Correction: Hansen et al. Persisting Verbal Memory Encoding and Recall Deficiency after mGluR5 Autoantibody-Mediated Encephalitis. Brain Sci. 2023, 13, 1537.

Affiliations: In the published publication [...].

Dataset for: Autoantibody profiles in patients with immune checkpoint inhibitor-induced neurological immune-related adverse events.

The rise of cancer immunotherapy has been a milestone in clinical oncology. Above all, immune checkpoint inhibitor treatment (ICI) with monoclonal antibodies targeting programmed cell death protein 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) has improved survival rates for an increasing number of malignancies. However, despite the clinical benefits, ICI-related autoimmunity has become a significant cause of non-relapse-related morbidity and mortality. Neurological immune-related adverse events (irAE-n) are particularly severe toxicities with a high risk for chronic illness, long-term steroid dependency, and early ICI treatment termination. While the clinical characteristics of irAE-n are well described, little is known about underlying immune mechanisms and potential biomarkers. Recently, high frequencies of neuronal autoantibodies in patients with irAE-n have been reported, however, their clinical relevance is unclear. Here, we present a dataset on neuronal autoantibody profiles in ICI-treated cancer patients with and without irAE-n, which was generated to investigate the potential role of neuronal autoantibodies in ICI-induced autoimmunity. Between September 2017 and January 2022 serum samples of 29 cancer patients with irAE-n post-ICI treatment) and 44 cancer control patients without high-grade immune-related adverse events (irAEs, n = 44 pre- and post-ICI treatment) were collected and tested for a large panel of brain-reactive and neuromuscular autoantibodies using indirect immunofluorescence and immunoblot assays. Prevalence of autoantibodies was compared between the groups and correlated with clinical characteristics such as outcome and irAE-n manifestation. These data represent the first systematic comparison of neuronal autoantibody profiles between ICI-treated cancer patients with and without irAE-n, providing valuable information for both researchers and clinicians. In the future, this dataset may be valuable for meta-analyses on the prevalence of neuronal autoantibodies in cancer patients.

Persisting Verbal Memory Encoding and Recall Deficiency after mGluR5 Autoantibody-Mediated Encephalitis.

BACKGROUND: Metabotropic glutamate receptors type 5 (mGluR5) play a central role in persistent forms of synaptic plasticity and memory formation. Antibodies to mGluR5 have been reported to be clinically associated with memory impairment. Here, we report on a patient with persistent amnestic cognitive impairment in a single cognitive domain after resolution of mGluR5-associated encephalitis. METHODS: We report on the clinical data of a patient in our Department of Psychiatry and Psychotherapy who underwent several diagnostic investigations including a detailed neuropsychological examination, magnetic resonance imaging, and cerebrospinal fluid analysis involving the determination of neural autoantibodies. RESULTS: A 54-year-old woman presented to our memory clinic with pleocytosis 4 months after remission of probable anti-mGluR5-mediated encephalitis, revealing initial pleocytosis and serum proof of anti-mGluR5 autoantibodies (1:32). A neuropsychological examination revealed mild cognitive impairment in verbal memory encoding and recall. The patient received immunotherapy with corticosteroids, and a subsequent cerebrospinal fluid analysis 1.5 months after the onset of encephalitis confirmed no further signs of inflammation. CONCLUSIONS: Our results suggest that although immunotherapy resulted in the remission of anti-mGluR5 encephalitis, a verbal memory encoding and recall dysfunction persisted. It remains unclear whether the reason for the persistent verbal memory impairment is attributable to insufficiently long immunotherapy or initially ineffective immunotherapy. Because mGluR5 plays an essential role in persistent synaptic plasticity in the hippocampus, it is tempting to speculate that the mGluR5 antibody-antigen complex could lead to persistent cognitive dysfunction, still present after the acute CNS inflammation stage of encephalitis.

Long-Term Course of Neural Autoantibody-Associated Psychiatric Disorders: Retrospective Data from a Specifically Immunopsychiatric Outpatient Clinic.

