RESUMEN
Here, we introduce the Tabulae Paralytica-a compilation of four atlases of spinal cord injury (SCI) comprising a single-nucleus transcriptome atlas of half a million cells, a multiome atlas pairing transcriptomic and epigenomic measurements within the same nuclei, and two spatial transcriptomic atlases of the injured spinal cord spanning four spatial and temporal dimensions. We integrated these atlases into a common framework to dissect the molecular logic that governs the responses to injury within the spinal cord1. The Tabulae Paralytica uncovered new biological principles that dictate the consequences of SCI, including conserved and divergent neuronal responses to injury; the priming of specific neuronal subpopulations to upregulate circuit-reorganizing programs after injury; an inverse relationship between neuronal stress responses and the activation of circuit reorganization programs; the necessity of re-establishing a tripartite neuroprotective barrier between immune-privileged and extra-neural environments after SCI and a failure to form this barrier in old mice. We leveraged the Tabulae Paralytica to develop a rejuvenative gene therapy that re-established this tripartite barrier, and restored the natural recovery of walking after paralysis in old mice. The Tabulae Paralytica provides a window into the pathobiology of SCI, while establishing a framework for integrating multimodal, genome-scale measurements in four dimensions to study biology and medicine.
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Núcleo Celular , Epigenómica , Multiómica , Neuronas , Análisis de la Célula Individual , Traumatismos de la Médula Espinal , Transcriptoma , Animales , Femenino , Masculino , Ratones , Atlas como Asunto , Núcleo Celular/metabolismo , Neuronas/patología , Neuronas/metabolismo , Parálisis/genética , Parálisis/patología , Parálisis/rehabilitación , Parálisis/terapia , Recuperación de la Función , Médula Espinal/patología , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/patología , Traumatismos de la Médula Espinal/rehabilitación , Traumatismos de la Médula Espinal/terapia , Caminata , Anatomía Artística , Vías Nerviosas , Terapia GenéticaRESUMEN
Speech brain-computer interfaces (BCIs) have the potential to restore rapid communication to people with paralysis by decoding neural activity evoked by attempted speech into text1,2 or sound3,4. Early demonstrations, although promising, have not yet achieved accuracies sufficiently high for communication of unconstrained sentences from a large vocabulary1-7. Here we demonstrate a speech-to-text BCI that records spiking activity from intracortical microelectrode arrays. Enabled by these high-resolution recordings, our study participant-who can no longer speak intelligibly owing to amyotrophic lateral sclerosis-achieved a 9.1% word error rate on a 50-word vocabulary (2.7 times fewer errors than the previous state-of-the-art speech BCI2) and a 23.8% word error rate on a 125,000-word vocabulary (the first successful demonstration, to our knowledge, of large-vocabulary decoding). Our participant's attempted speech was decoded at 62 words per minute, which is 3.4 times as fast as the previous record8 and begins to approach the speed of natural conversation (160 words per minute9). Finally, we highlight two aspects of the neural code for speech that are encouraging for speech BCIs: spatially intermixed tuning to speech articulators that makes accurate decoding possible from only a small region of cortex, and a detailed articulatory representation of phonemes that persists years after paralysis. These results show a feasible path forward for restoring rapid communication to people with paralysis who can no longer speak.
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Interfaces Cerebro-Computador , Prótesis Neurales , Parálisis , Habla , Humanos , Esclerosis Amiotrófica Lateral/fisiopatología , Esclerosis Amiotrófica Lateral/rehabilitación , Corteza Cerebral/fisiología , Microelectrodos , Parálisis/fisiopatología , Parálisis/rehabilitación , VocabularioRESUMEN
Speech neuroprostheses have the potential to restore communication to people living with paralysis, but naturalistic speed and expressivity are elusive1. Here we use high-density surface recordings of the speech cortex in a clinical-trial participant with severe limb and vocal paralysis to achieve high-performance real-time decoding across three complementary speech-related output modalities: text, speech audio and facial-avatar animation. We trained and evaluated deep-learning models using neural data collected as the participant attempted to silently speak sentences. For text, we demonstrate accurate and rapid large-vocabulary decoding with a median rate of 78 words per minute and median word error rate of 25%. For speech audio, we demonstrate intelligible and rapid speech synthesis and personalization to the participant's pre-injury voice. For facial-avatar animation, we demonstrate the control of virtual orofacial movements for speech and non-speech communicative gestures. The decoders reached high performance with less than two weeks of training. Our findings introduce a multimodal speech-neuroprosthetic approach that has substantial promise to restore full, embodied communication to people living with severe paralysis.
