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In Vivo N-Methyl-d-Aspartate Receptor (NMDAR) Density as Assessed Using Positron Emission Tomography During Recovery From NMDAR-Antibody Encephalitis
This case-control study uses a radiotracer and positron emission tomography to assess N-methyl-d-aspartate receptor (NMDAR) density changes during recovery from NMDAR-antibody encephalitis.
Regulatory T cell profiles in patients with N-methyl-ᴅ-aspartate receptor-antibody encephalitis
PurposePurpose 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.MethodsWe 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.ResultsThe 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).ConclusionAltered Treg homeostasis may be a feature of patients with NMDAR-Ab-E. Future studies with larger samples are warranted to validate these findings.
15. Neuronal Autoantibodies and Blood-Brain Barrier Disruption in Subjects at Ultra-High Risk for Psychosis
Abstract Background: Neuronal surface autoantibodies (NSAbs) have been identified in patients with psychotic disorders, with meta-analytical evidence indicating a higher prevalence in first-episode psychosis (FEP), probably dependent on the assay used. The causal significance of these NSAbs is unclear, with a suggestion that that blood–brain barrier disruption (BBBD) may be an important additional factor. We aimed to establish whether, prior to illness onset, NSAbs and BBBD are present in subjects at ultra-high risk (UHR) for psychosis. Methods: Sera from 260 UHR subjects in the EUGEI study and 110 healthy controls were tested with a fixed cell-based assay (CBA) using HEK293 cells that had been transfected to express one of 30+ NSAbs; IgG, IgA and IgM binding was assessed using indirect immunofluorescence. Levels of S100B, a putative marker of BBBD, were assessed using a chemoluminescence assay in this cohort and an FEP cohort (n = 226). Results: NSAbs were present in 8.8% of UHR subjects and 7.3% HCs (ns) with NMDAR the most frequent antigen. Serostatus did not predict transition to psychosis, and 2 of 3 seropositive patients who transitioned to psychosis had antibodies of diverse Ig isotype. Patients with brief limited intermittent psychotic symptoms (BLIPS) were twice as likely to be seropositive at baseline compared to patients who transitioned to psychosis. Interestingly, subjects who were positive on fixed CBA for any NSAb or for only NMDAR antibodies showed trends towards higher negative syndrome scores across multiple scales. These subjects had impaired verbal memory scores as measured by the Rey auditory verbal learning test (RAVLT) (P = .0019), a finding that mirrors patients with NMDAR encephalitis and may be reflective of hippocampal dysfunction. Samples were also tested for NMDAR IgG antibodies using a live CBA; this detected a higher prevalence of NMDAR IgG antibodies in the total cohort than did fixed CBA (19 subjects (5.1%) vs 2 (0.5%); P = .0025). Mean S100B levels were higher in FEP subjects than in UHR subjects (P < .001) and controls (P < .0001). UHR subjects with high S100B levels surprisingly showed lower total psychopathology scores (BPRS; P = .032), less negative symptoms (SANS; P = .039), and disability (GAF; P = .009), whereas in FEP S100B levels were associated with worse positive psychotic symptoms. Conclusion: A minority of subjects at risk of psychosis have NSAbs detectable in serum: These individuals may have worse negative symptoms and demonstrate impaired neurocognition. Further work is required to clarify the immunological and neuroanatomical substrates of these changes. BBBD may be progressive with the development of psychosis. The paradoxical finding of improved symptoms and function in subjects with evidence of greater BBBD differentiates UHR subjects from later stage psychosis and represents an exciting avenue for further investigation. This work was supported by a grant from The Wellcome Trust.
Autoimmune Epilepsies
Abstract In the last decade, serum autoantibodies have been identified that are likely to be pathogenic in many cases of epilepsy. Established antibody targets include membrane or membrane-associated neuronal proteins such as components of the voltage-gated potassium channel complex (LGI1, CASPR2 and Contactin-2) and the NMDA, GABAB and AMPA receptors. Many of the ‘autoimmune encephalitides’ associated with these antibodies include seizures as a prominent part of the syndrome, but commonly also present with amnesia and confusion. The seizures and cognitive deficits usually show marked improvements with immunotherapies, and their amelioration is well correlated with reductions in antibody levels in individual patients. Antibodies to VGKC-complexes or GAD have also been described in cohorts of patients with various forms of epilepsy, although the etiological role of these antibodies is not yet clear. Recently, a new seizure semiology has been described that is closely associated with the presence of LGI1-antibodies. Very frequent short-lived, adult-onset arm and face dystonic spasms, termed faciobrachial dystonic seizures (FBDS), were first identified within the context of LGI1-antibody associated limbic encephalitis (LE) but most cases precede LE. FBDS respond well to immunotherapies but relatively poorly to antiepileptic drugs. FBDS provide the first example of a pure epilepsy syndrome which is strongly associated with autoantibodies and a good response to immunotherapies. The field of autoimmune epilepsies is gathering pace and there are likely to be further developments in the next few years.
More and Less Fear in Serotonin Transporter Knockout Mice.
Recent theories suggest that reduced serotonin transporter (5-HTT) function, which increases serotonin (5-HT) levels at the synapse, enhances neural plasticity and affects sensitivity to environmental cues. This may promote learning about emotionally relevant events. However, the boundaries that define such emotional learning remain to be established. This was investigated using 5-HTT knockout (5-HTTKO) mice which provide a model of long-term elevated 5-HT transmission and are associated with increased anxiety. Compared to wild-type controls, 5-HTTKO mice were faster to discriminate between an auditory cue that predicted footshock (CS+) and a cue predicting no footshock (CS-). Notably, this enhanced discrimination performance was driven not by faster learning that the CS+ predicted footshock, but rather by faster learning that the CS- cue signals the absence of footshock and thus provides temporary relief from fear/anxiety. Similarly, 5-HTTKO mice were also faster to reduce their fear of the CS+ cue during subsequent extinction. These findings are consistent with facilitated inhibitory learning that predicts the absence of potential threats in 5-HTTKO mice. However, 5-HTTKO mice also exhibited increased generalisation of fear learning about ambiguous aversive cues in a novel context, different from the training context. Thus, 5-HTTKO mice can exhibit both more and less fear compared to wild-type controls. Taken together, our results support the idea that loss of 5-HTT function, and corresponding increases in synaptic 5-HT availability, may facilitate learning by priming of aversive memories. This both facilitates inhibitory learning for fear memories but also enhances generalisation of fear.
Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses
AbstractTo understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely.