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Traumatic brain injury (TBI) heterogeneity remains a critical barrier to translating therapies. Identifying final common pathways/molecular signatures that integrate this heterogeneity informs biomarker and therapeutic-target development. We present the first large-scale murine single-cell atlas of the transcriptomic response to TBI (334,376 cells) across clinically relevant models, sex, brain region, and time as a foundational step in molecularly deconstructing TBI heterogeneity. Results were unique to cell populations, injury models, sex, brain regions, and time, highlighting the importance of cell-level resolution. We identify cell-specific targets and previously unrecognized roles for microglial and ependymal subtypes. Ependymal-4 was a hub of neuroinflammatory signaling. A distinct microglial lineage shared features with disease-associated microglia at 24 h, with persistent gene-expression changes in microglia-4 even 6 months after contusional TBI, contrasting all other cell types that mostly returned to naive levels. Regional and sexual dimorphism were noted. CEREBRI, our searchable atlas (https://shiny.crc.pitt.edu/cerebri/), identifies previously unrecognized cell subtypes/molecular targets and is a leverageable platform for future efforts in TBI and other diseases with overlapping pathophysiology.
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Despite the high incidence and burden of stroke, biological biomarkers are not used routinely in clinical practice to diagnose, determine progression, or prognosticate outcomes of acute ischemic stroke (AIS). Because of its direct interface with neural tissue, cerebrospinal fluid (CSF) is a potentially valuable source for biomarker development. This systematic review was conducted using three databases. All trials investigating clinical and preclinical models for CSF biomarkers for AIS diagnosis, prognostication, and severity grading were included, yielding 22 human trials and five animal studies for analysis. In total, 21 biomarkers and other multiomic proteomic markers were identified. S100B, inflammatory markers (including tumor necrosis factor-alpha and interleukin 6), and free fatty acids were the most frequently studied biomarkers. The review showed that CSF is an effective medium for biomarker acquisition for AIS. Although CSF is not routinely clinically obtained, a potential benefit of CSF studies is identifying valuable biomarkers from the pathophysiologic microenvironment that ultimately inform optimization of targeted low-abundance assays from peripheral biofluid samples (e.g., plasma). Several important catabolic and anabolic markers can serve as effective measures of diagnosis, etiology identification, prognostication, and severity grading. Trials with large cohorts studying the efficacy of biomarkers in altering clinical management are still needed.
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Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular Isquémico/diagnóstico , Proteómica , Accidente Cerebrovascular/diagnóstico , Biomarcadores , Ácidos Grasos no EsterificadosRESUMEN
OBJECTIVES: Addressing traumatic brain injury (TBI) heterogeneity is increasingly recognized as essential for therapy translation given the long history of failed clinical trials. We evaluated differential effects of a promising treatment (glibenclamide) based on dose, TBI type (patient selection), and imaging endophenotype (outcome selection). Our goal to inform TBI precision medicine is contextually timely given ongoing phase 2/planned phase 3 trials of glibenclamide in brain contusion. DESIGN: Blinded randomized controlled preclinical trial of glibenclamide on MRI endophenotypes in two established severe TBI models: controlled cortical impact (CCI, isolated brain contusion) and CCI+hemorrhagic shock (HS, clinically common second insult). SETTING: Preclinical laboratory. SUBJECTS: Adult male C57BL/6J mice (n = 54). INTERVENTIONS: Mice were randomized to naïve, CCI±HS with vehicle/low-dose (20 µg/kg)/high-dose glibenclamide (10 µg/mouse). Seven-day subcutaneous infusions (0.4 µg/hr) were continued. MEASUREMENTS AND MAIN RESULTS: Serial MRI (3 hr, 6 hr, 24 hr, and 7 d) measured hematoma and edema volumes, T2 relaxation (vasogenic edema), apparent diffusion coefficient (ADC, cellular/cytotoxic edema), and 7-day T1-post gadolinium values (blood-brain-barrier [BBB] integrity). Linear mixed models assessed temporal changes. Marked heterogeneity was observed between CCI versus CCI+HS in terms of different MRI edema endophenotypes generated (all p < 0.05). Glibenclamide had variable impact. High-dose glibenclamide reduced hematoma volume ~60% after CCI (p = 0.0001) and ~48% after CCI+HS (p = 4.1 × 10-6) versus vehicle. Antiedema benefits were primarily in CCI: high-dose glibenclamide normalized several MRI endophenotypes in ipsilateral cortex (all p < 0.05, hematoma volume, T2, ADC, and T1-post contrast). Acute effects (3 hr) were specific to hematoma (p = 0.001) and cytotoxic edema reduction (p = 0.0045). High-dose glibenclamide reduced hematoma volume after TBI with concomitant HS, but antiedema effects were not robust. Low-dose glibenclamide was not beneficial. CONCLUSIONS: High-dose glibenclamide benefitted hematoma volume, vasogenic edema, cytotoxic edema, and BBB integrity after isolated brain contusion. Hematoma and cytotoxic edema effects were acute; longer treatment windows may be possible for vasogenic edema. Our findings provide new insights to inform interpretation of ongoing trials as well as precision design (dose, sample size estimation, patient selection, outcome selection, and Bayesian analysis) of future TBI trials of glibenclamide.