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Cara , Prótesis Neurales , Parálisis , Habla , Humanos , Corteza Cerebral/fisiología , Corteza Cerebral/fisiopatología , Ensayos Clínicos como Asunto , Comunicación , Aprendizaje Profundo , Gestos , Movimiento , Prótesis Neurales/normas , Parálisis/fisiopatología , Parálisis/rehabilitación , Vocabulario , VozRESUMEN
A spinal cord injury interrupts pathways from the brain and brainstem that project to the lumbar spinal cord, leading to paralysis. Here we show that spatiotemporal epidural electrical stimulation (EES) of the lumbar spinal cord1-3 applied during neurorehabilitation4,5 (EESREHAB) restored walking in nine individuals with chronic spinal cord injury. This recovery involved a reduction in neuronal activity in the lumbar spinal cord of humans during walking. We hypothesized that this unexpected reduction reflects activity-dependent selection of specific neuronal subpopulations that become essential for a patient to walk after spinal cord injury. To identify these putative neurons, we modelled the technological and therapeutic features underlying EESREHAB in mice. We applied single-nucleus RNA sequencing6-9 and spatial transcriptomics10,11 to the spinal cords of these mice to chart a spatially resolved molecular atlas of recovery from paralysis. We then employed cell type12,13 and spatial prioritization to identify the neurons involved in the recovery of walking. A single population of excitatory interneurons nested within intermediate laminae emerged. Although these neurons are not required for walking before spinal cord injury, we demonstrate that they are essential for the recovery of walking with EES following spinal cord injury. Augmenting the activity of these neurons phenocopied the recovery of walking enabled by EESREHAB, whereas ablating them prevented the recovery of walking that occurs spontaneously after moderate spinal cord injury. We thus identified a recovery-organizing neuronal subpopulation that is necessary and sufficient to regain walking after paralysis. Moreover, our methodology establishes a framework for using molecular cartography to identify the neurons that produce complex behaviours.
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Neuronas , Parálisis , Traumatismos de la Médula Espinal , Médula Espinal , Caminata , Animales , Humanos , Ratones , Neuronas/fisiología , Parálisis/genética , Parálisis/fisiopatología , Parálisis/terapia , Médula Espinal/citología , Médula Espinal/fisiología , Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/terapia , Caminata/fisiología , Estimulación Eléctrica , Región Lumbosacra/inervación , Rehabilitación Neurológica , Análisis de Secuencia de ARN , Perfilación de la Expresión GénicaRESUMEN
Aquaporin-4 (AQP4)-specific Th17 cells are thought to have a central role in neuromyelitis optica (NMO) pathogenesis. When modeling NMO, only AQP4-reactive Th17 cells from AQP4-deficient (AQP4-/-), but not wild-type (WT) mice, caused CNS autoimmunity in recipient WT mice, indicating that a tightly regulated mechanism normally ensures tolerance to AQP4. Here, we found that pathogenic AQP4 T cell epitopes bind MHC II with exceptionally high affinity. Examination of T cell receptor (TCR) α/ß usage revealed that AQP4-specific T cells from AQP4-/- mice employed a distinct TCR repertoire and exhibited clonal expansion. Selective thymic AQP4 deficiency did not fully restore AQP4-reactive T cells, demonstrating that thymic negative selection alone did not account for AQP4-specific tolerance in WT mice. Indeed, AQP4-specific Th17 cells caused paralysis in recipient WT or B cell-deficient mice, which was followed by complete recovery that was associated with apoptosis of donor T cells. However, donor AQP4-reactive T cells survived and caused persistent paralysis in recipient mice deficient in both T and B cells or mice lacking T cells only. Thus, AQP4 CNS autoimmunity was limited by T cell-dependent deletion of AQP4-reactive T cells. In contrast, myelin oligodendrocyte glycoprotein (MOG)-specific T cells survived and caused sustained disease in WT mice. These findings underscore the importance of peripheral T cell deletional tolerance to AQP4, which may be relevant to understanding the balance of AQP4-reactive T cells in health and in NMO. T cell tolerance to AQP4, expressed in multiple tissues, is distinct from tolerance to MOG, an autoantigen restricted in its expression.
