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Reflecting the first wave COVID-19 pandemic in Central Europe (i.e. March 16th–April 15th, 2020) the neurosurgical community witnessed a general diminution in the incidence of emergency neurosurgical cases, which was impelled by a reduced number of traumatic brain injuries (TBI), spine conditions, and chronic subdural hematomas (CSDH). This appeared to be associated with restrictions imposed on mobility within countries but also to possible delayed patient introduction and interdisciplinary medical counseling. In response to one year of COVID-19 experience, also mapping the third wave of COVID-19 in 2021 (i.e. March 16 to April 15, 2021), we aimed to reevaluate the current prevalence and outcomes for emergency non-elective neurosurgical cases in COVID-19-negative patients across Austria and the Czech Republic. The primary analysis was focused on incidence and 30-day mortality in emergency neurosurgical cases compared to four preceding years (2017–2020). A total of 5077 neurosurgical emergency cases were reviewed. The year 2021 compared to the years 2017–2019 was not significantly related to any increased odds of 30 day mortality in Austria or in the Czech Republic. Recently, there was a significant propensity toward increased incidence rates of emergency non-elective neurosurgical cases during the third COVID-19 pandemic wave in Austria, driven by their lower incidence during the first COVID-19 wave in 2020. Selected neurosurgical conditions commonly associated with traumatic etiologies including TBI, and CSDH roughly reverted to similar incidence rates from the previous non-COVID-19 years. Further resisting the major deleterious effects of the continuing COVID-19 pandemic, it is edifying to notice that the neurosurgical community´s demeanor to the recent third pandemic culmination keeps the very high standards of non-elective neurosurgical care alongside with low periprocedural morbidity. This also reflects the current state of health care quality in the Czech Republic and Austria.

The optic nerve sheath diameter (ONSD) can predict elevated intracranial pressure (ICP) but it is not known whether diagnostic characteristics differ between men and women. This observational study was performed at the Karolinska University Hospital in Sweden to assess sex differences in diagnostic accuracy for ONSD. We included 139 patients (65 women), unconscious and/or sedated, with invasive ICP monitoring. Commonly used ONSD derived measurements and associated ICP measurements were collected. Linear regression analyses were performed with ICP as dependent variable and ONSD as independent variable. Area under the receiver operator characteristics curve (AUROC) analyses were performed with a threshold for elevated ICP ≥ 20 mmHg. Analyses were stratified by sex. Optimal cut-offs and diagnostic characteristics were estimated. The ONSD was associated with ICP in women. The AUROCs in women ranged from 0.70 to 0.83. In men, the ONSD was not associated with ICP and none of the AUROCs were significantly larger than 0.5. This study suggests that ONSD is a useful predictor of ICP in women but may not be so in men. If this finding is verified in further studies, this would call for a re-evaluation of the usage and interpretation of ONSD to estimate ICP.

We identified a PSEN1 (presenilin 1) mutation carrier from the world’s largest autosomal dominant Alzheimer’s disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer’s disease.

Inflammasomes are molecular scaffolds that are activated by damage-associated and pathogen-associated molecular patterns and form a key element of innate immune responses. Consequently, the involvement of inflammasomes in several diseases that are characterized by inflammatory processes, such as multiple sclerosis, is widely appreciated. However, many other neurological conditions, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, stroke, epilepsy, traumatic brain injury, sepsis-associated encephalopathy and neurological sequelae of COVID-19, all involve persistent inflammation in the brain, and increasing evidence suggests that inflammasome activation contributes to disease progression in these conditions. Understanding the biology and mechanisms of inflammasome activation is, therefore, crucial for the development of inflammasome-targeted therapies for neurological conditions. In this Review, we present the current evidence for and understanding of inflammasome activation in neurological diseases and discuss current and potential interventional strategies that target inflammasome activation to mitigate its pathological consequences.Increasing evidence suggests that inflammasome activation contributes to disease progression in a wide variety of neurological conditions. In this Review, Ravichandran and Heneka discuss current understanding of inflammasome activation in neurological disorders and consider interventional strategies that target inflammasome activation.