Background: Autoantibody-associated psychiatric disorders are a new terrain that is currently underrepresented considering immunopsychiatry's potential importance for therapeutic aspects. The aim of our research was thus to present initial pilot data on the long-term clinical course of our patients in an outpatient clinic specializing in autoantibody-associated psychiatric disorders. Methods: Thirty-seven patients were examined clinically in our outpatient clinic at regular intervals over a 1.5-year period. We collected clinical data on their demographics, psychopathology, and cognition, and magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) data as well as the status of neural autoantibodies in blood and/or serum. Results: Our main finding was that affective, psychotic, and cognitive symptoms did not change significantly over the 1.5-year period, thus revealing no progression. We divided the entire cohort of autoantibody-positive patients (n = 32) into subgroups consisting of patients with dementia (n = 14), mild cognitive impairment (MCI) (n = 7), psychotic disorders (n = 6), and a CSF profile of Alzheimer's disease (n = 6). Relying on established classification schemes, we identified the following percentages in our autoantibody-positive cohort: 28% with autoimmune encephalitis, 15% with autoimmune psychosis, and 63% with autoimmune psychiatric syndromes. Discussion: These initial pilot results suggest that autoantibody-associated diseases do not show a significantly progressive course in the long-term and are often characterized by impaired verbal memory recall when cognitive impairment progresses to dementia. These initial data need to be verified in larger cohorts. We believe that this pilot study underscores the importance of promoting such a specialized outpatient clinic to better characterize various aspects of autoantibody-mediated psychiatric disorders.

Autoantibody profiles in patients with immune checkpoint inhibitor-induced neurological immune related adverse events.

Background: Neurological immune-related adverse events (irAE-n) are severe and potentially fatal toxicities of immune checkpoint inhibitors (ICI). To date, the clinical significance of neuronal autoantibodies in irAE-n is poorly understood. Here, we characterize neuronal autoantibody profiles in patients with irAE-n and compare these with ICI-treated cancer patients without irAE-n. Methods: In this cohort study (DRKS00012668), we consecutively collected clinical data and serum samples of 29 cancer patients with irAE-n (n = 2 pre-ICI, n = 29 post-ICI) and 44 cancer control patients without irAE-n (n = 44 pre- and post-ICI). Using indirect immunofluorescence and immunoblot assays, serum samples were tested for a large panel of neuromuscular and brain-reactive autoantibodies. Results: IrAE-n patients and controls received ICI treatment targeting programmed death protein (PD-)1 (61% and 62%), programmed death ligand (PD-L)1 (18% and 33%) or PD-1 and cytotoxic T-lymphocyte-associated protein (CTLA-)4 (21% and 5%). Most common malignancies were melanoma (both 55%) and lung cancer (11% and 14%). IrAE-n affected the peripheral nervous system (59%), the central nervous system (21%), or both (21%). Prevalence of neuromuscular autoantibodies was 63% in irAE-n patients, which was higher compared to ICI-treated cancer patients without irAE-n (7%, p <.0001). Brain-reactive autoantibodies targeting surface (anti-GABABR, -NMDAR, -myelin), intracellular (anti-GFAP, -Zic4, -septin complex), or unknown antigens were detected in 13 irAE-n patients (45%). In contrast, only 9 of 44 controls (20%) presented brain-reactive autoantibodies before ICI administration. However, seven controls developed de novo brain-reactive autoantibodies after ICI initiation, therefore, prevalence of brain-reactive autoantibodies was comparable between ICI-treated patients with and without irAE-n (p = .36). While there was no clear association between specific brain-reactive autoantibodies and clinical presentation, presence of at least one of six selected neuromuscular autoantibodies (anti-titin, anti-skeletal muscle, anti-heart muscle, anti-LRP4, anti-RyR, anti-AchR) had a sensitivity of 80% (95% CI 0.52-0.96) and a specificity of 88% (95% CI 0.76-0.95) for the diagnosis of myositis, myocarditis, or myasthenia gravis. Conclusion: Neuromuscular autoantibodies may serve as a feasible marker to diagnose and potentially predict life-threatening ICI-induced neuromuscular disease. However, brain-reactive autoantibodies are common in both ICI-treated patients with and without irAE-n, hence, their pathogenic significance remains unclear.