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Autoinmunidad , Neuromielitis Óptica , Animales , Ratones , Acuaporina 4/metabolismo , Autoanticuerpos , Glicoproteína Mielina-Oligodendrócito , Parálisis , Receptores de Antígenos de Linfocitos T/metabolismoRESUMEN
Enterovirus D68 (EV-D68) is an emerging pathogen that can cause severe respiratory and neurologic disease [acute flaccid myelitis (AFM)]. Intramuscular (IM) injection of neonatal Swiss Webster (SW) mice with US/IL/14-18952 (IL52), a clinical isolate from the 2014 EV-D68 epidemic, results in many of the pathogenic features of human AFM, including viral infection of the spinal cord, death of motor neurons, and resultant progressive paralysis. In distinction, CA/14-4231 (CA4231), another clinical isolate from the 2014 EV-D68 outbreak, does not cause paralysis in mice, does not grow in the spinal cord, and does not cause motor neuron loss following IM injection. A panel of chimeric viruses containing sequences from IL52 and CA4231 was used to demonstrate that VP1 is the main determinant of EV-D68 neurovirulence following IM injection of neonatal SW mice. VP1 contains four amino acid differences between IL52 and CA4231. Mutations resulting in substituting these four amino acids (CA4231 residues into the IL52 polyprotein) completely abolished neurovirulence. Conversely, mutations resulting in substituting VP1 IL52 amino acid residues into the CA4231 polyprotein created a virus that induced paralysis to the same degree as IL52. Neurovirulence following infection of neonatal SW mice with parental and chimeric viruses was associated with viral growth in the spinal cord. IMPORTANCE: Emerging viruses allow us to investigate mutations leading to increased disease severity. Enterovirus D68 (EV-D68), once the cause of rare cases of respiratory illness, recently acquired the ability to cause severe respiratory and neurologic disease. Chimeric viruses were used to demonstrate that viral structural protein VP1 determines growth in the spinal cord, motor neuron loss, and paralysis following intramuscular (IM) injection of neonatal Swiss Webster (SW) mice with EV-D68. These results have relevance for predicting the clinical outcome of future EV-D68 epidemics as well as targeting retrograde transport as a potential strategy for treating virus-induced neurologic disease.
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Proteínas de la Cápside , Enfermedades Virales del Sistema Nervioso Central , Modelos Animales de Enfermedad , Enterovirus Humano D , Infecciones por Enterovirus , Mielitis , Enfermedades Neuromusculares , Animales , Enterovirus Humano D/patogenicidad , Enterovirus Humano D/genética , Enterovirus Humano D/fisiología , Mielitis/virología , Ratones , Infecciones por Enterovirus/virología , Infecciones por Enterovirus/patología , Enfermedades Neuromusculares/virología , Enfermedades Neuromusculares/patología , Proteínas de la Cápside/genética , Proteínas de la Cápside/metabolismo , Enfermedades Virales del Sistema Nervioso Central/virología , Enfermedades Virales del Sistema Nervioso Central/patología , Humanos , Médula Espinal/virología , Médula Espinal/patología , Neuronas Motoras/virología , Neuronas Motoras/patología , Animales Recién Nacidos , Virulencia , Parálisis/virologíaRESUMEN
Antigen-specific therapies hold promise for treating autoimmune diseases such as multiple sclerosis while avoiding the deleterious side effects of systemic immune suppression due to delivering the disease-specific antigen as part of the treatment. In this study, an antigen-specific dual-sized microparticle (dMP) treatment reversed hind limb paralysis when administered in mice with advanced experimental autoimmune encephalomyelitis (EAE). Treatment reduced central nervous system (CNS) immune cell infiltration, demyelination, and inflammatory cytokine levels. Mechanistic insights using single-cell RNA sequencing showed that treatment impacted the MHC II antigen presentation pathway in dendritic cells, macrophages, B cells, and microglia, not only in the draining lymph nodes but also strikingly in the spinal cord. CD74 and cathepsin S were among the common genes down-regulated in most antigen presenting cell (APC) clusters, with B cells also having numerous MHC II genes reduced. Efficacy of the treatment diminished when B cells were absent, suggesting their impact in this therapy, in concert with other immune populations. Activation and inflammation were reduced in both APCs and T cells. This promising antigen-specific therapeutic approach advantageously engaged essential components of both innate and adaptive autoimmune responses and capably reversed paralysis in advanced EAE without the use of a broad immunosuppressant.
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Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Animales , Ratones , Antígenos , Citocinas , Ratones Endogámicos C57BL , Parálisis , Catepsinas , Inmunosupresores/uso terapéuticoRESUMEN
Stroke is a leading cause of paralysis, most frequently affecting the upper limbs and vocal folds. Despite recent advances in care, stroke recovery invariably reaches a plateau, after which there are permanent neurological impairments. Implantable brain-computer interface devices offer the potential to bypass permanent neurological lesions. They function by (1) recording neural activity, (2) decoding the neural signal occurring in response to volitional motor intentions, and (3) generating digital control signals that may be used to control external devices. While brain-computer interface technology has the potential to revolutionize neurological care, clinical translation has been limited. Endovascular arrays present a novel form of minimally invasive brain-computer interface devices that have been deployed in human subjects during early feasibility studies. This article provides an overview of endovascular brain-computer interface devices and critically evaluates the patient with stroke as an implant candidate. Future opportunities are mapped, along with the challenges arising when decoding neural activity following infarction. Limitations arise when considering intracerebral hemorrhage and motor cortex lesions; however, future directions are outlined that aim to address these challenges.
