Investigations in the last 10 years have revealed a new category of neurological diseases mediated by antibodies against cell surface and synaptic proteins. There are currently 16 such diseases all ...characterized by autoantibodies against neuronal proteins involved in synaptic signaling and plasticity. In clinical practice these findings have changed the diagnostic and treatment approach to potentially lethal, but now treatable, neurological and psychiatric syndromes previously considered idiopathic or not even suspected to be immune-mediated. Studies show that patients' antibodies can impair the surface dynamics of the target receptors eliminating them from synapses (e.g., NMDA receptor), block the function of the antigens without changing their synaptic density (e.g., GABAb receptor), interfere with synaptic protein-protein interactions (LGI1, Caspr2), alter synapse formation (e.g., neurexin-3α), or by unclear mechanisms associate to a new form of tauopathy (IgLON5). Here we first trace the process of discovery of these diseases, describing the triggers and symptoms related to each autoantigen, and then review in detail the structural and functional alterations caused by the autoantibodies with special emphasis in those (NMDA receptor, amphiphysin) that have been modeled in animals.
Sepsis is a major cause of death in intensive care units worldwide. The acute phase of sepsis is often accompanied by sepsis-associated encephalopathy, which is highly associated with increased ...mortality. Moreover, in the chronic phase, more than 50% of surviving patients suffer from severe and long-term cognitive deficits compromising their daily quality of life and placing an immense burden on primary caregivers. Due to a growing number of sepsis survivors, these long-lasting deficits are increasingly relevant. Despite the high incidence and clinical relevance, the pathomechanisms of acute and chronic stages in sepsis-associated encephalopathy are only incompletely understood, and no specific therapeutic options are yet available. Here, we review the emergence of sepsis-associated encephalopathy from initial clinical presentation to long-term cognitive impairment in sepsis survivors and summarize pathomechanisms potentially contributing to the development of sepsis-associated encephalopathy.
In this article, we present a novel hybrid framework, which integrates spatial-temporal semantic segmentation with postclassification relearning, for multitemporal land use and land cover (LULC) ...classification based on very high resolution (VHR) satellite imagery. To efficiently obtain optimal multitemporal LULC classification maps, the hybrid framework utilizes a spatial-temporal semantic segmentation model to harness temporal dependency for extracting high-level spatial-temporal features. In addition, the principle of postclassification relearning is adopted to efficiently optimize model output. Thereby, the initial outcome of a semantic segmentation model is provided to a subsequent model via an extended input space to guide the learning of discriminative feature representations in an end-to-end fashion. Last, object-based voting is coupled with postclassification relearning for coping with the high intraclass and low interclass variances. The framework was tested with two different postclassification relearning strategies (i.e., pixel-based relearning and object-based relearning) and three convolutional neural network models, i.e., UNet, a simple Convolutional LSTM, and a UNet Convolutional-LSTM. The experiments were conducted on two datasets with LULC labels that contain rich semantic information and variant building morphologic features (e.g., informal settlements). Each dataset contains four time steps from WorldView-2 and Quickbird imagery. The experimental results unambiguously underline that the proposed framework is efficient in terms of classifying complex LULC maps with multitemporal VHR images.
Sepsis is the most common cause of admission to intensive care units worldwide. Sepsis patients frequently suffer from sepsis-associated encephalopathy (SAE) reflecting acute brain dysfunction. SAE ...may result in increased mortality, extended length of hospital stay, and long-term cognitive dysfunction. The diagnosis of SAE is based on clinical assessments, but a valid biomarker to identify and confirm SAE and to assess SAE severity is missing. Several blood-based biomarkers indicating neuronal injury have been evaluated in sepsis and their potential role as early diagnosis and prognostic markers has been studied. Among those, the neuroaxonal injury marker neurofilament light chain (NfL) was identified to potentially serve as a prognostic biomarker for SAE and to predict long-term cognitive impairment. In this review, we summarize the current knowledge of biomarkers, especially NfL, in SAE and discuss a possible future clinical application considering existing limitations.