Cerebrospinal Fluid Homer-3 Autoantibodies in a Patient with Amnestic Mild Cognitive Impairment.

(1) Background: Homer-3 antibodies are associated with cerebellar disease ranging from subacute degeneration to cerebellitis. However, cognitive impairment associated with Homer-3 autoantibodies has not been reported until now. (2) Methods: in retrospect, we systematically studied clinical, cranial magnetic resonance imaging (cMRI), electroencephalography (EEG) and lumbar puncture data, including neural autoantibodies of a clinical case. (3) Results: we describe the case of a 56-year-old woman presenting with amnestic mild cognitive impairment in association with serum and CSF detection of Homer-3 autoantibodies and a depressive syndrome. cMRI revealed cerebellar atrophy. CSF analysis showed elevated ptau181 protein. Applying the criteria for an autoimmune psychiatric syndrome revealed a plausible autoimmune basis for the mild cognitive impairment. (4) Discussions: our case report demonstrates an amnestic mild cognitive impairment and depressive symptoms associated with Homer-3 autoantibodies as a novel feature of Homer-3 antibody-related disease. We also propose that cognitive dysfunction might result from impaired AMPAR signaling in the hippocampus induced by Homer-3 antibodies, which will have to be verified in further research.

Immunotherapy with corticosteroids in anti-neural autoantibody-associated cognitive impairment: Retrospective case series.

Background: Anti-neural autoantibody-associated cognitive impairment is an increasing phenomenon in memory clinics deserving more attention to applying immunotherapy such as methylprednisolone to improve cognition. Our study aims to investigate the usefulness of intravenous high-dosage corticosteroids in a small cohort of patients suffering from anti-neural autoantibody-associated cognitive impairment. Materials and methods: We included in our retrospective case series seven patients presenting diverse neural autoantibodies and cognitive impairments varying from a mild impairment to dementia. We conducted neuropsychological and psychopathological investigations before and after the application of high intravenous methylprednisolone therapy over a 6-month period. Neuropsychological function was assessed by the CERAD (Consortium to Establish a Registry for Alzheimer's Disease) test battery. Patients were also characterized by assessing their patient files for demographic and clinical data. Results: The patients' cognitive subdomains did not improve according to CERAD in their z-scores before and after immunotherapy. We noted a non-significant trend toward an improvement in semantic fluency and verbal memory consolidation. Patients did not do worse in 4 of 12 (33%) cognitive subdomains in the CERAD test battery. Furthermore, mood dysfunction lessened as a non-significant trend in specific psychopathological features such as reduced affective symptoms, loss of drive, and ruminations. Affective symptoms, loss of drive and ruminations were reduced by 43% after immunotherapy. Discussion: Our small pilot study revealed no relevant alleviation of cognitive dysfunction in patients with neural autoantibodies. However, mood dysfunction became less obvious in specific functions concerning affect, drive, and rumination. However, we do not know whether methylprednisolone affects mood dysfunction, as some patients were taking antidepressant drugs at the same time. Our results might indicate that methylprednisolone immunotherapy is associated with impeding the progression of cognitive dysfunction and reducing mood dysfunction. Further large-scale, placebo-controlled studies in a more homogeneous patient population presenting a uniform pattern of neural autoantibodies should be undertaken.

Anti-Homer-3 antibodies in cerebrospinal fluid and serum samples from a 58-year-old woman with subacute cerebellar degeneration and diffuse breast adenocarcinoma.