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Interfaces Cerebro-Computador , Rehabilitación de Accidente Cerebrovascular , Accidente Cerebrovascular , Humanos , Parálisis/etiología , Accidente Cerebrovascular/complicaciones , Prótesis e ImplantesRESUMEN
People bitten by Alpine vipers are usually treated with antivenom antisera to prevent the noxious consequences caused by the injected venom. However, this treatment suffers from a number of drawbacks and additional therapies are necessary. The venoms of Vipera ammodytes and of Vipera aspis are neurotoxic and cause muscle paralysis by inducing neurodegeneration of motor axon terminals because they contain a presynaptic acting sPLA2 neurotoxin. We have recently found that any type of damage to motor axons is followed by the expression and activation of the intercellular signaling axis consisting of the CXCR4 receptor present on the membrane of the axon stump and of its ligand, the chemokine CXCL12 released by activated terminal Schwann cells. We show here that also V. ammodytes and V. aspis venoms cause the expression of the CXCL12-CXCR4 axis. We also show that a small molecule agonist of CXCR4, dubbed NUCC-390, induces a rapid regeneration of the motor axon terminal with functional recovery of the neuromuscular junction. These findings qualify NUCC-390 as a promising novel therapeutics capable of improving the recovery from the paralysis caused by the snakebite of the two neurotoxic Alpine vipers.
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Indazoles , Receptores CXCR4 , Venenos de Víboras , Viperidae , Animales , Parálisis/inducido químicamente , Receptores CXCR4/agonistas , Venenos de Víboras/antagonistas & inhibidores , Venenos de Víboras/toxicidad , Vipera/metabolismo , Viperidae/metabolismo , Ratones , Indazoles/farmacología , Indazoles/uso terapéutico , Piperidinas/farmacología , Piperidinas/uso terapéutico , Piridinas/farmacología , Piridinas/uso terapéutico , Mordeduras de Serpientes/tratamiento farmacológicoRESUMEN
The D620N mutation in vacuolar protein sorting protein 35 (VPS35) gene has been identified to be linked to late onset familial Parkinson disease (PD). However, the pathophysiological roles of VPS35-D620N in PD remain unclear. Here, we generated the transgenic Caenorhabditis elegans overexpressing either human wild type or PD-linked mutant VPS35-D620N in neurons. C. elegans expressing VPS35-D620N, compared with non-transgenic controls, showed movement disorders and dopaminergic neuron loss. VPS35-D620N worms displayed more swimming induced paralysis but showed no defects in BSR assays, thus indicating the disruption of dopamine (DA) recycling back inside neurons. Moreover, VPS35 formed a protein interaction complex with DA transporter (DAT), RAB5, RAB11 and FAM21. In contrast, the VPS35-D620N mutant destabilized these interactions, thus disrupting DAT transport from early endosomes to recycling endosomes, and decreasing DAT at the cell surface. These effects together increased DA in synaptic clefts, and led to dopaminergic neuron degeneration and motor dysfunction. Treatment with reserpine significantly decreased the swimming induced paralysis in VPS35-D620N worms, as compared with vehicle treated VPS35-D620N worms. Our studies not only provide novel insights into the mechanisms of VPS35-D620N-induced dopaminergic neuron degeneration and motor dysfunction via disruption of DAT function and the DA signaling pathway but also indicate a potential strategy to treat VPS35-D620N-related PD and other disorders.
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Dopamina , Enfermedad de Parkinson , Animales , Humanos , Dopamina/metabolismo , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Transporte de Proteínas , Neuronas Dopaminérgicas/metabolismo , Enfermedad de Parkinson/metabolismo , Degeneración Nerviosa/patología , Parálisis/genética , Parálisis/metabolismo , Parálisis/patologíaRESUMEN
Botulinum neurotoxin (BoNT) is a potent protein toxin that causes muscle paralysis and death by asphyxiation. Treatments for symptomatic botulism are intubation and supportive care until respiratory function recovers. Aminopyridines have recently emerged as potential treatments for botulism. The clinically approved drug 3,4-diaminopyridine (3,4-DAP) rapidly reverses toxic signs of botulism and has antidotal effects when continuously administered in rodent models of lethal botulism. Although the therapeutic effects of 3,4-DAP likely result from the reversal of diaphragm paralysis, the corresponding effects on respiratory physiology are not understood. Here, we combined unrestrained whole-body plethysmography (UWBP) with arterial blood gas measurements to study the effects of 3,4-DAP, and other aminopyridines, on ventilation and respiration at terminal stages of botulism in mice. Treatment with clinically relevant doses of 3,4-DAP restored ventilation in a dose-dependent manner, producing significant improvements in ventilatory parameters within 10 minutes. Concomitant with improved ventilation, 3,4-DAP treatment reversed botulism-induced respiratory acidosis, restoring blood levels of CO2, pH, and lactate to normal physiologic levels. Having established that 3,4-DAP-mediated improvements in ventilation were directly correlated with improved respiration, we used UWBP to quantitatively evaluate nine additional aminopyridines in BoNT/A-intoxicated mice. Multiple aminopyridines were identified with comparable or enhanced therapeutic efficacies compared with 3,4-DAP, including aminopyridines that selectively improved tidal volume versus respiratory rate and vice versa. In addition to contributing to a growing body of evidence supporting the use of aminopyridines to treat clinical botulism, these data lay the groundwork for the development of aminopyridine derivatives with improved pharmacological properties. SIGNIFICANCE STATEMENT: There is a critical need for fast-acting treatments to reverse respiratory paralysis in patients with botulism. This study used unrestrained, whole-body plethysmography and arterial blood gas analysis to show that aminopyridines rapidly restore ventilation and respiration and reverse respiratory acidosis when administered to mice at terminal stages of botulism. In addition to supporting the use of aminopyridines as first-line treatments for botulism symptoms, these data are expected to contribute to the development of new aminopyridine derivatives with improved pharmacological properties.
