A self-sustained loop of inflammation-driven inhibition of beige adipogenesis in obesity.

In obesity, inflammation of white adipose tissue (AT) is associated with diminished generation of beige adipocytes ('beige adipogenesis'), a thermogenic and energy-dissipating function mediated by beige adipocytes that express the uncoupling protein UCP1. Here we delineated an inflammation-driven inhibitory mechanism of beige adipogenesis in obesity that required direct adhesive interactions between macrophages and adipocytes mediated by the integrin α4 and its counter-receptor VCAM-1, respectively; expression of the latter was upregulated in obesity. This adhesive interaction reciprocally and concomitantly modulated inflammatory activation of macrophages and downregulation of UCP1 expression dependent on the kinase Erk in adipocytes. Genetic or pharmacological inactivation of the integrin α4 in mice resulted in elevated expression of UCP1 and beige adipogenesis of subcutaneous AT in obesity. Our findings, established in both mouse systems and human systems, reveal a self-sustained cycle of inflammation-driven impairment of beige adipogenesis in obesity.

Differential effects of anti-CD20 therapy on CD4 and CD8 T cells and implication of CD20-expressing CD8 T cells in MS disease activity.

A small proportion of multiple sclerosis (MS) patients develop new disease activity soon after starting anti-CD20 therapy. This activity does not recur with further dosing, possibly reflecting deeper depletion of CD20-expressing cells with repeat infusions. We assessed cellular immune profiles and their association with transient disease activity following anti-CD20 initiation as a window into relapsing disease biology. Peripheral blood mononuclear cells from independent discovery and validation cohorts of MS patients initiating ocrelizumab were assessed for phenotypic and functional profiles using multiparametric flow cytometry. Pretreatment CD20-expressing T cells, especially CD20dimCD8+ T cells with a highly inflammatory and central nervous system (CNS)-homing phenotype, were significantly inversely correlated with pretreatment MRI gadolinium-lesion counts, and also predictive of early disease activity observed after anti-CD20 initiation. Direct removal of pretreatment proinflammatory CD20dimCD8+ T cells had a greater contribution to treatment-associated changes in the CD8+ T cell pool than was the case for CD4+ T cells. Early disease activity following anti-CD20 initiation was not associated with reconstituting CD20dimCD8+ T cells, which were less proinflammatory compared with pretreatment. Similarly, this disease activity did not correlate with early reconstituting B cells, which were predominantly transitional CD19+CD24highCD38high with a more anti-inflammatory profile. We provide insights into the mode-of-action of anti-CD20 and highlight a potential role for CD20dimCD8+ T cells in MS relapse biology; their strong inverse correlation with both pretreatment and early posttreatment disease activity suggests that CD20-expressing CD8+ T cells leaving the circulation (possibly to the CNS) play a particularly early role in the immune cascades involved in relapse development.

Auricular Transcutaneous Vagus Nerve Stimulation Specifically Enhances Working Memory Gate Closing Mechanism: A System Neurophysiological Study.

Everyday tasks and goal-directed behavior involve the maintenance and continuous updating of information in working memory (WM). WM gating reflects switches between these two core states. Neurobiological considerations suggest that the catecholaminergic and the GABAergic are likely involved in these dynamics. Both of these neurotransmitter systems likely underlie the effects to auricular transcutaneous vagus nerve stimulation (atVNS). We examine the effects of atVNS on WM gating dynamics and their underlying neurophysiological and neurobiological processes in a randomized crossover study design in healthy humans of both sexes. We show that atVNS specifically modulates WM gate closing and thus specifically modulates neural mechanisms enabling the maintenance of information in WM. WM gate opening processes were not affected. atVNS modulates WM gate closing processes through the modulation of EEG alpha band activity. This was the case for clusters of activity in the EEG signal referring to stimulus information, motor response information, and fractions of information carrying stimulus-response mapping rules during WM gate closing. EEG-beamforming shows that modulations of activity in fronto-polar, orbital, and inferior parietal regions are associated with these effects. The data suggest that these effects are not because of modulations of the catecholaminergic (noradrenaline) system as indicated by lack of modulatory effects in pupil diameter dynamics, in the inter-relation of EEG and pupil diameter dynamics and saliva markers of noradrenaline activity. Considering other findings, it appears that a central effect of atVNS during cognitive processing refers to the stabilization of information in neural circuits, putatively mediated via the GABAergic system.SIGNIFICANCE STATEMENT Goal-directed behavior depends on how well information in short-term memory can be flexibly updated but also on how well it can be shielded from distraction. These two functions were guarded by a working memory gate. We show how an increasingly popular brain stimulation techniques specifically enhances the ability to close the working memory gate to shield information from distraction. We show what physiological and anatomic aspects underlie these effects.