INTRODUCTION: Subacute cerebellar ataxia combined with cerebrospinal fluid (CSF) pleocytosis is the result of an immune response that can occur due to viral infections, paraneoplastic diseases or autoimmune-mediated mechanisms. In the following we present the first description of a patient with anti-Homer-3 antibodies in serum and CSF who has been diagnosed with paraneoplastic subacute cerebellar degeneration due to a papillary adenocarcinoma of the breast. CASE PRESENTATION: A 58-year-old female was admitted to our clinical department because of increasing gait and visual disturbances starting nine months ago. The neurological examination revealed a downbeat nystagmus, oscillopsia, a severe standing and gait ataxia and a slight dysarthria. Cranial MRI showed no pathological findings. Examination of CSF showed a lymphocytic pleocytosis of 11 cells/µl and an intrathecal IgG synthesis of 26%. Initially, standard serological testing in serum and CSF did not indicate any autoimmune or paraneoplastic aetiology. However, an antigen-specific indirect immunofluorescence test (IIFT) revealed the presence of anti-Homer-3 antibodies (IgG) with a serum titer of 1: 32,000 and a titer of 1: 100 in CSF. Subsequent histological examination of a right axillary lymph node mass showed papillary adenocarcinoma cells. Breast MRI detected multiple bilateral lesions as a diffuse tumour manifestation indicative of adenocarcinoma of the breast. Treatment with high-dose methylprednisolone followed by five plasmaphereses and treatment with 4-aminopyridine resulted in a moderate decrease of the downbeat nystagmus and she was able to move independently with a wheeled walker after 3 weeks. The patient was subsequently treated with chemotherapy (epirubicin, cyclophosphamide) and two series of immunoglobulins (5 × 30 g each). This resulted in a moderate improvement of the cerebellar symptoms with a decrease of ataxia and disappearance of the downbeat nystagmus. CONCLUSION: The presented case of anti-Homer-3 antibody-associated cerebellar degeneration is the first that is clearly associated with the detection of a tumour. Interestingly, the Homer-3 protein interaction partner metabotropic glutamate receptor subtype 1A (mGluR1A) is predominantly expressed in Purkinje cells where its function is essential for motor coordination and motor learning. Based on our findings, in subacute cerebellar degeneration, we recommend considering serological testing for anti-Homer-3 antibodies in serum and cerebrospinal fluid together with tumor screening.

Prevalence of Anti-neural Autoantibodies in a Psychiatric Patient Cohort-Paradigmatic Application of Criteria for Autoimmune-Based Psychiatric Syndromes.

Background: Anti-neural autoantibodies associated with psychiatric syndromes is an increasing phenomenon in psychiatry. Our investigation aimed to assess the frequency and type of neural autoantibodies associated with distinct psychiatric syndromes in a mixed cohort of psychiatric patients. Methods: We recruited 167 patients retrospectively from the Department of Psychiatry and Psychotherapy, University Medical Center Göttingen for this study. Clinical features including the assessment of psychopathology via the Manual for Assessment and Documentation of Psychopathology in Psychiatry (AMDP), neurological examination, cerebrospinal fluid (CSF), magnetic resonance imaging (MRI) and electroencephalography (EEG) analysis were done in patients. Serum and or CSF anti- neural autoantibodies were measured in all patients for differential diagnostic reasons. Results: We divided patients in three different groups: (1) psychiatric patients with CSF and/or serum autoantibodies [PSYCH-AB+, n = 25 (14.9%)], (2) psychiatric patients with CSF autoantibodies [PSYCH-AB CSF+, n = 13 (7.8%)] and (3) those psychiatric patients without autoantibodies in serum and/or CSF [PSYCH-AB-, n = 131]. The prevalence of serum neural autoantibodies was 14.9% (PSYCH-AB+), whereas 7.2% had CSF autoantibodies (PSYCH-AB CSF+) in our psychiatric cohort. The most prevalent psychiatric diagnoses were neurocognitive disorders (61-67%) and mood disorders (25-36%) in the patients presenting neural autoantibodies (PSYCH-AB+ and PSYCH-AB CSF+). However, psychiatric diagnoses, neurological deficits, and laboratory results from CSF, EEG or MRI did not differ between the three groups. To evaluate the relevance of neural autoantibody findings, we applied recent criteria for possible, probable, or definitive autoimmune based psychiatric syndromes in an paradigmatic patient with delirium and in the PSYCH-AB+ cohort. Applying criteria for any autoimmune-based psychiatric syndromes, we detected a probable autoimmune-based psychiatric syndrome in 13 of 167 patients (7.8%) and a definitive autoimmune-based psychiatric syndrome in 11 of 167 patients (6.6%). Conclusions: Neural autoantibodies were detected mainly in patients presenting neurocognitive and mood disorders in our psychiatric cohort. The phenotypical appearance of psychiatric syndromes in conjunction with neural autoantibodies did not differ from those without neural autoantibodies. More research is therefore warranted to optimize biomarker research to help clinicians differentiate patients with potential neural autoantibodies when a rapid clinical response is required as in delirium states.