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Acidosis Respiratoria , Toxinas Botulínicas Tipo A , Botulismo , Ratones , Humanos , Animales , Botulismo/tratamiento farmacológico , Aminopiridinas/farmacología , Amifampridina/uso terapéutico , Acidosis Respiratoria/tratamiento farmacológico , Toxinas Botulínicas Tipo A/uso terapéutico , Toxinas Botulínicas Tipo A/toxicidad , Parálisis/tratamiento farmacológico , RespiraciónRESUMEN
In 2014, 2016, and 2018, the United States experienced unprecedented spikes in pediatric cases of acute flaccid myelitis (AFM), which is a poliomyelitis-like paralytic illness. Accumulating clinical, immunological, and epidemiological evidence has identified enterovirus D68 (EV-D68) as a major causative agent of these biennial AFM outbreaks. There are currently no available FDA-approved antivirals that are effective against EV-D68, and the treatment for EV-D68-associated AFM is primarily supportive. Telaprevir is an food and drug administration (FDA)-approved protease inhibitor that irreversibly binds the EV-D68 2A protease and inhibits EV-D68 replication in vitro. Here, we utilize a murine model of EV-D68 associated AFM to show that early telaprevir treatment improves paralysis outcomes in Swiss Webster (SW) mice. Telaprevir reduces both viral titer and apoptotic activity in both muscles and spinal cords at early disease time points, which results in improved AFM outcomes in infected mice. Following intramuscular inoculation in mice, EV-D68 infection results in a stereotypic pattern of weakness that is reflected by the loss of the innervating motor neuron population, in sequential order, of the ipsilateral (injected) hindlimb, the contralateral hindlimb, and then the forelimbs. Telaprevir treatment preserved motor neuron populations and reduced weakness in limbs beyond the injected hindlimb. The effects of telaprevir were not seen when the treatment was delayed, and toxicity limited doses beyond 35 mg/kg. These studies are a proof of principle, provide the first evidence of benefit of an FDA-approved antiviral drug with which to treat AFM, and emphasize both the need to develop better tolerated therapies that remain efficacious when administered after viral infections and the development of clinical symptoms. IMPORTANCE Recent outbreaks of EV-D68 in 2014, 2016, and 2018 have resulted in over 600 cases of a paralytic illness that is known as AFM. AFM is a predominantly pediatric disease with no FDA-approved treatment, and many patients show minimal recovery from limb weakness. Telaprevir is an FDA-approved antiviral that has been shown to inhibit EV-D68 in vitro. Here, we demonstrate that a telaprevir treatment that is given concurrently with an EV-D68 infection improves AFM outcomes in mice by reducing apoptosis and viral titers at early time points. Telaprevir also protected motor neurons and improved paralysis outcomes in limbs beyond the site of viral inoculation. This study improves understanding of EV-D68 pathogenesis in the mouse model of AFM. This study serves as a proof of principle for the first FDA-approved drug that has been shown to improve AFM outcomes and have in vivo efficacy against EV-D68 as well as underlines the importance of the continued development of EV-D68 antivirals.
