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  • The neuropathic potential of anti-GM1 autoantibodies is regulated by the local glycolipid environment in mice.

    16 March 2018

    Anti-GM1 ganglioside autoantibodies are used as diagnostic markers for motor axonal peripheral neuropathies and are believed to be the primary mediators of such diseases. However, their ability to bind and exert pathogenic effects at neuronal membranes is highly inconsistent. Using human and mouse monoclonal anti-GM1 antibodies to probe the GM1-rich motor nerve terminal membrane in mice, we here show that the antigenic oligosaccharide of GM1 in the live plasma membrane is cryptic, hidden on surface domains that become buried for a proportion of anti-GM1 antibodies due to a masking effect of neighboring gangliosides. The cryptic GM1 binding domain was exposed by sialidase treatment that liberated sialic acid from masking gangliosides including GD1a or by disruption of the live membrane by freezing or fixation. This cryptic behavior was also recapitulated in solid-phase immunoassays. These data show that certain anti-GM1 antibodies exert potent complement activation-mediated neuropathogenic effects, including morphological damage at living terminal motor axons, leading to a block of synaptic transmission. This occurred only when GM1 was topologically available for antibody binding, but not when GM1 was cryptic. This revised understanding of the complexities in ganglioside membrane topology provides a mechanistic account for wide variations in the neuropathic potential of anti-GM1 antibodies.

  • Antibodies to heteromeric glycolipid complexes in multifocal motor neuropathy.

    31 May 2018

    BACKGROUND: Measurement of anti-GM1 IgM antibodies in multifocal motor neuropathy (MMN) sera is confounded by relatively low sensitivity that limits clinical usefulness. Combinatorial assay methods, in which antibodies react to heteromeric complexes of two or more glycolipids, are being increasingly applied to this area of diagnostic testing. METHODS: A newly developed combinatorial glycoarray able to identify antibodies to 45 different heteromeric glycolipid complexes and their 10 individual glycolipid components was applied to a randomly selected population of 33 MMN cases and 57 normal or disease controls. Comparison with an enzyme-linked immunosorbent assay (ELISA) was conducted for selected single glycolipids and their complexes. RESULTS: By ELISA, 22/33 MMN cases had detectable anti-GM1 IgM antibodies, whereas 19/33 MMN samples were positive for anti-GM1 antibodies by glycoarray. Analysis of variance (anova) revealed that of the 55 possible single glycolipids and their 1:1 complexes, antibodies to the GM1:galactocerebroside (GM1:GalC) complex were most significantly associated with MMN, returning 33/33 MMN samples as positive by glycoarray and 29/33 positive by ELISA. Regression analysis revealed a high correlation in absolute values between ELISA and glycoarray. Receiver operator characteristic analysis revealed insignificantly different diagnostic performance between the two methods. However, the glycoarray appeared to offer slightly improved sensitivity by identifying antibodies in four ELISA-negative samples. CONCLUSIONS: The use of combinatorial glycoarray or ELISA increased the diagnostic sensitivity of anti-glycolipid antibody testing in this cohort of MMN cases, without significantly affecting specificity, and may be a useful assay modification for routine clinical screening.

  • The GD1a glycan is a cellular receptor for adenoviruses causing epidemic keratoconjunctivitis.

    13 June 2018

    Adenovirus type 37 (Ad37) is a leading cause of epidemic keratoconjunctivitis (EKC), a severe and highly contagious ocular disease. Whereas most other adenoviruses infect cells by engaging CD46 or the coxsackie and adenovirus receptor (CAR), Ad37 binds previously unknown sialic acid-containing cell surface molecules. By glycan array screening, we show here that the receptor-recognizing knob domain of the Ad37 fiber protein specifically binds a branched hexasaccharide that is present in the GD1a ganglioside and that features two terminal sialic acids. Soluble GD1a glycan and GD1a-binding antibodies efficiently prevented Ad37 virions from binding and infecting corneal cells. Unexpectedly, the receptor is constituted by one or more glycoproteins containing the GD1a glycan motif rather than the ganglioside itself, as shown by binding, infection and flow cytometry experiments. Molecular modeling, nuclear magnetic resonance and X-ray crystallography reveal that the two terminal sialic acids dock into two of three previously established sialic acid-binding sites in the trimeric Ad37 knob. Surface plasmon resonance analysis shows that the knob-GD1a glycan interaction has high affinity. Our findings therefore form a basis for the design and development of sialic acid-containing antiviral drugs for topical treatment of EKC.

  • Heteromeric glycolipid complexes as modulators of autoantibody and lectin binding.