Inhibitory control in WM gate-opening: Insights from alpha desynchronization and norepinephrine activity under atDCS stimulation.

Our everyday activities require the maintenance and continuous updating of information in working memory (WM). To control this dynamic, WM gating mechanisms have been suggested to be in place, but the neurophysiological mechanisms behind these processes are far from being understood. This is especially the case when it comes to the role of oscillatory neural activity. In the current study we combined EEG recordings, and anodal transcranial direct current stimulation (atDCS) and pupil diameter recordings to triangulate neurophysiology, functional neuroanatomy and neurobiology. The results revealed that atDCS, compared to sham stimulation, affected the WM gate opening mechanism, but not the WM gate closing mechanism. The altered behavioral performance was associated with specific changes in alpha band activities (reflected by alpha desynchronization), indicating a role for inhibitory control during WM gate opening. Functionally, the left superior and inferior parietal cortices, were associated with these processes. The findings are the first to show a causal relevance of alpha desynchronization processes in WM gating processes. Notably, pupil diameter recordings as an indirect index of the norepinephrine (NE) system activity revealed that individuals with stronger inhibitory control (as indexed through alpha desynchronization) showed less pupil dilation, suggesting they needed less NE activity to support WM gate opening. However, when atDCS was applied, this connection disappeared. The study suggests a close link between inhibitory controlled WM gating in parietal cortices, alpha band dynamics and the NE system.

Integrating large language models in care, research, and education in multiple sclerosis management.

Use of techniques derived from generative artificial intelligence (AI), specifically large language models (LLMs), offer a transformative potential on the management of multiple sclerosis (MS). Recent LLMs have exhibited remarkable skills in producing and understanding human-like texts. The integration of AI in imaging applications and the deployment of foundation models for the classification and prognosis of disease course, including disability progression and even therapy response, have received considerable attention. However, the use of LLMs within the context of MS remains relatively underexplored. LLMs have the potential to support several activities related to MS management. Clinical decision support systems could help selecting proper disease-modifying therapies; AI-based tools could leverage unstructured real-world data for research or virtual tutors may provide adaptive education materials for neurologists and people with MS in the foreseeable future. In this focused review, we explore practical applications of LLMs across the continuum of MS management as an initial scope for future analyses, reflecting on regulatory hurdles and the indispensable role of human supervision.

Effects of obstructive sleep apnea treatment on neurodegenerative biomarker neurofilament light chain and cognitive performance.

Obstructive sleep apnea is associated with cognitive impairment and increased risk for neurodegenerative diseases. Obstructive sleep apnea treatment with positive airway pressure therapy helps to improve cognitive symptoms and reduces long-term dementia risk. To test whether these treatment effects are due to a reduction in neuronal damage, we examined longitudinal changes in the neurodegenerative serum neurofilament light chain and cognitive performance of patients with obstructive sleep apnea. In this study, 17 patients with obstructive sleep apnea completed baseline and follow-up (9 month after starting PAP treatment) investigation of sleep, daytime symptoms, cognitive testing and serum neurofilament light chain measurements. Depending on treatment adherence and efficacy, participants were assigned either to the effective treatment (n = 10) or non-effective treatment group (n = 7). As results at baseline lower mean oxygen saturation during sleep was associated with higher serum neurofilament light chain. Patients in the non-effective treatment group showed a significant increase of age-adjusted percentile of serum neurofilament light chain levels at follow-up, whereas serum neurofilament light chain values remained constant in the effective treatment group. At a functional level, effective treatment leads to an improvement in processing speed, which was not the case in the non-effective treatment group. Longitudinal changes of age-adjusted serum neurofilament light chain levels were associated with changes in cognitive performance. To conclude, this longitudinal observational study showed that effective obstructive sleep apnea treatment positively affects the amount of neuronal damage as well as working memory performance. As cognitive symptoms might not only be attributed to obstructive sleep apnea-related sleep deficiency, but also neurodegeneration, our results underline the importance of treatment adherence and efficacy for the prevention of neuronal damage and cognitive consequences.