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Enfermedades Virales del Sistema Nervioso Central , Enterovirus Humano D , Infecciones por Enterovirus , Animales , Estados Unidos , Ratones , Enterovirus Humano D/fisiología , Modelos Animales de Enfermedad , Parálisis/tratamiento farmacológico , Parálisis/etiología , Infecciones por Enterovirus/patología , Antivirales/farmacología , Antivirales/uso terapéuticoRESUMEN
Powassan virus (POWV) is an emerging tick-borne flavivirus that causes neuroinvasive diseases, including encephalitis, meningitis, and paralysis. Similar to other neuroinvasive flaviviruses, such as West Nile virus (WNV) and Japanese encephalitis virus (JEV), POWV disease presentation is heterogeneous, and the factors influencing disease outcome are not fully understood. We used Collaborative Cross (CC) mice to assess the impact of host genetic factors on POWV pathogenesis. We infected a panel of Oas1b-null CC lines with POWV and observed a range of susceptibility, indicating that host factors other than the well-characterized flavivirus restriction factor Oas1b modulate POWV pathogenesis in CC mice. Among the Oas1b-null CC lines, we identified multiple highly susceptible lines (0% survival), including CC071 and CC015, and two resistant lines, CC045 and CC057 (>75% survival). The susceptibility phenotypes generally were concordant among neuroinvasive flaviviruses, although we did identify one line, CC006, that was specifically resistant to JEV, suggesting that both pan-flavivirus and virus-specific mechanisms contribute to susceptibility phenotypes in CC mice. We found that POWV replication was restricted in bone marrow-derived macrophages from CC045 and CC057 mice, suggesting that resistance could result from cell-intrinsic restriction of viral replication. Although serum viral loads at 2 days postinfection were equivalent between resistant and susceptible CC lines, clearance of POWV from the serum was significantly enhanced in CC045 mice. Furthermore, CC045 mice had significantly lower viral loads in the brain at 7 days postinfection than did CC071 mice, suggesting that reduced central nervous system (CNS) infection contributes to the resistant phenotype of CC045 mice. IMPORTANCE Neuroinvasive flaviviruses, such as WNV, JEV, and POWV, are transmitted to humans by mosquitoes or ticks and can cause neurologic diseases, such as encephalitis, meningitis, and paralysis, and they can result in death or long-term sequelae. Although potentially severe, neuroinvasive disease is a rare outcome of flavivirus infection. The factors that determine whether someone develops severe disease after a flavivirus infection are not fully understood, but host genetic differences in polymorphic antiviral response genes likely contribute to the outcome of infection. We evaluated a panel of genetically diverse mice and identified lines with distinct outcomes following infection with POWV. We found that resistance to POWV pathogenesis corresponded to reduced viral replication in macrophages, more rapid clearance of virus in peripheral tissues, and reduced viral infection in the brain. These susceptible and resistant mouse lines will provide a system for investigating the pathogenic mechanisms of POWV and identifying polymorphic host genes that contribute to resistance.
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Virus de la Encefalitis Japonesa (Especie) , Virus de la Encefalitis Transmitidos por Garrapatas , Encefalitis , Infecciones por Flavivirus , Flavivirus , Virus del Nilo Occidental , Humanos , Ratones , Animales , Flavivirus/genética , Ratones de Colaboración Cruzada , Infecciones por Flavivirus/genética , Virus de la Encefalitis Transmitidos por Garrapatas/fisiología , Virus de la Encefalitis Japonesa (Especie)/genética , Susceptibilidad a Enfermedades , Parálisis , 2',5'-Oligoadenilato Sintetasa/genéticaRESUMEN
PURPOSE: To compare rates of diagnosis of neuro-ophthalmic conditions across the Coronavirus Disease 2019 (COVID-19) pandemic with pre-pandemic levels. DESIGN: Multicenter, retrospective, observational study. PARTICIPANTS: Patients seen for eye care between March 11, 2019, and December 31, 2021. METHODS: A multicenter electronic health record database, Sight Outcomes Research Collaborative (SOURCE), was queried for new diagnoses of neuro-ophthalmic conditions (cranial nerve [CN] III, IV, VI, and VII palsy; diplopia; and optic neuritis) and new diagnoses of other ophthalmic conditions from January 1, 2016, to December 31, 2021. Data were divided into 3 periods (pre-COVID, pre-COVID vaccine, and after introduction of COVID vaccine), with a 3-year look-back period. Logistic regressions were used to compare diagnosis rates across periods. Two-sample z-test was used to compare the log odds ratio (OR) of the diagnosis in each period with emergent ocular conditions: retinal detachment (RD) and acute angle-closure glaucoma (AACG). MAIN OUTCOME MEASURES: Diagnosis rate of neuro-ophthalmic conditions in each study period. RESULTS: A total of 323 261 unique patients (median age 59 years [interquartile range, 43-70], 58% female, 68% White) across 5 academic centers were included, with 180 009 patients seen in the pre-COVID period, 149 835 patients seen in the pre-COVID vaccine period, and 164 778 patients seen in the COVID vaccine period. Diagnosis rates of CN VII palsy, diplopia, glaucoma, and cataract decreased from the pre-COVID period to the pre-vaccine period. However, the optic neuritis diagnoses increased, in contrast to a decrease in RD diagnoses (P = 0.021). By comparing the diagnosis rates before and after widespread vaccination, all eye conditions evaluated were diagnosed at higher rates in the COVID vaccination period compared with pre-COVID and pre-vaccine periods. The log OR of neuro-ophthalmic diagnosis rates across every period comparison were largely similar to emergency conditions (RD and AACG, P > 0.05). However, the log OR of cataract and glaucoma diagnoses were different to RD or AACG (P < 0.05) in each period comparison. CONCLUSIONS: Neuro-ophthalmic diagnoses had a similar reduction in diagnosis rates as emergent eye conditions in the first part of the pandemic, except optic neuritis. After widespread COVID-19 vaccination, all ophthalmic diagnosis rates increased compared with pre-pandemic rates, and the increase in neuro-ophthalmic diagnosis rates did not exceed the increase in RD and AACG diagnosis rates. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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COVID-19 , Catarata , Enfermedades de los Nervios Craneales , Glaucoma , Neuritis Óptica , Humanos , Femenino , Persona de Mediana Edad , Masculino , COVID-19/epidemiología , COVID-19/prevención & control , Vacunas contra la COVID-19 , Diplopía/diagnóstico , Diplopía/epidemiología , Pandemias/prevención & control , Estudios Retrospectivos , Neuritis Óptica/diagnóstico , Neuritis Óptica/epidemiología , Parálisis , Prueba de COVID-19RESUMEN
TMEM106B is a risk modifier of multiple neurological conditions, where a single coding variant and multiple non-coding SNPs influence the balance between susceptibility and resilience. Two key questions that emerge from past work are whether the lone T185S coding variant contributes to protection, and if the presence of TMEM106B is helpful or harmful in the context of disease. Here, we address both questions while expanding the scope of TMEM106B study from TDP-43 to models of tauopathy. We generated knockout mice with constitutive deletion of TMEM106B, alongside knock-in mice encoding the T186S knock-in mutation (equivalent to the human T185S variant), and crossed both with a P301S transgenic tau model to study how these manipulations impacted disease phenotypes. We found that TMEM106B deletion accelerated cognitive decline, hind limb paralysis, tau pathology, and neurodegeneration. TMEM106B deletion also increased transcriptional correlation with human AD and the functional pathways enriched in KO:tau mice aligned with those of AD. In contrast, the coding variant protected against tau-associated cognitive decline, synaptic impairment, neurodegeneration, and paralysis without affecting tau pathology. Our findings reveal that TMEM106B is a critical safeguard against tau aggregation, and that loss of this protein has a profound effect on sequelae of tauopathy. Our study further demonstrates that the coding variant is functionally relevant and contributes to neuroprotection downstream of tau pathology to preserve cognitive function.
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Proteínas de la Membrana , Proteínas del Tejido Nervioso , Tauopatías , Animales , Humanos , Ratones , Modelos Animales de Enfermedad , Proteínas de la Membrana/genética , Ratones Noqueados , Ratones Transgénicos , Mutación , Proteínas del Tejido Nervioso/genética , Parálisis/genética , Polimorfismo de Nucleótido Simple , Proteínas tau/genética , Proteínas tau/metabolismo , Tauopatías/patologíaRESUMEN
INTRODUCTION: Computed tomography (CT) is routinely employed on the evaluation of dyspnea, yet limited data exist on its assessment of diaphragmatic muscle. This study aimed to determine the capability of CT in identifying structural changes in the diaphragm among patients with ultrasound-confirmed diaphragmatic dysfunction. METHODS: Diaphragmatic ultrasounds conducted between 2018 and 2021 at our center in Marseille, France, were retrospectively collected. Diaphragmatic pillars were measured on CT scans at the L1 level and the celiac artery. Additionally, the difference in height between the two diaphragmatic domes in both diaphragmatic dysfunction cases and controls was measured and compared. RESULTS: A total of 65 patients were included, comprising 24 with diaphragmatic paralysis, 13 with diaphragmatic weakness, and 28 controls. In the case group (paralysis and weakness) with left dysfunctions (n = 24), the CT thickness of the pillars at the level of L1 and the celiac artery was significantly thinner compared with controls (2.0 mm vs. 7.4 mm and 1.8 mm vs. 3.1 mm, p < 0.001 respectively). Significantly different values were observed for paralysis (but not weakness) in the right dysfunction subgroup (n = 15) (2.6 mm vs. 7.4 mm and 2.2 mm vs. 3.8 mm, p < 0.001 respectively, for paralysis vs. controls). Regardless of the side of dysfunction, a significant difference in diaphragmatic height was observed between cases and controls (7.70 cm vs. 1.16 cm and 5.51 cm vs. 1.16 cm, p < 0.001 for right and left dysfunctions, respectively). Threshold values determined through ROC curve analyses for height differences between the two diaphragmatic domes, indicative of paralysis or weakness in the right dysfunctions, were 4.44 cm and 3.51 cm, respectively. Similarly for left dysfunctions, the thresholds were 2.70 cm and 2.48 cm, respectively, demonstrating good performance (aera under the curve of 1.00, 1.00, 0.98, and 0.79, respectively). CONCLUSION: In cases of left diaphragmatic dysfunction, as well as in paralysis associated with right diaphragmatic dysfunction, CT revealed thinner pillars. Additionally, a notable increase in the difference in diaphragmatic height demonstrated a strong potential to identify diaphragmatic dysfunction, with specific threshold values.