Case report: Amnestic mild cognitive impairment in multiple domains associated with neurofascin 186 autoantibodies: Case series with follow-up and review.

Background: Neurofascin 186 autoantibodies are known to occur with a diseased peripheral nervous system. Recently, also additional central nervous system (CNS) involvement has been reported in conjunction with neurofascin 186 autoantibodies. Our case enlarges the spectrum of neurofascin 186 antibody-related disease to include mild cognitive impairment (MCI). Methods: We report here a case after having examined the patient files retrospectively, including diagnostics such as blood and cerebrospinal fluid (CSF) analysis involving the determination of neural autoantibodies, brain magnetic resonance imaging (MRI), brain fluorodesoxyglucose positron emission tomography (FDG-PET), and extensive neuropsychological testing. Results: We report on two patients with MCI. Brain MRI showed cerebral microangiopathy in both patients, but brain FDG-PET demonstrated pathology in the right prefrontal cortex, in the right inferior parietal cortex, and in both lateral occipital cortices in one patient. Neurofascin 186 antibodies were detected in serum in both patients, and neurofascin 186 autoantibodies were also detected in the CSF of one of these patients. At follow-up six month later, neurofascin 186 autoantibodies disappeared in one patient while persisting in the other. Conclusion: We report on two individuals presenting MCI associated with neurofascin 186 antibodies, thus expanding the potential spectrum of neurofascin 186-associated disease. This report supports the recommendation to consider also neurofascin 186 autoantibodies in not just peripheral nerve disease, but also in disorders involving CNS autoimmunity. More studies are needed to clarify the lack of association between neurofascin 186 autoantibodies and cognitive decline.

Association Between Neuronal Autoantibodies and Cognitive Impairment in Patients With Lung Cancer.

IMPORTANCE: Paraneoplastic neurological syndromes are associated with neuronal autoantibodies, and some of these autoantibodies are associated with neuropsychological symptoms. The most common underlying tumor is lung cancer. The association of neuronal autoantibodies with cognitive deficits has not been systematically investigated in patients with small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). OBJECTIVE: To assess the frequency of neuronal autoantibodies in patients with lung cancer and analyze their association with cognitive function. DESIGN, SETTING, AND PARTICIPANTS: This prospective, cross-sectional study included 167 patients with lung cancer (both SCLC and NSCLC) recruited at a single lung cancer center in Berlin, Germany, between June 2015 and April 2016. Detailed neuropsychological testing was performed in a carefully selected subgroup of 97 patients (from which patients with potential confounding factors were excluded). Investigators were blinded to patients' autoantibody status and cognitive test results. Data were analyzed from May 2016 to December 2019. MAIN OUTCOMES AND MEASURES: Prevalence of neuronal autoantibodies and their association with cognitive impairment. The evaluation of autoantibodies as potential risk factors for cognitive impairment was performed using bayesian logistic regression models. RESULTS: Among 167 patients with lung cancer (median age, 66.0 years [interquartile range, 59.0-72.0 years]; 105 men [62.9%]), 127 had NSCLC, and 40 had SCLC. Brain-directed autoantibodies were detected in 61 of 167 patients (36.5%); 33 patients (19.8%) had known autoantibodies and 28 patients (16.8%) had autoantibodies against currently unknown antigens that were detected through immunohistochemical analysis. Cognitive impairment was found in 65 of 97 patients (67.0%). Among patients with SCLC, the odds of cognitive impairment for those with any autoantibodies was 11-fold higher (odds ratio [OR], 11.0; 95% credible interval [CrI], 1.2-103.6) than that of autoantibody-negative patients, and the increased odds were independent of age, sex, and neurological deficit. Among patients with NSCLC, those with immunoglobin A autoantibodies targeting the N-methyl-d-aspartate receptor had a relevantly increased odds of verbal memory deficits (OR, 182.8; 95% CrI, 3.1-10 852.4). Autoantibodies against currently unknown antigens were also associated with increased odds of cognitive impairment (OR, 2.8; 95% CrI, 0.6-12.1). CONCLUSIONS AND RELEVANCE: In this prospective, cross-sectional study, more than one-third of patients with lung cancer had neuronal autoantibodies that were found to be associated with cognitive impairment. These autoantibodies might represent a potentially treatable mechanism of immune-mediated cognitive impairment among patients with lung cancer.