    23 May 2018

    Glycolipids act as receptors for a wide range of antibodies, lectins and microbes. It has long been recognised that the local topography of glycolipids in the plasma membrane is critical to these recognition events, although the biological basis for this has been relatively under-investigated. Within the last five years, emerging evidence indicates that hetero-dimeric clusters of different glycolipids can form highly distinct and specific epitopes for antibody and lectin binding. The initial observation that these ganglioside complexes (GSC) could either dramatically enhance or equally well inhibit the binding of neuropathy sera has now been reproduced for a number of other lectins, including siglecs and bacterial toxins. Here we review the initial discovery of GSC as antibody binding domains and the subsequent studies delineating their broader functional importance. Potential mechanisms underlying these effects are considered, although much remains to be investigated and explained. However, the implications for this field are potentially widespread, ranging from glycoarray design, structural biology and membrane biophysics, through to the biological consequences of glycolipid complex organisation in plasma membranes.

  • Lipid arrays identify myelin-derived lipids and lipid complexes as prominent targets for oligoclonal band antibodies in multiple sclerosis.

    13 June 2018

    The presence of oligoclonal bands of IgG (OCB) in cerebrospinal fluid (CSF) is used to establish a diagnosis of multiple sclerosis (MS), but their specificity has remained an enigma since its first description over forty years ago. We now report that the use of lipid arrays identifies heteromeric complexes of myelin derived lipids as a prominent target for this intrathecal B cell response.

  • The effect of BDNF val66met polymorphism on visuomotor adaptation.

    26 April 2018

    Brain-derived neurotrophic factor (BDNF) plays an important role in learning, memory, and brain plasticity. Humans with a val66met polymorphism in the BDNF gene have reduced levels of BDNF and alterations in motor learning and short-term cortical plasticity. In the current study, we sought to further explore the role of BDNF in motor learning by testing human subjects on a visuomotor adaptation task. In experiment 1, 21 subjects with the polymorphism (val/met) and 21 matched controls (val/val) were tested during learning, short-term retention (45 min), long-term retention (24 h), and de-adaptation of a 60° visuomotor deviation. We measured both mean error as well as rate of adaptation during each session. There was no difference in mean error between groups; however, val/met subjects had a reduced rate of adaptation during learning as well as during long-term retention, but not short-term retention or de-adaptation. In experiment 2, 12 val/met and 12 val/val subjects were tested on a larger 80° deviation, revealing a more pronounced difference in mean error during adaptation than the 60° deviation. These results suggest that BDNF may play an important role in visuomotor adaptive processes in the human.

  • γ oscillations in the human basal ganglia.

    8 June 2018

    Interest in beta activity in the basal ganglia has mushroomed since it was first identified in the subthalamic nucleus of patients with Parkinson's disease in Jonathan Dostrovsky's landmark paper (Levy et al., 2000). Here we consider a less explored phenomenon; namely gamma frequency synchronisation of neurons in the basal ganglia. Gamma oscillations have been reported in a distributed network involving the basal ganglia, thalamus and motor cortex, and have been described in a wide range of diseases as well as during increased arousal and voluntary movement. In Parkinson's disease, gamma activity is promoted by dopaminergic therapy. These features suggest that its elevation may be involved in the production of movement and this hypothesis is supported by the correlation between the amplitude of gamma activity and limb kinematics. Here we review these data, discuss the functional anatomy of gamma activity in basal ganglia and question how closely it relates to the coding of movement parameters.

  • The fate of the oculomotor system in clinical bilateral anophthalmia.

    31 May 2018

    The interdependence of the development of the eye and oculomotor system during embryogenesis is currently unclear. The occurrence of clinical anophthalmia, where the globe fails to develop, permits us to study the effects this has on the development of the complex neuromuscular system controlling eye movements. In this study, we use very high-resolution T2-weighted imaging in five anophthalmic subjects to visualize the extraocular muscles and the cranial nerves that innervate them. The subjects differed in the presence or absence of the optic nerve, the abducens nerve, and the extraocular muscles, reflecting differences in the underlying disruption to the eye's morphogenetic pathway. The oculomotor nerve was present in all anophthalmic subjects and only slightly reduced in size compared to measurements in sighted controls. As might be expected, the presence of rudimentary eye-like structures in the socket appeared to correlate with development and persistence of the extraocular muscles in some cases. Our study supports in part the concept of an initial independence of muscle development, with its maintenance subject to the presence of these eye-like structures.

  • Cholinesterase inhibitors for dementia with Lewy bodies, Parkinson's disease dementia and cognitive impairment in Parkinson's disease.