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Contusión Encefálica , Edema Encefálico , Lesiones Traumáticas del Encéfalo , Lesiones Encefálicas , Animales , Masculino , Ratones , Teorema de Bayes , Contusión Encefálica/complicaciones , Contusión Encefálica/tratamiento farmacológico , Edema Encefálico/diagnóstico por imagen , Edema Encefálico/tratamiento farmacológico , Edema Encefálico/etiología , Lesiones Encefálicas/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/complicaciones , Modelos Animales de Enfermedad , Endofenotipos , Gliburida/farmacología , Gliburida/uso terapéutico , Imagen por Resonancia Magnética , Ratones Endogámicos C57BLRESUMEN
The choroid plexus, located in the ventricular system of the central nervous system (CNS), obtains numerous roles critical for the proper development and operating of the CNS. The functions range from the best-known ones of the barrier and cerebrospinal fluid (CSF) producer, through participation in immune answer, 'nourishment, detoxification and reparation of the rest of the CNS. Increase number of studies point out the association between choroid plexus dysfunction, characterized by alterations in secretory, transport and barrier capabilities, and the broad spectrum of clinical conditions, as well as physiological aging. We present a brief overview of pathological states known or speculated to be connected to choroid plexus dysfunction, ranging from neurodevelopmental, to autoimmune and neurodegenerative diseases. We also cover the topic of choroid plexus tumors, as well explained involvement of the choroid plexus in pathogen invasion of the CNS, also referring to the currently actual SARS-CoV-2 infection. Finally, we have also touched conducted studies on the choroid plexus regenerative potential. With the information provided in the review we want to point out the importance and call for further research on the role of the choroid plexus in the sustainability of central nervous system health.
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Encefalopatías , COVID-19 , Barrera Hematoencefálica , Plexo Coroideo , Humanos , SARS-CoV-2RESUMEN
INTRODUCTION: Cerebral edema is a key contributor to death and disability in several forms of brain injury. Current treatment options are limited, reactive, and associated with significant morbidity. Targeted therapies are emerging based on a growing understanding of the molecular underpinnings of cerebral edema. AREAS COVERED: We review the pathophysiology and relationships between different cerebral edema subtypes to provide a foundation for emerging therapies. Mechanisms for promising molecular targets are discussed, with an emphasis on those advancing in clinical trials, including ion and water channels (AQP4, SUR1-TRPM4) and other proteins/lipids involved in edema signaling pathways (AVP, COX2, VEGF, and S1P). Research on novel treatment modalities for cerebral edema [including recombinant proteins and gene therapies] is presented and finally, insights on reducing secondary injury and improving clinical outcome are offered. EXPERT OPINION: Targeted molecular strategies to minimize or prevent cerebral edema are promising. Inhibition of SUR1-TRPM4 (glyburide/glibenclamide) and VEGF (bevacizumab) are currently closest to translation based on advances in clinical trials. However, the latter, tested in glioblastoma multiforme, has not demonstrated survival benefit. Research on recombinant proteins and gene therapies for cerebral edema is in its infancy, but early results are encouraging. These newer modalities may facilitate our understanding of the pathobiology underlying cerebral edema.