Development and multi-center validation of a fully automated digital immunoassay for neurofilament light chain: toward a clinical blood test for neuronal injury.

OBJECTIVES: Neurofilament light chain (NfL) has emerged as a promising biomarker for detecting and monitoring axonal injury. Until recently, NfL could only be reliably measured in cerebrospinal fluid, but digital single molecule array (Simoa) technology has enabled its precise measurement in blood samples where it is typically 50-100 times less abundant. We report development and multi-center validation of a novel fully automated digital immunoassay for NfL in serum for informing axonal injury status. METHODS: A 45-min immunoassay for serum NfL was developed for use on an automated digital analyzer based on Simoa technology. The analytical performance (sensitivity, precision, reproducibility, linearity, sample type) was characterized and then cross validated across 17 laboratories in 10 countries. Analytical performance for clinical NfL measurement was examined in individual patients with relapsing remitting multiple sclerosis (RRMS) after 3 months of disease modifying treatment (DMT) with fingolimod. RESULTS: The assay exhibited a lower limit of detection (LLoD) of 0.05 ng/L, a lower limit of quantification (LLoQ) of 0.8 ng/L, and between-laboratory imprecision <10 % across 17 validation sites. All tested samples had measurable NfL concentrations well above the LLoQ. In matched pre-post treatment samples, decreases in NfL were observed in 26/29 RRMS patients three months after DMT start, with significant decreases detected in a majority of patients. CONCLUSIONS: The sensitivity characteristics and reproducible performance across laboratories combined with full automation make this assay suitable for clinical use for NfL assessment, monitoring in individual patients, and cross-comparisons of results across multiple sites.

Neurological complications in oncology and their monitoring and management in clinical practice: a narrative review.

IMPORTANCE: New anti-tumor treatments, such as immune checkpoint inhibitors and CAR T-cell therapy, are associated with an increasing number of neurological issues linked to tumors not arising from nervous system such as neurological and neuropsychological side effects that can significantly impair quality of life in the short or long term. The science of pathomechanisms, therapeutic approaches, and preventive measures is still in its early stages, and the progress is hampered by the lack of studied connection between neurological and oncological disciplines. OBJECTIVES: This work aimed to provide an overview of the questions raised in the field of clinical neuroscience that concern the outcomes of oncological diseases and their treatment. Furthermore, we give an outline of how a collaborative approach between neurology and oncology, with the implementation of neuroscience techniques including up-to-date diagnostics and therapy, can help to improve the quality of oncological patients' lives. EVIDENCE REVIEW: The covered areas of investigation in the evaluated articles primarily encompassed the review of known neurological complications of oncological diseases caused by neurotoxic mechanisms of performed therapies or those linked to concurrent pathological conditions. Similarly, the methods of their diagnostics were assessed. FINDINGS: Our literature review of 65 articles, including clinical trials, cohort studies, reviews, and theoretically based in vitro studies published between 1998 and 2023, outlines the broad spectrum of neurological complications primarily associated with malignant diseases and the anti-tumor therapies employed. Notably, immune-mediated complications, whose incidence is increasing due to the expanding use of new immunotherapies, require early detection and targeted treatment to prevent severe progression. In this context, neurological complications mediated by immune checkpoint inhibitors are often associated with significant impairments and high mortality, necessitating specialist consultation for early detection and differentiation from other phenotypically similar syndromes. Current data on the pathophysiology of these neurological complications are not reliable due to the limited number of studies. Moreover, there is a lack of evidence regarding the appropriate oncological approach in the event of therapy-related complications. Initial study results suggest that the establishment of interdisciplinary treatment interfaces for the management of oncology patients could improve the safety of these therapies and enhance the patients' quality of life. CONCLUSIONS AND RELEVANCE: The accumulated knowledge on neurotoxicity caused by oncological diseases shows that the challenges in diagnosing and managing this condition are expanding in tandem with the growing array of therapies being employed. Therefore, it requires interdisciplinary approach with the introduction of new facilities enabling more personalized patient care.