    13 June 2018

    BACKGROUND: Previous Cochrane reviews have considered the use of cholinesterase inhibitors in both Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB). The clinical features of DLB and PDD have much in common and are distinguished primarily on the basis of whether or not parkinsonism precedes dementia by more than a year. Patients with both conditions have particularly severe deficits in cortical levels of the neurotransmitter acetylcholine. Therefore, blocking its breakdown using cholinesterase inhibitors may lead to clinical improvement. OBJECTIVES: To assess the efficacy, safety and tolerability of cholinesterase inhibitors in dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), and cognitive impairment in Parkinson's disease falling short of dementia (CIND-PD) (considered as separate phenomena and also grouped together as Lewy body disease). SEARCH METHODS: The trials were identified from a search of ALOIS, the Specialised Register of the Cochrane Dementia and Cognitive Improvement Group (on 30 August 2011) using the search terms Lewy, Parkinson, PDD, DLB, LBD. This register consists of records from major healthcare databases (MEDLINE, EMBASE, PsycINFO, CINAHL) and many ongoing trial databases and is updated regularly.Reference lists of relevant studies were searched for additional trials. SELECTION CRITERIA: Randomised, double-blind, placebo-controlled trials assessing the efficacy of treatment with cholinesterase inhibitors in DLB, PDD and cognitive impairment in Parkinson's disease (CIND-PD). DATA COLLECTION AND ANALYSIS: Data were extracted from published reports by one review author (MR). The data for each 'condition' (that is DLB, PDD or CIND-PD) were considered separately and, where possible, also pooled together. Statistical analysis was conducted using Review Manager version 5.0. MAIN RESULTS: Six trials met the inclusion criteria for this review, in which a total of 1236 participants were randomised. Four of the trials were of a parallel group design and two cross-over trials were included. Four of the trials included participants with a diagnosis of Parkinson's disease with dementia (Aarsland 2002a; Dubois 2007; Emre 2004; Ravina 2005), of which Dubois 2007 remains unpublished. Leroi 2004 included patients with cognitive impairment and Parkinson's disease (both with and without dementia). Patients with dementia with Lewy bodies (DLB) were included in only one of the trials (McKeith 2000).For global assessment, three trials comparing cholinesterase inhibitor treatment to placebo in PDD (Aarsland 2002a; Emre 2004; Ravina 2005) reported a difference in the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) score of -0.38, favouring the cholinesterase inhibitors (95% CI -0.56 to -0.24, P < 0.0001).For cognitive function, a pooled estimate of the effect of cholinesterase inhibitors on cognitive function measures was consistent with the presence of a therapeutic benefit (standardised mean difference (SMD) -0.34, 95% CI -0.46 to -0.23, P < 0.00001). There was evidence of a positive effect of cholinesterase inhibitors on the Mini-Mental State Examination (MMSE) in patients with PDD (WMD 1.09, 95% CI 0.45 to 1.73, P = 0.0008) and in the single PDD and CIND-PD trial (WMD 1.05, 95% CI 0.42 to 1.68, P = 0.01) but not in the single DLB trial.For behavioural disturbance, analysis of the pooled continuous data relating to behavioural disturbance rating scales favoured treatment with cholinesterase inhibitors (SMD -0.20, 95% CI -0.36 to -0.04, P = 0.01).For activities of daily living, combined data for the ADCS and the Unified Parkinson's Disease Rating Scale (UPDRS) activities of daily living rating scales favoured treatment with cholinesterase inhibitors (SMD -0.20, 95% CI -0.38 to -0.02, P = 0.03).For safety and tolerability, those taking a cholinesterase inhibitor were more likely to experience an adverse event (318/452 versus 668/842; odds ratio (OR) 1.64, 95% CI 1.26 to 2.15, P = 0.0003) and to drop out (128/465 versus 45/279; OR 1.94, 95% CI 1.33 to 2.84, P = 0.0006). Adverse events were more common amongst those taking rivastigmine (357/421 versus 173/240; OR 2.28, 95% CI 1.53 to 3.38, P < 0.0001) but not those taking donepezil (311/421 versus 145/212; OR 1.24, 95% CI 0.86 to 1.80, P = 0.25). Parkinsonian symptoms in particular tremor (64/739 versus 12/352; OR 2.71, 95% CI 1.44 to 5.09, P = 0.002), but not falls (P = 0.39), were reported more commonly in the treatment group but this did not have a significant impact on the UPDRS (total and motor) scores (P = 0.71). Fewer deaths occurred in the treatment group than in the placebo group (4/465 versus 9/279; OR 0.28, 95% CI 0.09 to 0.84, P = 0.03). AUTHORS' CONCLUSIONS: The currently available evidence supports the use of cholinesterase inhibitors in patients with PDD, with a positive impact on global assessment, cognitive function, behavioural disturbance and activities of daily living rating scales. The effect in DLB remains unclear. There is no current disaggregated evidence to support their use in CIND-PD.