Case Report: Semantic Variant of Primary Progressive Aphasia Associated With Anti-Glial Fibrillary Acid Protein Autoantibodies.

Background: Frontotemporal lobar degeneration is a heterogeneous disorder entailing a semantic variant of primary progressive aphasia (svPPA). A subtype of frontotemporal dementia associated with glutamate receptor subunit 3 (GluA3) antibody of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) was recently identified. Here, we describe the novelty of a svPPA associated with anti-glial fibrillary acid protein (GFAP) antibodies. Methods: To diagnose this 68-year-old woman we conducted a clinical examination, neuropsychological testing, CSF analysis, MRI and 18F-fluorodeoxyglucose (18F-FDG) Positron Emission Tomography (PET)/computed tomography (CT) imaging. Results: The clinical phenotype corresponds to a svPPA based on impaired confrontation naming and single-word comprehension. In addition, we observed spared speech production, impaired object knowledge, and surface dyslexia - further supporting the diagnosis of svPPA. Additional characteristic imaging features such as anterior temporal hypometabolism in 18F-FDG PET/CT confirmed patient's svPPA diagnosis. CSF analysis revealed signs of axonal degeneration, as both tau and phosphorylated tau proteins exceeded normal levels. Her serum showed anti-GFAP autoantibodies. Conclusion: We diagnosed a svPPA in this patient and report an association between serum anti-GFAP antibodies and svPPA never reported in the literature so far, thereby expanding the clinical spectrum of svPPA and anti-GFAP-antibody related disease. Further research is needed to elucidate the underlying immunopathology of this disease entity to ultimately improve treatment.

Dysfunctional Learning and Verbal Memory in Patients with Elevated Tau Protein Levels and Serum Recoverin Autoantibodies-Case Series and Review.

Recoverin-antibody-related disease is currently restricted to late-onset ataxia and autoimmune retinopathy, which can be paraneoplastic or not. However, cognitive dysfunction associated with recoverin antibodies has not been reported so far in a homogeneous patient group. Our case series is dedicated to describing the novel phenotype of cognitive impairment associated with recoverin antibodies. We included five patients with cognitive impairment who presented serum recoverin autoantibodies detected by immunoblots in our case series investigation. We also analyzed their psychopathology, clinical data, cerebrospinal fluid (CSF), and neuroimaging data. Five patients with cognitive impairment associated with serum recoverin antibodies exhibited profound dysfunctional learning and verbal memory. In the CSF of 40% of them, we also diagnosed axonal neurodegeneration entailing elevated tau and phosphorylated tau protein levels. Psychopathologies such as affective symptoms (restlessness, depressive mood, anxiety, complaintiveness) and formal thought disorder, such as rumination, were detected in 25-75% of the patients. We hypothesized a role of recoverin autoimmunity in the pineal gland involving consecutive modulation of hippocampus-based memory caused by an altered release of melatonin. We describe a novel phenotype of possible recoverin autoimmunity in patients with cognitive impairment. However, no clear diagnostic clues can be extracted because of the low diagnostic validity of the testing strategies applied. The possibility of recoverin antibody autoimmunity in the pineal gland correlating with a modulation of hippocampus-based memory should be further investigated.

Multiple inducers and novel roles of autoantibodies against the obligatory NMDAR subunit NR1: a translational study from chronic life stress to brain injury.

