Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

A proof-of-concept study for the use of a computerised avatar to embody the eating disorder voice in anorexia nervosa

Purpose This study assessed (1) the experience of the eating disorder voice in people with anorexia nervosa or in remission, and (2) the feasibility of creating and interacting with a computerised representation (i.e., avatar) of this voice. Methods Twenty-one individuals with anorexia nervosa and 18 individuals who were in remission participated in the study. They reported on the characteristics of their eating disorder voice and created a personalised avatar (a visual and auditory representation of the eating disorder voice), using a computerised software. Participants assessed closeness of match between the voice and the avatar, perceived distress and acceptability of re-exposure to the avatar. Results Patients felt less powerful than their eating disorder voice and unable to disregard the voice's commands. The experience of the voice was associated with negative, as well as some positive emotions, reflecting the prototypical ambivalence towards the illness. Individuals in remission had an opposite pattern of responses. They attributed only negative emotions to the voice, felt more powerful than the voice, and able to disregard its commands. Overall participants reported that there was a good match between the voice and the sound of the avatar. Patients expressed willingness to repeat exposure to the avatar. Conclusion Individuals with anorexia can create personalised digital avatars representing the eating disorder voice and are willing to engage therapeutically with the avatar. The next step is to test the feasibility of repeated exposure to the avatar to address the power and distress associated with the eating disorder voice

A case series to test the acceptability, feasibility and preliminary efficacy of AVATAR therapy in anorexia nervosa

Abstract Background Patients with anorexia nervosa tend to experience an inner “eating disorder” voice. They struggle to recognise and assert their own identity over the illness’s identity and relate to it from a powerless and subordinate position. AVATAR therapy was developed to help patients with psychosis to gain greater power and control over distressing voices. The goal of this study was to test the feasibility, acceptability, safety and preliminary efficacy of an adaptation of AVATAR therapy for anorexia nervosa. Methods Twelve adult patients with anorexia nervosa were recruited. Ten completed an assessment session and between five to seven therapy sessions. The assessment session consisted in the creation of an avatar to represent the “eating disorder”. This was accomplished by manipulating auditory and visual characteristics through a specialist computer software. During the therapy sessions, patients interacted with the avatar to assert their own desires and will. Patients completed baseline, end of intervention and follow-up (4-week) online questionnaires. A non-concurrent multiple baselines single case experimental design (SCED) was used (A1BA2). Feasibility, acceptability, safety and preliminary efficacy of the intervention were assessed. Results The therapy met pre-specified criteria relating to (1) Feasibility: sample recruited within three months; retention rate at the end of the treatment phase = 81.9%; therapy completion rate = 90.1%. (2) Safety: no serious adverse events associated with the intervention. (3) Acceptability: mean ratings = 7.5 (SD = 2.61) out of ten, on a 0–10 scale of acceptability (10 = complete satisfaction). With regards to efficacy, participants reported significantly lower levels of distress associated with the eating disorder voice and higher levels of self-compassion at the end of treatment. No other significant changes were observed in frequency of the eating disorder voice, voice’s characteristics, such as omnipotence and malevolence, eating disorder symptoms and symptoms of anxiety, depression and stress. Patients’ feedback indicated that the therapy had helped with their ability to stand up to the illness, make positive changes around eating, and increase their motivation to recover and self-compassion. Conclusion AVATAR therapy for anorexia nervosa is feasible, acceptable and safe for patients. Larger studies are needed to test clinical efficacy. Trial registration The study was pre-registered on the clinicaltrials.gov registry (https://clinicaltrials.gov/ct2/show/NCT04778423)

Immunotherapy with Cleavage-Specific 12A12mAb Reduces the Tau Cleavage in Visual Cortex and Improves Visuo-Spatial Recognition Memory in Tg2576 AD Mouse Model