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Diafragma , Debilidad Muscular , Humanos , Diafragma/diagnóstico por imagen , Estudios Retrospectivos , Ultrasonografía/métodos , Parálisis , Tomografía Computarizada por Rayos X , TomografíaRESUMEN
Acute flaccid myelitis (AFM) is a serious neurologic condition primarily affecting children; AFM can cause acute respiratory failure and permanent paralysis. AFM is a rare but known complication of various viral infections, particularly those of enteroviruses (EVs). Increases in AFM cases during 2014, 2016, and 2018 were associated with EV-D68 infection. This report examines trends in confirmed AFM cases during 2018-2022 and patients' clinical and laboratory characteristics. The number of AFM cases was low during 2019-2022 (28-47 cases per year); the number of cases remained low in 2022 despite evidence of increased EV-D68 circulation in the United States. Compared with cases during the most recent peak year (2018), fewer cases during 2019-2021 had upper limb involvement, prodromal respiratory or febrile illness, or cerebrospinal fluid pleocytosis, and more were associated with lower limb involvement. It is unclear why EV-D68 circulation in 2022 was not associated with an increase in AFM cases or when the next increase in AFM cases will occur. Nonetheless, clinicians should continue to suspect AFM in any child with acute flaccid limb weakness, especially those with a recent respiratory or febrile illness.
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Enfermedades Virales del Sistema Nervioso Central , Enterovirus Humano D , Infecciones por Enterovirus , Mielitis , Enfermedades Neuromusculares , Niño , Humanos , Estados Unidos/epidemiología , Enfermedades Neuromusculares/epidemiología , Parálisis , Mielitis/epidemiología , Enfermedades Virales del Sistema Nervioso Central/epidemiología , Infecciones por Enterovirus/epidemiologíaRESUMEN
BACKGROUND AND PURPOSE: Diagnosis of lymphoma involving the central nervous system (CNS) is challenging. This study aimed to explore the abnormal vestibular and ocular motor findings in CNS lymphoma. METHODS: A retrospective search of the medical records identified 30 patients with CNS lymphoma presenting ocular motor and vestibular abnormalities from four neurology clinics of university hospitals in South Korea (22 men, age range 14-81 years, mean 60.6 ± 15.2). The demographic and clinical features and the results of laboratory, radiological and pathological evaluation were analyzed. RESULTS: Patients presented with diplopia (13/30, 43%), vestibular symptoms (15/30, 50%) or both (2/30, 7%). In 15 patients with diplopia, abnormal ocular motor findings included ocular motor nerve palsy (n = 10, 67%), internuclear ophthalmoplegia (n = 2, 13%), external ophthalmoplegia (n = 2, 13%) and exophoria (n = 1, 7%). The vestibular abnormalities were isolated in 14 (82%) of 17 patients with vestibular symptoms and included combined unilateral peripheral and central vestibulopathy in three from lesions involving the vestibular nuclei. CNS lymphoma involved the brainstem (53%), cerebellum (33%), leptomeninges (30%), deep gray nuclei (23%) or cranial nerves (17%). Two patients showed the "double-panda" sign by involving the midbrain. CONCLUSIONS: This study expands the clinical and radiological spectra of CNS lymphoma. Neuro-ophthalmological and neuro-otological evaluation may guide the early diagnosis of CNS lymphoma.
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Diplopía , Trastornos de la Motilidad Ocular , Masculino , Humanos , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Estudios Retrospectivos , Trastornos de la Motilidad Ocular/diagnóstico , Movimientos Oculares , Cerebelo , ParálisisRESUMEN
BACKGROUND AND AIMS: Scrub typhus is an endemic disease in the fall season that occurs in a limited number of places known as the Tsutsugamushi Triangle. Peripheral neuropathy is a common complication of scrub typhus. Herein, we encountered several patients with ascending paralysis after scrub typhus infection, who were diagnosed with Guillain-Barré syndrome (GBS). We aimed to investigate the clinical and laboratory characteristics of patients who developed GBS after scrub typhus. METHODS: Patients were retrospectively recruited from six nationwide tertiary centers in South Korea from January 2017 to December 2021. Patients who had been clinically diagnosed with GBS and confirmed to have scrub typhus via laboratory examination and/or the presence of an eschar before the onset of acute limb paralysis were included. The GBS-associated clinical and electrophysiological characteristics, outcomes, and scrub typhus-associated features were collected. RESULTS: Of the seven enrolled patients, six were female and one was male. The median time from scrub typhus infection to the onset of limb weakness was 6 (range: 2-14) days. All patients had eschar on their bodies. Four patients (57.1%) were admitted to the intensive care unit and received artificial ventilation for respiratory distress. At 6 months, the median GBS disability score was 2 (range, 1-4) points. INTERPRETATION: Patients with scrub typhus-associated GBS have a severe clinical presentation and require intensive treatment with additional immunotherapies. Therefore, GBS should be included in the differential diagnosis when peripheral neuropathies develop during scrub typhus treatment. Notably, scrub typhus is associated to GBS.