Circulating autoantibodies (AB) of different immunoglobulin classes (IgM, IgA, and IgG), directed against the obligatory N-methyl-D-aspartate-receptor subunit NR1 (NMDAR1-AB), belong to the mammalian autoimmune repertoire, and appear with age-dependently high seroprevalence across health and disease. Upon access to the brain, they can exert NMDAR-antagonistic/ketamine-like actions. Still unanswered key questions, addressed here, are conditions of NMDAR1-AB formation/boosting, intraindividual persistence/course in serum over time, and (patho)physiological significance of NMDAR1-AB in modulating neuropsychiatric phenotypes. We demonstrate in a translational fashion from mouse to human that (1) serum NMDAR1-AB fluctuate upon long-term observation, independent of blood-brain barrier (BBB) perturbation; (2) a standardized small brain lesion in juvenile mice leads to increased NMDAR1-AB seroprevalence (IgM + IgG), together with enhanced Ig-class diversity; (3) CTLA4 (immune-checkpoint) genotypes, previously found associated with autoimmune disease, predispose to serum NMDAR1-AB in humans; (4) finally, pursuing our prior findings of an early increase in NMDAR1-AB seroprevalence in human migrants, which implicated chronic life stress as inducer, we independently replicate these results with prospectively recruited refugee minors. Most importantly, we here provide the first experimental evidence in mice of chronic life stress promoting serum NMDAR1-AB (IgA). Strikingly, stress-induced depressive-like behavior in mice and depression/anxiety in humans are reduced in NMDAR1-AB carriers with compromised BBB where NMDAR1-AB can readily reach the brain. To conclude, NMDAR1-AB may have a role as endogenous NMDAR antagonists, formed or boosted under various circumstances, ranging from genetic predisposition to, e.g., tumors, infection, brain injury, and stress, altogether increasing over lifetime, and exerting a spectrum of possible effects, also including beneficial functions.

Multicenter prospective study on multivariant diagnostics of autoimmune bullous dermatoses using the BIOCHIP technology.

BACKGROUND: The current standard in the serologic diagnosis of autoimmune bullous diseases (AIBD) is a multistep procedure sequentially applying different assays. In contrast, the BIOCHIP Mosaic technology combines multiple substrates for parallel analysis by indirect immunofluorescence. METHODS: Sera from 749 consecutive, prospectively recruited patients with direct immunofluorescence-positive AIBD from 13 international study centers were analyzed independently and blinded by using (1) a BIOCHIP Mosaic including primate esophagus, salt-split skin, rat bladder, monkey liver, monkey liver with serosa, recombinant BP180 NC16A, and gliadin GAF3X, as well as HEK293 cells expressing recombinant desmoglein 1, desmoglein 3, type VII collagen, and BP230 C-terminus and (2) the conventional multistep approach of the Department of Dermatology, University of Lübeck. RESULTS: In 731 of 749 sera (97.6%), specific autoantibodies could be detected with the BIOCHIP Mosaic, similar to the conventional procedure (725 cases, 96.8%). The Cohen κ for both serologic approaches ranged from 0.84 to 1.00. In 6.5% of sera, differences between the 2 approaches occurred and were mainly attributed to autoantigen fragments not present on the BIOCHIP Mosaic. LIMITATIONS: Laminin 332 and laminin γ1 are not represented on the BIOCHIP Mosaic. CONCLUSIONS: The BIOCHIP Mosaic is a standardized time- and serum-saving approach that further facilitates the serologic diagnosis of AIBD.

Routine detection of serum antidesmocollin autoantibodies is only useful in patients with atypical pemphigus.

Autoantibodies against the 3 desmocollin (Dsc; Dsc1-Dsc3) isoforms have been described in different pemphigus variants. Here, we developed state-of-the-art detection systems for serum anti-Dsc1, Dsc2 and Dsc1 IgG and IgA. These assays were applied in 5 different cohorts including pemphigus vulgaris (PV) patients with compatible direct immunofluorescence (IF) microscopy but no reactivity against desmogleins 1 and 3 (n = 24) and sera from patients with autoimmune blistering diseases with positive direct IF microscopy taken at the time of diagnosis (n = 749). We found that detection of anti-Dsc serum reactivity is not helpful in the routine diagnosis of PV, pemphigus foliaceus and paraneoplastic pemphigus but may be valuable in pemphigus vegetans.

