Background Previous research suggested that quadripulse (QPS)-induced synaptic plasticity is associated with both cognitive and motor function in patients with multiple sclerosis (MS) and does not ...appear to be reduced compared to healthy controls (HCs). Objective This study aimed to explore the relationship between the degree of QPS-induced plasticity and clinically significant decline in motor and cognitive functions over time. We hypothesized that MS patients experiencing functional decline would exhibit lower levels of baseline plasticity compared to those without decline. Methods QPS-induced plasticity was evaluated in 80 MS patients (56 with relapsing-remitting MS and 24 with progressive MS), and 69 age-, sex-, and education-matched HCs. Cognitive and motor functions, as well as overall disability status were evaluated annually over a median follow-up period of 2 years. Clinically meaningful change thresholds were predefined for each outcome measure. Linear mixed-effects models, Cox proportional hazard models, logistic regression, and receiver-operating characteristic analysis were applied to analyse the relationship between baseline plasticity and clinical progression in the symbol digit modalities test, brief visuospatial memory test revised (BVMT-R), nine-hole peg test (NHPT), timed 25-foot walk test, and expanded disability status scale. Results Overall, the patient cohort showed no clinically relevant change in any functional outcome over time. Variability in performance was observed across time points in both patients and HCs. MS patients who experienced clinically relevant decline in manual dexterity and/or visuospatial learning and memory had significantly lower levels of synaptic plasticity at baseline compared to those without such decline (NHPT: β = −0.25, p = 0.02; BVMT-R: β = −0.50, p = 0.005). Receiver-operating characteristic analysis underscored the predictive utility of baseline synaptic plasticity in discerning between patients experiencing functional decline and those maintaining stability only for visuospatial learning and memory (area under the curve = 0.85). Conclusion Our study suggests that QPS-induced plasticity could be linked to clinically relevant functional decline in patients with MS. However, to solidify these findings, longer follow-up periods are warranted, especially in cohorts with higher prevalences of functional decline. Additionally, the variability in cognitive performance in both patients with MS and HCs underscores the importance of conducting further research on reliable change based on neuropsychological tests.
Cumulative evidence along several lines indicates that B cells play an important role in the pathological course of multiple sclerosis (MS), neuromyelitisoptica spectrum disorders (NMOSD) and related ...CNS diseases. This has prompted extensive research in exploring the utility of targeting B cells to contain disease activity in these disorders. In this review, we first recapitulate the development of B cells from their origin in the bone marrow to their migration to the periphery, including the expression of therapy-relevant surface immunoglobulin isotypes. Not only the ability of B cells to produce cytokines and immunoglobulins seems to be essential in driving neuroinflammation, but also their regulatory functions strongly impact pathobiology. We then critically assess studies of B cell depleting therapies, including CD20 and CD19 targeting monoclonal antibodies, as well as the new class of B cell modulating substances, Bruton´s tyrosinekinase (BTK) inhibitors, in MS, NMOSD and MOGAD.
The three different botulinum toxin type A (BoNT/A) preparations being licensed in Europe and the U.S. differ in protein content, which seems to be a major factor influencing the antigenicity of ...BoNT/A. In the present study, several arguments out of our research pool were collected to demonstrate that the clinical response and antigenicity were different for the three BoNT/A preparations: some results of (1) a cross-sectional study on clinical outcome and antibody formation of 212 patients with cervical dystonia (CD) being treated between 2 and 22 years; 2) another cross-sectional study on the clinical aspects and neutralizing antibody (NAB) induction of 63 patients having developed partial secondary treatment under abobotulinum (aboBoNT/A) onabotulinumtoxin (onaBoNT/A) who were switched to incobotulinumtoxin (incoBoNT/A) in comparison to 32 patients being exclusively treated with incoBoNT/A. These results imply that (1) the presence of NAB cannot be concluded from the course of treatment, that (2) an increase in the dose and variability of outcome with treatment duration indicates the ongoing induction of NABs over time, that (3) the higher protein load of BoNT/A goes along with a higher incidence and prevalence of NAB induction and that (4) the best response to a BoNT/A is also dependent on the protein load of the preparation.
Abstract Retinal optical coherence tomography has been identified as biomarker for disease progression in relapsing-remitting multiple sclerosis (RRMS), while the dynamics of retinal atrophy in ...progressive MS are less clear. We investigated retinal layer thickness changes in RRMS, primary and secondary progressive MS (PPMS, SPMS), and their prognostic value for disease activity. Here, we analyzed 2651 OCT measurements of 195 RRMS, 87 SPMS, 125 PPMS patients, and 98 controls from five German MS centers after quality control. Peripapillary and macular retinal nerve fiber layer (pRNFL, mRNFL) thickness predicted future relapses in all MS and RRMS patients while mRNFL and ganglion cell-inner plexiform layer (GCIPL) thickness predicted future MRI activity in RRMS (mRNFL, GCIPL) and PPMS (GCIPL). mRNFL thickness predicted future disability progression in PPMS. However, thickness change rates were subject to considerable amounts of measurement variability. In conclusion, retinal degeneration, most pronounced of pRNFL and GCIPL, occurs in all subtypes. Using the current state of technology, longitudinal assessments of retinal thickness may not be suitable on a single patient level.