AMPA receptors are essential for fast excitatory transmission in the CNS. Autoantibodies to AMPA receptors have been identified in humans with autoimmune encephalitis and severe defects of ...hippocampal function. Here, combining electrophysiology and high-resolution imaging with neuronal culture preparations and passive-transfer models in wild-type and GluA1-knockout mice, we analyze how specific human autoantibodies against the AMPA receptor subunit GluA2 affect receptor function and composition, synaptic transmission, and plasticity. Anti-GluA2 antibodies induce receptor internalization and a reduction of synaptic GluA2-containing AMPARs followed by compensatory ryanodine receptor-dependent incorporation of synaptic non-GluA2 AMPARs. Furthermore, application of human pathogenic anti-GluA2 antibodies to mice impairs long-term synaptic plasticity in vitro and affects learning and memory in vivo. Our results identify a specific immune-neuronal rearrangement of AMPA receptor subunits, providing a framework to explain disease symptoms.
•Human GluA2 autoantibodies (ABs) cause changes in AMPA receptor subunit composition•ABs mediate internalization of AMPA receptors and synaptic scaling-like mechanisms•Passive transfer of ABs impairs synaptic plasticity and triggers disease symptoms•Disease symptoms may be caused by AMPA receptor subunit rearrangement
Haselmann et al. explore molecular mechanisms of autoimmune encephalitis with autoantibodies to the AMPA receptor. Human anti-GluA2 autoantibodies induce internalization of AMPA receptors followed by synaptic scaling-like changes leading to defective synaptic transmission and plasticity resulting in memory dysfunction.
Previous applications of machine learning in remote sensing for the identification of damaged buildings in the aftermath of a large-scale disaster have been successful. However, standard methods do ...not consider the complexity and costs of compiling a training data set after a large-scale disaster. In this article, we study disaster events in which the intensity can be modeled via numerical simulation and/or instrumentation. For such cases, two fully automatic procedures for the detection of severely damaged buildings are introduced. The fundamental assumption is that samples that are located in areas with low disaster intensity mainly represent nondamaged buildings. Furthermore, areas with moderate to strong disaster intensities likely contain damaged and nondamaged buildings. Under this assumption, a procedure that is based on the automatic selection of training samples for learning and calibrating the standard support vector machine classifier is utilized. The second procedure is based on the use of two regularization parameters to define the support vectors. These frameworks avoid the collection of labeled building samples via field surveys and/or visual inspection of optical images, which requires a significant amount of time. The performance of the proposed method is evaluated via application to three real cases: the 2011 Tohoku-Oki earthquake-tsunami, the 2016 Kumamoto earthquake, and the 2018 Okayama floods. The resulted accuracy ranges between 0.85 and 0.89, and thus, it shows that the result can be used for the rapid allocation of affected buildings.
Super‐resolution microscopy requires small fluorescent labels. We report the application of genetic code expansion in combination with bioorthogonal click chemistry to label the NR1 domain of the ...NMDA receptor. We generated NR1 mutants incorporating an unnatural amino acid at various positions in order to attach small organic fluorophores such as Cy5‐tetrazine site‐specifically to the extracellular domain of the receptor. Mutants were optimized with regard to protein expression, labeling efficiency and receptor functionality as tested by fluorescence microscopy and whole‐cell patch clamp. The results show that bioorthogonal click chemistry in combination with small organic dyes is superior to available immunocytochemistry protocols for receptor labeling in live and fixed cells and enables single‐molecule sensitive super‐resolution microscopy experiments.
The extracellular part of the NR1 domain of the NMDA receptor was labelled by genetic code expansion in combination with bioorthogonal click chemistry. Receptor labeling with small organic dyes has advantages over immunocytochemistry protocols in live‐cell and super‐resolution imaging.