Raman Spectroscopy of Optically Trapped Living Human T Cell Subsets and Monocytes.

In recent years, Raman spectroscopy has garnered growing interest in the field of biomedical research. It offers a non-invasive and label-free approach to defining the molecular fingerprint of immune cells. We utilized Raman spectroscopy on optically trapped immune cells to investigate their molecular compositions. While numerous immune cell types have been studied in the past, the characterization of living human CD3/CD28-stimulated T cell subsets remains incomplete. In this study, we demonstrate the capability of Raman spectroscopy to readily distinguish between naïve and stimulated CD4 and CD8 cells. Additionally, we compared these cells with monocytes and discovered remarkable similarities between stimulated T cells and monocytes. This paper contributes to expanding our knowledge of Raman spectroscopy of immune cells and serves as a launching point for future clinical applications.

[Current and innovative Approaches to Multiple Sclerosis Therapy]. / Neue Therapieansätze bei Multipler Sklerose inkl. Stellenwert älterer Präparate.

The landscape of immunotherapies in the management of Multiple Sclerosis (MS) is currently particularly dynamic. Over 21 immunotherapeutic options are approved by the European Meidcines Agency (EMA), Food and Drug Administration (FDA) and newer approaches are ongoing in clinical trials. With advancements in the understanding of MS pathophysiology and further development of diagnosis criteria, newer and more specific disease-modifying therapies (DMTs) have emerged in recent years. The selection and timing of proper therapeutic approaches is increasingly complex. We provide an overview of the available immunotherapies for a personalized MS treatment and discuss practical insights into their application. The importance of early intervention, distinction between escalation and induction approaches, and consideration of high-efficacy treatments for specific patient groups are in discussed. We emphasize the significance of a patient-centered approach, taking into account various factors such as comorbidities, family planning, administration preferences and potential side effects in treatment decision-making.

Serum neurofilament light concentrations are associated with cortical thinning in anorexia nervosa.

BACKGROUND: Anorexia nervosa (AN) is characterized by severe emaciation and drastic reductions of brain mass, but the underlying mechanisms remain unclear. The present study investigated the putative association between the serum-based protein markers of brain damage neurofilament light (NF-L), tau protein, and glial fibrillary acidic protein (GFAP) and cortical thinning in acute AN. METHODS: Blood samples and magnetic resonance imaging scans were obtained from 52 predominantly adolescent, female patients with AN before and after partial weight restoration (increase in body mass index >14%). The effect of marker levels before weight gain and change in marker levels on cortical thickness (CT) was modeled at each vertex of the cortical surface using linear mixed-effect models. To test whether the observed effects were specific to AN, follow-up analyses exploring a potential general association of marker levels with CT were conducted in a female healthy control (HC) sample (n = 147). RESULTS: In AN, higher baseline levels of NF-L, an established marker of axonal damage, were associated with lower CT in several regions, with the most prominent clusters located in bilateral temporal lobes. Tau protein and GFAP were not associated with CT. In HC, no associations between damage marker levels and CT were detected. CONCLUSIONS: A speculative interpretation would be that cortical thinning in acute AN might be at least partially a result of axonal damage processes. Further studies should thus test the potential of serum NF-L to become a reliable, low-cost and minimally invasive marker of structural brain alterations in AN.

Differential effects of selective versus unselective sphingosine 1-phosphate receptor modulators on T- and B-cell response to SARS-CoV-2 vaccination.

BACKGROUND: Sphingosine 1-phosphat receptor modulators (S1PRMs) have been linked to attenuated immune response to SARS-CoV-2 vaccines. OBJECTIVE: To characterize differences in the immune response to SARS-CoV-2 vaccines in patients on selective versus unselective S1PRMs. METHODS: Monocentric, longitudinal study on people with multiple sclerosis (pwMS) on fingolimod (FTY), siponimod (SIP), ozanimod (OZA), or without disease-modifying therapy (DMT) following primary and booster SARS-CoV-2 vaccination. Anti-SARS-CoV-2 antibodies and T-cell response was measured with electro-chemiluminescent immunoassay and interferon-γ release assay. RESULTS: Primary vaccination induced a significant antibody response in pwMS without DMT while S1PRM patients exhibited reduced antibody titers. The lowest antibodies were found in patients on FTY, whereas patients on OZA and SIP presented significantly higher levels. Booster vaccinations induced increased antibody levels in untreated patients and comparable titers in patients on OZA and SIP, but no increase in FTY-treated patients. While untreated pwMS developed a T-cell response, patients on S1PRMs presented a diminished/absent response. Patients undergoing SARS-CoV-2 vaccination before onset of S1PRMs presented a preserved, although attenuated humoral response, while T-cellular response was blunted. CONCLUSION: Our data confirm differential effects of selective versus unselective S1PRMs on T- and B-cell response to SARS-CoV-2 vaccination and suggest association with S1PRM selectivity rather than lymphocyte redistribution.

