N-methyl-D-aspartate receptor- antibody encephalitis impairs maintenance of attention to items in working memory

NMDA receptors (NMDAR) may be crucial to working memory (WM). Computational models predict that they sustain neural firing and produce associative memory, which may underpin maintaining and binding information respectively. We test this in patients with antibodies to NMDAR (n=10, female) and compare them with healthy control participants (n=55, 20 male, 35 female). Patients were tested after recovery with a task that separates two aspects of WM: sustaining attention and feature binding. Participants had to remember two colored arrows. Then attention was directed to one of them. After a variable delay, they reported the direction of either the same arrow (congruent cue), or of the other arrow (incongruent cue). We asked how congruency affected recall precision and measured types of error. Patients had difficulty in both sustaining attention to an item over time and feature binding. Controls were less precise after longer delays and incongruent cues. In contrast, patients did not benefit from congruent cues at longer delays (Group x Congruency [long condition], p=0.041), indicating they could not sustain attention. Additionally, patients reported the wrong item (misbinding errors) more than controls after congruent cues (Group x Delay [congruent condition], main effect of group, p=Significance Statement Computational theories suggest NMDA receptors (NMDARs) are critical for actively maintaining information, while other theories propose they allow us to associate or "bind" objects features together. This is the first causal test in humans of the role of NMDARs in actively maintaining attention in working memory and feature binding. We find patients have difficulty with both these processes in support of computational models. Notably, we demonstrate that patients with NMDA receptor-antibody encephalitis are an ideal model condition to study roles of receptors in human cognition. Secondly, few studies follow these patients long after treatment. Our findings demonstrate a specific long-term neuropsychological deficit, previously unreported to our knowledge, that highlights the need for greater focus on neurocognitive rehabilitation with these patients

Hippocampal Functional Dynamics Are Clinically Implicated in Autoimmune Encephalitis With Faciobrachial Dystonic Seizures

This is the first study to investigate functional brain activity in patients affected by autoimmune encephalitis with faciobrancial dystonic seizures (FBDS). Multimodal 3T MRI scans, including structural neuroimaging (T1-weighted, diffusion weighted) and functional neuroimaging (scene-encoding task known to activate hippocampal regions), were performed. This case series analysis included eight patients treated for autoimmune encephalitis with FBDS, scanned during the convalescent phase of their condition (median 1.1 years post-onset), and eight healthy volunteers. Compared to controls, 50% of patients showed abnormal hippocampal activity during scene-encoding relative to familiar scene-viewing. Higher peak FBDS frequency was significantly related to lower hippocampal activity during scene-encoding (p = 0.02), though not to markers of hippocampal microstructure (mean diffusivity, p = 0.3) or atrophy (normalized volume, p = 0.4). During scene-encoding, stronger within-medial temporal lobe (MTL) functional connectivity correlated with poorer Addenbrooke's Cognitive Examination-Revised memory score (p = 0.03). These findings suggest that in autoimmune encephalitis, frequent seizures may have a long-term impact on hippocampal activity, beyond that of structural damage. These observations also suggest a potential approach to determine on-going MTL performance in this condition to guide long-term management and future clinical trials

Regulatory T cell profiles in patients with N-methyl-ᴅ-aspartate receptor-antibody encephalitis

Purpose Purpose Regulatory T cells (Tregs) have been implicated in the pathogenesis of several autoimmune disorders and used in adoptive cell transfer therapies. Neither have been explored in patients with autoimmune encephalitis where treated patient outcomes remain suboptimal with frequent relapses. Here, to identify new treatment strategies for autoimmune encephalitis, we sought to evaluate the proportion of circulating Tregs and Treg subpopulations in peripheral blood of patients with N-methyl-ᴅ-aspartate receptor-antibody encephalitis (NMDAR-Ab-E) and compared this with healthy controls. Methods We compared the phenotype of peripheral blood Tregs in four adult NMDAR-Ab-E patients and four age- and sex-matched healthy controls using an 11-color flow cytometry assay panel for characterization of Tregs (CD4+ CD25+ FoxP3+) cells into naïve (chemokine receptor [CCR] 7+ CD45RA+), central memory (CCR7+ CD45RA–), and effector memory (CCR7– CD45RA–) cells. We also examined and compared the expression of the CCR6 by circulating Tregs and the respective Treg subpopulations between the study groups. Results The proportion of circulating Tregs was similar between patients with NMDAR-Ab-E and healthy controls but the proportion of naïve Tregs was lower in NMDAR-Ab-E patients (p = 0.0026). Additionally, the frequency of circulating effector memory Tregs was higher, and the proportion of circulating effector memory Tregs expressing CCR6 was lower, in NMDAR-Ab-E patients compared with healthy controls (p = 0.0026). Conclusion Altered Treg homeostasis may be a feature of patients with NMDAR-Ab-E. Future studies with larger samples are warranted to validate these findings