Spinal poly-GA inclusions in a C9orf72 mouse model trigger motor deficits and inflammation without neuron loss.

Translation of the expanded (ggggcc)n repeat in C9orf72 patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) causes abundant poly-GA inclusions. To elucidate their role in pathogenesis, we generated transgenic mice expressing codon-modified (GA)149 conjugated with cyan fluorescent protein (CFP). Transgenic mice progressively developed poly-GA inclusions predominantly in motoneurons and interneurons of the spinal cord and brain stem and in deep cerebellar nuclei. Poly-GA co-aggregated with p62, Rad23b and the newly identified Mlf2, in both mouse and patient samples. Consistent with the expression pattern, 4-month-old transgenic mice showed abnormal gait and progressive balance impairment, but showed normal hippocampus-dependent learning and memory. Apart from microglia activation we detected phosphorylated TDP-43 but no neuronal loss. Thus, poly-GA triggers behavioral deficits through inflammation and protein sequestration that likely contribute to the prodromal symptoms and disease progression of C9orf72 patients.

Multiparametric serological testing in autoimmune encephalitis using computer-aided immunofluorescence microscopy (CAIFM).

Autoantibodies against neuronal cell surface antigens are tightly associated with immunotherapy-responsive autoimmune encephalitis, and a considerable number of corresponding autoantigens has been identified in recent years. Most patients initially present with overlapping symptoms, and a broad range of autoantibodies has to be considered to establish the correct diagnosis and initiate treatment as soon as possible to prevent irreversible and sometimes even life-threatening damage to the brain. Recombinant cell-based immunofluorescence allows to authentically present fragile membrane-associated surface antigens and, in combination with multiparametric analysis in the form of biochip mosaics, has turned out to be highly beneficial for parallel and prompt determination of anti-neuronal autoantibodies and comprehensive differential diagnostics. For the evaluation of recombinant cell-based IIFT, a semi-automated novel function was introduced into an established platform for computer-aided immunofluorescence microscopy. The system facilitates the microscopic analysis of the tests and supports the laboratory personnel in the rapid issuance of diagnostic findings, which is of major importance for autoimmune encephalitis patients since timely initiation of treatment may lead to their full recovery.

Multicentre comparison of a diagnostic assay: aquaporin-4 antibodies in neuromyelitis optica.

OBJECTIVE: Antibodies to cell surface central nervous system proteins help to diagnose conditions which often respond to immunotherapies. The assessment of antibody assays needs to reflect their clinical utility. We report the results of a multicentre study of aquaporin (AQP) 4 antibody (AQP4-Ab) assays in neuromyelitis optica spectrum disorders (NMOSD). METHODS: Coded samples from patients with neuromyelitis optica (NMO) or NMOSD (101) and controls (92) were tested at 15 European diagnostic centres using 21 assays including live (n=3) or fixed cell-based assays (n=10), flow cytometry (n=4), immunohistochemistry (n=3) and ELISA (n=1). RESULTS: Results of tests on 92 controls identified 12assays as highly specific (0-1 false-positive results). 32 samples from 50 (64%) NMO sera and 34 from 51 (67%) NMOSD sera were positive on at least two of the 12 highly specific assays, leaving 35 patients with seronegative NMO/spectrum disorder (SD). On the basis of a combination of clinical phenotype and the highly specific assays, 66 AQP4-Ab seropositive samples were used to establish the sensitivities (51.5-100%) of all 21 assays. The specificities (85.8-100%) were based on 92 control samples and 35 seronegative NMO/SD patient samples. CONCLUSIONS: The cell-based assays were most sensitive and specific overall, but immunohistochemistry or flow cytometry could be equally accurate in specialist centres. Since patients with AQP4-Ab negative NMO/SD require different management, the use of both appropriate control samples and defined seronegative NMOSD samples is essential to evaluate these assays in a clinically meaningful way. The process described here can be applied to the evaluation of other antibody assays in the newly evolving field of autoimmune neurology.