Diroximel fumarate in patients with relapsing-remitting multiple sclerosis: Final safety and efficacy results from the phase 3 EVOLVE-MS-1 study.

BACKGROUND: Diroximel fumarate (DRF) is approved for adults with relapsing-remitting multiple sclerosis (RRMS) in Europe and for relapsing forms of MS in the United States. DRF and dimethyl fumarate (DMF) yield bioequivalent exposure of the active metabolite monomethyl fumarate. Prior studies indicated fewer gastrointestinal (GI)-related adverse events (AEs) with DRF compared with DMF. OBJECTIVE: To report final outcomes from EVOLVE-MS-1. METHODS: EVOLVE-MS-1 was an open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in patients with RRMS. The primary endpoint was safety and tolerability; efficacy endpoints were exploratory. RESULTS: Overall, 75.7% (800/1057) of patients completed the study; median exposure was 1.8 (range: 0.0-2.0) years. AEs occurred in 938 (88.7%) patients, mostly of mild (28.9%) or moderate (50.3%) severity. DRF was discontinued due to AEs in 85 (8.0%) patients, with < 2% discontinuing due to GI or flushing/flushing-related AEs. At Week 96, mean number of gadolinium-enhancing lesions was significantly reduced from baseline (72.7%; p < 0.0001); adjusted annualized relapse rate was 0.13 (95% confidence interval: 0.11-0.15). CONCLUSION: DRF was generally well tolerated over 2 years, with few discontinuations due to AEs; radiological measures indicated decreased disease activity from baseline. These outcomes support DRF as a treatment option in patients with RRMS.

The chronic stress risk phenotype mirrored in the human retina as a neurodegenerative condition.

The brain is the key organ that orchestrates the stress response which translates to the retina. The retina is an extension of the brain and retinal symptoms in subjects with neurodegenerative diseases substantiated the eye as a window to the brain. The retina is used in this study to determine whether chronic stress reflects neurodegenerative signs indicative of neurodegenerative conditions. A three-year prospective cohort (n = 333; aged 46 ± 9 years) was stratified into stress-phenotype cases (n = 212) and controls (n = 121) by applying the Malan stress-phenotype index. Neurodegenerative risk markers included ischemia (astrocytic S100 calcium-binding protein B/S100B); 24-h blood pressure, proteomics; inflammation (tumor-necrosis-factor-α/TNF-α); neuronal damage (neuron-specific-enolase); anti-apoptosis of retinal-ganglion-cells (beta-nerve-growth-factor), astrocytic activity (glial-fibrillary-acidic-protein); hematocrit (viscosity) and retinal follow-up data [vessels; stress-optic-neuropathy]. Stress-optic-neuropathy risk was calculated from two indices: a newly derived diastolic-ocular-perfusion-pressure cut-point ≥68 mmHg relating to the stress-phenotype; combined with an established cup-to-disk ratio cut-point ≥0.3. Higher stress-optic-neuropathy (39% vs. 17%) and hypertension (73% vs. 16%) prevalence was observed in the stress-phenotype cases vs. controls. Elevated diastolic-ocular-perfusion-pressure, indicating hypoperfusion, was related to arterial narrowing and trend for ischemia increases in the stress-phenotype. Ischemia in the stress-phenotype at baseline, follow-up and three-year changes was related to consistent inflammation (TNF-α and cytokine-interleukin-17-receptor-A), neuron-specific-enolase increases, consistent apoptosis (chitinase-3-like protein 1, low beta-nerve-growth-factor), glial-fibrillary-acidic-protein decreases, elevated viscosity, vein widening as risk marker of endothelial dysfunction in the blood-retinal barrier, lower vein count, and elevated stress-optic-neuropathy. The stress-phenotype and related neurodegenerative signs of ongoing brain ischemia, apoptosis and endothelial dysfunction compromised blood-retinal barrier permeability and optic nerve integrity. In fact, the stress-phenotype could identify persons at high risk of neurodegeneration to indicate a neurodegenerative condition.

