechanical cervicalgia 7 mo after sustaining a type II odontoid fracture and undergoing anterior odontoid screw placement at an outside institution. Cervical radiography and computed tomography exhibited haloing around the screw and nonunion across the fracture. We demonstrate C1-2 posterior instrumented fusion with Goel-Harms technique (C1 lateral mass and C2 pedicle screws), utilizing computer-assisted navigation, and modified Sonntag technique with rib strut autograft. Posterior C1-2-instrumented fusion with rib strut autograft is an essential technique in the spine surgeon's armamentarium for the management of C1-2 instability, which can be a sequela of type II dens fracture. Detailed video demonstration has not been published to date. Appropriate patient consent was obtained., (© Congress of Neurological Surgeons 2021.)