The glutamate/cystine antiporter system x(c)- transports cystine into cells in exchange for the important neurotransmitter glutamate at a ratio of 1:1. It is composed of a specific light chain, xCT, ...and a heavy chain, 4F2, linked by a disulfide bridge. Both subunits are localized prominently in the mouse and human brain especially in border areas between the brain and periphery including vascular endothelial cells, ependymal cells, choroid plexus, and leptomeninges. Glutamate exported by system x(c)- is largely responsible for the extracellular glutamate concentration in the brain, whereas the imported cystine is required for the synthesis of the major endogenous antioxidant, glutathione. System x(c)- thus connects the antioxidant defense with neurotransmission and behavior. Disturbances in the function of system x(c)- have been implicated in nerve cell death due to increased extracellular glutamate and reduced intracellular glutathione. In vitro, inhibition of cystine import through system x(c)- leads to cell death by a mechanism called oxidative glutamate toxicity or oxytosis, which includes depletion of intracellular glutathione, activation of 12-lipoxygenase, accumulation of intracellular peroxides, and the activation of a cyclic guanosine monophosphate (cGMP)-dependent calcium channel towards the end of the death cascade. Cell death caused by oxytosis is distinct from classical apoptosis. In this contribution, we discuss the function of system x(c)- in vitro and in vivo, the role of xCT as an important but due to its dual role probably ambivalent drug target, and the relevance of oxytosis as an in vitro assay for the identification of novel neuroprotective proteins and signaling pathways.
In multiple sclerosis (MS), neurodegeneration is the main reason for chronic disability. Alpha-lipoic acid (LA) is a naturally occurring antioxidant which has recently been demonstrated to reduce the ...rate of brain atrophy in progressive MS. However, it remains uncertain if it is also beneficial in the early, more inflammatory-driven phases. As clinical studies are costly and time consuming, optic neuritis (ON) is often used for investigating neuroprotective or regenerative therapeutics. We aimed to investigate the prospect for success of a clinical ON trial using an experimental autoimmune encephalomyelitis-optic neuritis (EAE-ON) model with visual system readouts adaptable to a clinical ON trial.
Using an in vitro cell culture model for endogenous oxidative stress, we compared the neuroprotective capacity of racemic LA with the R/S-enantiomers and its reduced form. In vivo, we analyzed retinal neurodegeneration using optical coherence tomography (OCT) and the visual function by optokinetic response (OKR) in MOG
-induced EAE-ON in C57BL/6J mice. Ganglion cell counts, inflammation, and demyelination were assessed by immunohistological staining of retinae and optic nerves.
All forms of LA provided equal neuroprotective capacities in vitro. In EAE-ON, prophylactic LA therapy attenuated the clinical EAE score and prevented the thinning of the inner retinal layer while therapeutic treatment was not protective on visual outcomes.
A prophylactic LA treatment is necessary to protect from visual loss and retinal thinning in EAE-ON, suggesting that a clinical ON trial starting therapy after the onset of symptoms may not be successful.
In amyotrophic lateral sclerosis, down-regulation of the astrocyte-specific glutamate excitatory amino acid transporter 2 is hypothesized to increase extracellular glutamate, thereby leading to ...excitotoxic motor neuron death. The antibiotic ceftriaxone was recently reported to induce excitatory amino acid transporter 2 and to prolong the survival of mutant superoxide dismutase 1 transgenic mice. Here we show that ceftriaxone also protects fibroblasts and the hippocampal cell line HT22, which are not sensitive to excitotoxicity, against oxidative glutamate toxicity, where extracellular glutamate blocks cystine import via the glutamate/cystine-antiporter system xc⁻. Lack of intracellular cystine leads to glutathione depletion and cell death because of oxidative stress. Ceftriaxone increased system xc⁻ and glutathione levels independently of its effect on excitatory amino acid transporters by induction of the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2), a known inducer of system xc⁻, and the specific xc⁻ subunit xCT. No significant effect was apparent in fibroblasts deficient in Nrf2 or xCT. Similar ceftriaxone-stimulated changes in Nrf2, system xc⁻, and glutathione were observed in rat cortical and spinal astrocytes. In addition, ceftriaxone induced xCT mRNA expression in stem cell-derived human motor neurons. We conclude that ceftriaxone-mediated neuroprotection might relate more strongly to activation of the antioxidant defense system including Nrf2 and system xc⁻ than to excitatory amino acid transporter induction.
Abstract
Neurological manifestations of coronavirus disease 2019 (COVID-19) have been frequently described. In this prospective study of hospitalized COVID-19 patients without a history of ...neurological conditions, we aimed to analyze their prevalence and prognostic value based on established, standardized and objective methods. Patients were investigated using a multimodal electrophysiological approach, accompanied by neuropsychological and neurological examinations. Prevalence rates of central (CNS) and peripheral (PNS) nervous system affections were calculated and the relationship between neurological affections and mortality was analyzed using Firth logistic regression models. 184 patients without a history of neurological diseases could be enrolled. High rates of PNS affections were observed (66% of 138 patients receiving electrophysiological PNS examination). CNS affections were less common but still highly prevalent (33% of 139 examined patients). 63% of patients who underwent neuropsychological testing (
n
= 155) presented cognitive impairment. Logistic regression models revealed pathology in somatosensory evoked potentials as an independent risk factor of mortality (Odds Ratio: 6.10 1.01–65.13,
p
= 0.049). We conclude that hospitalized patients with moderate to severe COVID-19 display high rates of PNS and CNS affection, which can be objectively assessed by electrophysiological examination. Electrophysiological assessment may have a prognostic value and could thus be helpful to identify patients at risk for deterioration.
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