Tau-targeted immunotherapy is a promising approach for treatment of Alzheimer’s disease (AD). Beyond cognitive decline, AD features visual deficits consistent with the manifestation of Amyloid β-protein (Aβ) plaques and neurofibrillary tangles (NFT) in the eyes and higher visual centers, both in animal models and affected subjects. We reported that 12A12—a monoclonal cleavage-specific antibody (mAb) which in vivo neutralizes the neurotoxic, N-terminal 20–22 kDa tau fragment(s)–significantly reduces the retinal accumulation in Tg(HuAPP695Swe)2576 mice of both tau and APP/Aβ pathologies correlated with local inflammation and synaptic deterioration. Here, we report the occurrence of N-terminal tau cleavage in the primary visual cortex (V1 area) and the beneficial effect of 12A12mAb treatment on phenotype-associated visuo-spatial deficits in this AD animal model. We found out that non-invasive administration of 12 A12mAb markedly reduced the pathological accumulation of both truncated tau and Aβ in the V1 area, correlated to significant improvement in visual recognition memory performance along with local increase in two direct readouts of cortical synaptic plasticity, including the dendritic spine density and the expression level of activity-regulated cytoskeleton protein Arc/Arg3.1. Translation of these findings to clinical therapeutic interventions could offer an innovative tau-directed opportunity to delay or halt the visual impairments occurring during AD progressio

Low molecular weight, non-peptidic agonists of TrkA receptor with NGF-mimetic activity

Exploitation of the biologic activity of neurotrophins is desirable for medical purposes, but their protein nature intrinsically bears adverse pharmacokinetic properties. Here, we report synthesis and biologic characterization of a novel class of low molecular weight, non-peptidic compounds with NGF (nerve growth factor)-mimetic properties. MT2, a representative compound, bound to Trk (tropomyosin kinase receptor) A chain on NGF-sensitive cells, as well as in cell-free assays, at nanomolar concentrations and induced TrkA autophosphorylation and receptor-mediated internalization. MT2 binding involved at least two amino-acid residues within TrkA molecule. Like NGF, MT2 increased phosphorylation of extracellular signal-regulated kinase1/2 and Akt proteins and production of MKP-1 phosphatase (dual specificity phosphatase 1), modulated p38 mitogen-activated protein kinase activation, sustained survival of serum-starved PC12 or RDG cells, and promoted their differentiation. However, the intensity of such responses was heterogenous, as the ability of maintaining survival was equally possessed by NGF and MT2, whereas the induction of differentiation was expressed at definitely lower levels by the mimetic. Analysis of TrkA autophosphorylation patterns induced by MT2 revealed a strong tyrosine (Tyr) 490 and a limited Tyr785 and Tyr674/675 activation, findings coherent with the observed functional divarication. Consistently, in an NGF-deprived rat hippocampal neuronal model of Alzheimer Disease, MT2 could correct the biochemical abnormalities and sustain cell survival. Thus, NGF mimetics may reveal interesting investigational tools in neurobiology, as well as promising drug candidates. Cell Death and Disease (2012) 3, e339; doi:10.1038/cddis.2012.80; published online 5 July 201

Low molecular weight, non-peptidic agonists of TrkA receptor with NGF-mimetic activity

Exploitation of the biologic activity of neurotrophins is desirable for medical purposes, but their protein nature intrinsically bears adverse pharmacokinetic properties. Here, we report synthesis and biologic characterization of a novel class of low molecular weight, non-peptidic compounds with NGF (nerve growth factor)-mimetic properties. MT2, a representative compound, bound to Trk (tropomyosin kinase receptor)A chain on NGF-sensitive cells, as well as in cell-free assays, at nanomolar concentrations and induced TrkA autophosphorylation and receptor-mediated internalization. MT2 binding involved at least two amino-acid residues within TrkA molecule. Like NGF, MT2 increased phosphorylation of extracellular signal-regulated kinase1/2 and Akt proteins and production of MKP-1 phosphatase (dual specificity phosphatase 1), modulated p38 mitogen-activated protein kinase activation, sustained survival of serum-starved PC12 or RDG cells, and promoted their differentiation. However, the intensity of such responses was heterogenous, as the ability of maintaining survival was equally possessed by NGF and MT2, whereas the induction of differentiation was expressed at definitely lower levels by the mimetic. Analysis of TrkA autophosphorylation patterns induced by MT2 revealed a strong tyrosine (Tyr)490 and a limited Tyr785 and Tyr674/675 activation, findings coherent with the observed functional divarication. Consistently, in an NGF-deprived rat hippocampal neuronal model of Alzheimer Disease, MT2 could correct the biochemical abnormalities and sustain cell survival. Thus, NGF mimetics may reveal interesting investigational tools in neurobiology, as well as promising drug candidates