Switching locomotion direction is a common task in daily life, and it has been studied extensively in healthy people. Little is known, however, about the locomotor adjustments involved in changing locomotion direction from forward (FW) to sideways (SW) in children with cerebral palsy (CP). The importance of testing the ability of children with CP in this task lies in the assessment of flexible, adaptable adjustments of locomotion as a function of the environmental context. On the one hand, the ability of a child to cope with novel task requirements may provide prognostic cues as to the chances of modifying the gait adaptively. On the other hand, challenging the child with the novel task may represent a useful rehabilitation tool to improve the locomotor performance. SW is an asymmetrical locomotor task and requires a differential control of right and left limb muscles. Here, we report the results of a cross-sectional study comparing FW and SW in 27 children with CP (17 diplegic, 10 hemiplegic, 2–10 years) and 18 age-matched typically developing (TD) children. We analyzed gait kinematics, joint moments, EMG activity of 12 pairs of bilateral muscles, and muscle modules evaluated by factorization of EMG signals. Task performance in several children with CP differed drastically from that of TD children. Only 2/3 of children with CP met the primary outcome, i.e. they succeeded to step sideways, and they often demonstrated attempts to step forward. They tended to rotate their trunk FW, cross one leg over the other, flex the knee and hip. Moreover, in contrast to TD children, children with CP often exhibited similar motor modules for FW and SW. Overall, the results reflect developmental deficits in the control of gait, bilateral coordination and adjustment of basic motor modules in children with CP. We suggest that the sideways (along with the backward) style of locomotion represents a novel rehabilitation protocol that challenges the child to cope with novel contextual requirements.

Blood-derived biomarkers for brain and spinal cord diseases are urgently needed. The introduction of highly sensitive immunoassays led to a rapid increase in the number of potential blood-derived biomarkers for diagnosis and monitoring of neurological disorders. In 2018, the FDA authorized a blood test for clinical use in the evaluation of mild traumatic brain injury (TBI). The test measures levels of the astrocytic intermediate filament glial fibrillary acidic protein (GFAP) and neuroaxonal marker ubiquitin carboxy-terminal hydrolase L1. In TBI, blood GFAP levels are correlated with clinical severity and extent of intracranial pathology. Evidence also indicates that blood GFAP levels hold the potential to reflect, and might enable prediction of, worsening of disability in individuals with progressive multiple sclerosis. A growing body of evidence suggests that blood GFAP levels can be used to detect even subtle injury to the CNS. Most importantly, the successful completion of the ongoing validation of point-of-care platforms for blood GFAP might ameliorate the decision algorithms for acute neurological diseases, such as TBI and stroke, with important economic implications. In this Review, we provide a systematic overview of the evidence regarding the utility of blood GFAP as a biomarker in neurological diseases. We propose a model for GFAP concentration dynamics in different conditions and discuss the limitations that hamper the widespread use of GFAP in the clinical setting. In our opinion, the clinical use of blood GFAP measurements has the potential to contribute to accelerated diagnosis and improved prognostication, and represents an important step forward in the era of precision medicine.In this Review, the authors provide an overview of the evidence regarding the use of blood levels of glial fibrillary acidic protein as a biomarker in a range of neurological diseases, including traumatic brain injury, stroke, multiple sclerosis and Alzheimer disease.

Dementia have substantial negative impact on the affected individual, their care partners and society. Persons living with Parkinson’s disease (PwP) are also to a large extent living with dementia. The aim of this study is to estimate time to dementia in PD using data from a large quality register with access to baseline clinical and patient reported data merged with Swedish national health registries. Persons with Parkinson’s disease in the Swedish Neuro Registries/Parkinson’s Disease Swedish PD Registry (PARKreg) in Sweden were included and linked to national health registries and matched by sex and age to controls without PD. Time to dementia was analysed with Cox regression models assuming proportional hazards, with time since diagnosis as the underlying time variable. In this large prospective cohort study, PwP had approximately four times higher risk of developing dementia as compared to age and sex-matched controls, a finding which remained after adjusting for potential confounders. The present results underline the high risk of dementia in PD and further emphasize the importance of developing symptomatic and ultimately disease modifying strategies to counteract this part of the non-motor symptomatology in PD.

Accuracy in copying a figure is one of the most sensitive measures of visuo-constructional ability. However, drawing tasks also involve other cognitive and motor abilities, which may influence the final graphic produced. Nevertheless, these aspects are not taken into account in conventional scoring methodologies. In this study, we have implemented a novel Tablet-based assessment, acquiring data and information for the entire execution of the Rey Complex Figure copy task (T-RCF). This system extracts 12 indices capturing various dimensions of drawing abilities. We have also analysed the structure of relationships between these indices and provided insights into the constructs that they capture. 102 healthy adults completed the T-RCF. A subgroup of 35 participants also completed a paper-and-pencil drawing battery from which constructional, procedural, and motor measures were obtained. Principal component analysis of the T-RCF indices was performed, identifying spatial, procedural and kinematic components as distinct dimensions of drawing execution. Accordingly, a composite score for each dimension was determined. Correlational analyses provided indications of their validity by showing that spatial, procedural, and kinematic scores were associated with constructional, organisational and motor measures of drawing, respectively. Importantly, final copy accuracy was found to be associated with all of these aspects of drawing. In conclusion, copying complex figures entails an interplay of multiple functions. T-RCF provides a unique opportunity to analyse the entire drawing process and to extract scores for three critical dimensions of drawing execution.

The genetic underpinnings and end-stage pathological hallmarks of neurodegenerative diseases are increasingly well defined, but the cellular pathophysiology of disease initiation and propagation remains poorly understood, especially in sporadic forms of these diseases. Altered nucleocytoplasmic transport is emerging as a prominent pathomechanism of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer disease, frontotemporal dementia and Huntington disease. The nuclear pore complex (NPC) and interactions between its individual nucleoporin components and nuclear transport receptors regulate nucleocytoplasmic transport, as well as genome organization and gene expression. Specific nucleoporin abnormalities have been identified in sporadic and familial forms of neurodegenerative disease, and these alterations are thought to contribute to disrupted nucleocytoplasmic transport. The specific nucleoporins and nucleocytoplasmic transport proteins that have been linked to different neurodegenerative diseases are partially distinct, suggesting that NPC injury contributes to the cellular specificity of neurodegenerative disease and could be an early initiator of the pathophysiological cascades that underlie neurodegenerative disease. This concept is consistent with the fact that rare genetic mutations in some nucleoporins cause cell-type-specific neurological disease. In this Review, we discuss nucleoporin and NPC disruptions and consider their impact on cellular function and the pathophysiology of neurodegenerative disease.In this Review, Coyne and Rothstein discuss disruptions to the nuclear pore complex and nucleocytoplasmic transport, which are emerging as pathological mechanisms in multiple neurodegenerative diseases, and consider the effects of these changes on cellular function and their potential for therapeutic targeting.

Key Points Vascular endothelial growth factor (VEGF) has been implicated in the aetiology and treatment of various neurological diseases VEGF exerts effects on multiple cell types in the nervous system, including endothelial cells, neurons, astrocytes, microglia, oligodendrocytes and Schwann cells VEGF protects neurons and fosters neurogenesis, and reduced VEGF levels contribute to neurodegenerative disorders VEGF can improve brain perfusion, partly by promoting angiogenesis, but pathological VEGF levels induce blood–brain barrier breakdown and vessel leakage Preclinical studies indicate that VEGF administration is beneficial in neurodegenerative diseases, peripheral neuropathies and epilepsy VEGF inhibition is approved as a treatment for neovascular ocular diseases, and might be beneficial in other neurological disorders involving BBB breakdown or excessive angiogenesis The archetypal vascular endothelial growth factor, VEGF, arose in evolution as a signal affecting neural cells, and was subsequently co-opted to regulate vascular function. Here, the authors review the roles of the VEGF family as both aetiological factors and therapeutic targets in neurological disease. Brain function critically relies on blood vessels to supply oxygen and nutrients, to establish a barrier for neurotoxic substances, and to clear waste products. The archetypal vascular endothelial growth factor, VEGF, arose in evolution as a signal affecting neural cells, but was later co-opted by blood vessels to regulate vascular function. Consequently, VEGF represents an attractive target to modulate brain function at the neurovascular interface. On the one hand, VEGF is neuroprotective, through direct effects on neural cells and their progenitors and indirect effects on brain perfusion. In accordance, preclinical studies show beneficial effects of VEGF administration in neurodegenerative diseases, peripheral neuropathies and epilepsy. On the other hand, pathologically elevated VEGF levels enhance vessel permeability and leakage, and disrupt blood–brain barrier integrity, as in demyelinating diseases, for which blockade of VEGF may be beneficial. Here, we summarize current knowledge on the role and therapeutic potential of VEGF in neurological diseases.