Fine needle aspiration of human lymph nodes reveals cell populations and soluble interactors pivotal to immunological priming

Lymph node (LN) fine needle aspiration (LN FNA) represents a powerful technique for minimally invasive sampling of human LNs in vivo and has been used effectively to directly study aspects of the human germinal center response. However, systematic deep phenotyping of the cellular populations and cell-free proteins recovered by LN FNA has not been performed. Thus, we studied human cervical LN FNAs as a proof-of-concept and used single-cell RNA-sequencing and proteomic analysis to benchmark this compartment, define the purity of LN FNA material, and facilitate future studies in this immunologically pivotal environment. Our data provide evidence that LN FNAs contain bone-fide LN-resident innate immune populations, with minimal contamination of blood material. Examination of these populations reveals unique biology not predictable from equivalent blood-derived populations. LN FNA supernatants represent a specific source of lymph- and lymph node-derived proteins, and can, aided by transcriptomics, identify likely receptor–ligand interactions. This represents the first description of the types and abundance of immune cell populations and cell-free proteins that can be efficiently studied by LN FNA. These findings are of broad utility for understanding LN physiology in health and disease, including infectious or autoimmune perturbations, and in the case of cervical nodes, neuroscience

Description of the fecal microbiota of siblings from Costa Rica with and without affective and psychotic disorders

Peer reviewe

Neuroimmunology 2017: making progress over 20 years

In 1997, two prescient case reports described an encephalopathy associated with ovarian teratoma presenting with a psychiatric illness that responded to tumour resection.1,2 10 years later, Dalmau and colleagues3 first reported an association between this syndrome and antibodies against the NMDA receptor. NMDAR-antibody encephalitis is notable for a clinical-radiological paradox of often normal structural MRI but severe and disabling illness. In 2017, Peer and colleagues4 reported the largest functional imaging analysis of such patients to date

Neuroimmunology 2017: making progress over 20 years

In 1997, two prescient case reports described an encephalopathy associated with ovarian teratoma presenting with a psychiatric illness that responded to tumour resection.1,2 10 years later, Dalmau and colleagues3 first reported an association between this syndrome and antibodies against the NMDA receptor. NMDAR-antibody encephalitis is notable for a clinical-radiological paradox of often normal structural MRI but severe and disabling illness. In 2017, Peer and colleagues4 reported the largest functional imaging analysis of such patients to date

Synaptic and neuronal autoantibody-associated psychiatric syndromes:Controversies and hypotheses

Autoimmune encephalitis (AE) mediated by antibodies against synaptic and neuronal surface targets frequently presents with a psychiatric syndrome. In these patients, removal of autoantibodies treats the disease and outcomes are closely linked to early intervention. The discovery of these autoantibodies in isolated psychiatric syndromes has raised the possibility that these patients may derive similar benefits from immunotherapy, a potentially transformational approach to the treatment of mental illness. Although open-label case series suggest impressive therapeutic outcomes, the pathological relevance of these autoantibodies outside of canonical presentations is debated. The advent of diagnostic criteria for AE attempts to facilitate its prompt identification but risks prematurely neglecting the potential scientific and clinical significance of isolated syndromes that do not satisfy these criteria. Here, we propose using a syndrome-level taxonomy that has occasional, but not necessary, overlap with AE: synaptic and neuronal autoantibody-associated psychiatric syndromes or "SNAps". This will prevent confusion with AE and act heuristically to promote active investigation into this rare example of psychopathology defined on a molecular level. We suggest that this concept would have application in other autoantibody-associated syndromes including seizure, cognitive, and movement disorders, in which similar issues arise. We review putative direct and indirect mechanisms and outline experimentally testable hypotheses that would help to determine prospectively in whom autoantibody detection is relevant, and as important, in whom it is not. We summarize a pragmatic approach to autoantibody testing and management in severe mental illness in order to promptly diagnose AE and advocate a research-orientated experimental medicine paradigm for SNAps, where there is greater equipoise. We conclude that SNAps remains a nascent area of clinical neuroscience with great potential and in ongoing need of psychiatry-led basic and clinical research