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Edema Encefálico , Canales Catiónicos TRPM , Edema Encefálico/terapia , Gliburida/farmacología , Humanos , Receptores de Sulfonilureas/genética , Receptores de Sulfonilureas/metabolismo , Canales Catiónicos TRPM/genética , Canales Catiónicos TRPM/metabolismoRESUMEN
Sulfonylurea receptor 1 (SUR1) is a member of the adenosine triphosphate (ATP)-binding cassette (ABC) protein superfamily, encoded by Abcc8, and is recognized as a key mediator of central nervous system (CNS) cellular swelling via the transient receptor potential melastatin 4 (TRPM4) channel. Discovered approximately 20 years ago, this channel is normally absent in the CNS but is transcriptionally upregulated after CNS injury. A comprehensive review on the pathophysiology and role of SUR1 in the CNS was published in 2012. Since then, the breadth and depth of understanding of the involvement of this channel in secondary injury has undergone exponential growth: SUR1-TRPM4 inhibition has been shown to decrease cerebral edema and hemorrhage progression in multiple preclinical models as well as in early clinical studies across a range of CNS diseases including ischemic stroke, traumatic brain injury, cardiac arrest, subarachnoid hemorrhage, spinal cord injury, intracerebral hemorrhage, multiple sclerosis, encephalitis, neuromalignancies, pain, liver failure, status epilepticus, retinopathies and HIV-associated neurocognitive disorder. Given these substantial developments, combined with the timeliness of ongoing clinical trials of SUR1 inhibition, now, another decade later, we review advances pertaining to SUR1-TRPM4 pathobiology in this spectrum of CNS disease-providing an overview of the journey from patch-clamp experiments to phase III trials.
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Lesiones Encefálicas/patología , Enfermedades del Sistema Nervioso Central/patología , Receptores de Sulfonilureas/metabolismo , Animales , Lesiones Encefálicas/etiología , Lesiones Encefálicas/metabolismo , Enfermedades del Sistema Nervioso Central/etiología , Enfermedades del Sistema Nervioso Central/metabolismo , HumanosRESUMEN
Tauopathies represent a heterogeneous group of neurodegenerative disorders characterized by abnormal deposition of the hyperphosphorylated microtubule-associated protein tau. Chronic neuroinflammation in tauopathies is driven by glial cells that potentially trigger the disruption of the blood-brain barrier (BBB). Pro-inflammatory signaling molecules such as cytokines, chemokines and adhesion molecules produced by glial cells, neurons and endothelial cells, in general, cooperate to determine the integrity of BBB by influencing vascular permeability, enhancing migration of immune cells and altering transport systems. We considered the effect of tau about vascular permeability of peripheral blood cells in vitro and in vivo using primary rat BBB model and transgenic rat model expressing misfolded truncated protein tau. Immunohistochemistry, electron microscopy and transcriptomic analysis were employed to characterize the structural and functional changes in BBB manifested by neurofibrillary pathology in a transgenic model. Our results show that misfolded protein tau ultimately modifies the endothelial properties of BBB, facilitating blood-to-brain cell transmigration. Our results suggest that the increased diapedesis of peripheral cells across the BBB, in response to tau protein, could be mediated by the increased expression of endothelial signaling molecules, namely ICAM-1, VCAM-1, and selectins. We suggest that the compensation of BBB in the diseased brain represents a crucial factor in neurodegeneration of human tauopathies.
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Barrera Hematoencefálica/inmunología , Encéfalo/inmunología , Ovillos Neurofibrilares/inmunología , Linfocitos T/inmunología , Tauopatías/inmunología , Proteínas tau/metabolismo , Animales , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Encéfalo/metabolismo , Encéfalo/patología , Moléculas de Adhesión Celular/metabolismo , Movimiento Celular , Endotelio Vascular/inmunología , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Femenino , Humanos , Ovillos Neurofibrilares/metabolismo , Ovillos Neurofibrilares/patología , Neuroglía/inmunología , Neuroglía/metabolismo , Neuroglía/patología , Ratas , Ratas Endogámicas SHR , Ratas Transgénicas , Linfocitos T/metabolismo , Linfocitos T/patología , Tauopatías/metabolismo , Tauopatías/patologíaRESUMEN
Hypertrophic osteoarthropathy is a syndrome presenting with dclubbing, limbs enlargement, pain and swelling of foot and long bones osteitis. Hypertrophic osteoarthropathy is a rare paraneoplastic syndrome in the patients with primary or metastatic lung cancer. We report 39-year old female patient who presented with arthritis and paraneoplastic hypertrophic osteoarthropathy revealing lung adenocarcinoma.