Approximately 30% of individuals with severe SARS-CoV-2 infections also develop neurological and psychiatric complaints. In rare cases, the occurrence of autoimmune encephalitis has been reported ...after SARS-CoV-2 infection. In this systematic review, we have identified eight SARS-CoV-2-associated cases of anti-NMDA receptor encephalitis. All had cerebrospinal fluid antibodies against the NMDA receptor and a recent onset of working memory deficits, altered mental status, or psychiatric symptoms, such as confusion, agitation, auditory hallucination, catatonia and speech dysfunction. All patients received high-dose steroid and immunoglobulin therapeutics and conditions improved in each case. These findings suggest that clinical attention should be paid to warning signs of autoimmune encephalitis in severe COVID-19 cases. If characteristic features of autoimmune encephalitis are present, autoantibody diagnostics should be performed and confirmed cases should be treated with immunotherapy to minimize neurological impairments.
Tolerance to the analgesic effects of opioids occurs after their chronic administration, a pharmacological phenomenon that has been associated with the development of abnormal pain sensitivity such ...as hyperalgesia. In the present study, we investigated the role of TRPV1, which is crucial for the transduction of noxious chemical and thermal stimuli, in morphine tolerance and tolerance-associated thermal hyperalgesia. After chronic morphine treatment, a marked increase in TRPV1 immunoreactivity (IR) was detected in L4 dorsal root ganglion (DRG) neurons, spinal cord dorsal horn, and sciatic nerve. Real-time reverse transcription (RT)-PCR demonstrated that TRPV1 mRNA was upregulated in spinal cord and sciatic nerve but not in the DRG. Intrathecal pretreatment with SB366791 N-(3-methoxyphenyl)-4-chlorocinnamide, a selective antagonist of TRPV1, attenuated both morphine tolerance and associated thermal hyperalgesia. Chronic morphine exposure induced increases in phosphorylation of mitogen-activated protein kinases (MAPKs), including p38 MAPK-IR, extracellular signal-regulated protein kinase (ERK)-IR, and c-Jun N-terminal kinase (JNK)-IR, in L4 DRG neurons. Intrathecal administration of the selective p38, ERK, or JNK inhibitors not only reduced morphine tolerance and associated thermal hyperalgesia but also suppressed the morphine-induced increase of TRPV1-IR in DRG neurons, spinal cord, and sciatic nerve and of mRNA levels in spinal cord and sciatic nerve. Together, we have identified a novel mechanism by which sustained morphine treatment results in tolerance and tolerance-associated thermal hyperalgesia, by regulating TRPV1 expression, in a MAPK-dependent manner. Thus, blocking TRPV1 might be a way to reduce morphine tolerance.
Objective
To demonstrate that ephrin‐B2 (the ligand of EphB2 receptor) antagonizes the pathogenic effects of patients' N‐methyl‐D‐aspartate receptor (NMDAR) antibodies on memory and synaptic ...plasticity.
Methods
One hundred twenty‐two C57BL/6J mice infused with cerebrospinal fluid (CSF) from patients with anti‐NMDAR encephalitis or controls, with or without ephrin‐B2, were investigated. CSF was infused through ventricular catheters connected to subcutaneous osmotic pumps over 14 days. Memory, behavioral tasks, locomotor activity, presence of human antibodies specifically bound to hippocampal NMDAR, and antibody effects on the density of cell‐surface and synaptic NMDAR and EphB2 were examined at different time points using reported techniques. Short‐ and long‐term synaptic plasticity were determined in acute brain sections; the Schaffer collateral pathway was stimulated and the field excitatory postsynaptic potentials were recorded in the CA1 region of the hippocampus.
Results
Mice infused with patients' CSF, but not control CSF, developed progressive memory deficit and depressive‐like behavior along with deposits of NMDAR antibodies in the hippocampus. These findings were associated with a decrease of the density of cell‐surface and synaptic NMDAR and EphB2, and marked impairment of long‐term synaptic plasticity without altering short‐term plasticity. Administration of ephrin‐B2 prevented the pathogenic effects of the antibodies in all the investigated paradigms assessing memory, depressive‐like behavior, density of cell‐surface and synaptic NMDAR and EphB2, and long‐term synaptic plasticity.
Interpretation
Administration of ephrin‐B2 prevents the pathogenic effects of anti‐NMDAR encephalitis antibodies on memory and behavior, levels of cell‐surface NMDAR, and synaptic plasticity. These findings reveal a strategy beyond immunotherapy to antagonize patients' antibody effects. Ann Neurol 2016;80:388–400
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