Autoantibodies against central nervous system antigens in a subset of B cell-dominant multiple sclerosis patients.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS), with characteristic inflammatory lesions and demyelination. The clinical benefit of cell-depleting therapies targeting CD20 has emphasized the role of B cells and autoantibodies in MS pathogenesis. We previously introduced an enzyme-linked immunospot spot (ELISpot)-based assay to measure CNS antigen-specific B cells in the blood of MS patients and demonstrated its usefulness as a predictive biomarker for disease activity in measuring the successful outcome of disease-modifying therapies (DMTs). Here we used a planar protein array to investigate CNS-reactive antibodies in the serum of MS patients as well as in B cell culture supernatants after polyclonal stimulation. Anti-CNS antibody reactivity was evident in the sera of the MS cohort, and the antibodies bound a heterogeneous set of molecules, including myelin, axonal cytoskeleton, and ion channel antigens, in individual patients. Immunoglobulin reactivity in supernatants of stimulated B cells was directed against a broad range of CNS antigens. A group of MS patients with a highly active B cell component was identified by the ELISpot assay. Those antibody reactivities remained stable over time. These assays with protein arrays identify MS patients with a highly active B cell population with antibodies directed against a swathe of CNS proteins.

Influence of Pre-Analytic Conditions on Quantity of Lymphocytes.

Lymphocytes are key players in the pathogenesis of multiple sclerosis and a distinct target of several immunomodulatory treatment strategies. In this study, we aim to evaluate the effect of various pre-analytic conditions on immune cell counts to conclude the relevance for clinical implications. Twenty healthy donors were assessed for the effects of distinct storage temperatures and times after blood draws, different durations of tourniquet application, body positions and varying aspiration forces during blood draws. Immune cell frequencies were analyzed using multicolor flowcytometry. While storage for 24 h at 37 °C after blood draws was associated with significantly lower cell counts, different durations of tourniquet application, body positions and varying aspirations speeds did not have significant impacts on the immune cell counts. Our data suggest that immune cell counts are differently affected by pre-analytic conditions being more sensitive to storage temperature. Pre-analytic conditions should be carefully considered when interpreting the laboratory values of immune cell subpopulations.

FastCAT Accelerates Absolute Quantification of Proteins Using Multiple Short Nonpurified Chimeric Standards.

Absolute (molar) quantification of clinically relevant proteins determines their reference values in liquid and solid biopsies. The FastCAT (for Fast-track QconCAT) method employs multiple short (<50 kDa), stable-isotope labeled chimeric proteins (CPs) composed of concatenated quantotypic (Q)-peptides representing the quantified proteins. Each CP also comprises scrambled sequences of reference (R)-peptides that relate its abundance to a single protein standard (bovine serum albumin, BSA). FastCAT not only alleviates the need to purify CP or use sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) but also improves the accuracy, precision, and dynamic range of the absolute quantification by grouping Q-peptides according to the expected abundance of the target proteins. We benchmarked FastCAT against the reference method of MS Western and tested it in the direct molar quantification of neurological markers in human cerebrospinal fluid at the low ng/mL level.

Brain Atrophy Is Substantially Accelerated in Neurological Wilson's Disease: A Longitudinal Study.

BACKGROUND: Although brain atrophy is common in neurological Wilson's disease, longitudinal studies are lacking. OBJECTIVE: The objective of this study was to measure longitudinal brain atrophy rate and to relate it to the change in neurological impairment in Wilson's disease. METHODS: We included patients with brain imaging done at diagnosis and at least 12 months later. The atrophy rate was measured as percentage change in ventricular volume, whereas the change in neurological impairment was scored on the Unified Wilson's Disease Rating Scale. RESULTS: Of 57 patients, 36 had neurological presentation, 17 had hepatic presentation, and 4 were presymptomatic. The annualized atrophy rate was significantly greater in patients with the neurological presentation than in other patients (P = 0.001). In the neurological presentation, the atrophy rate correlated with the change in impairment (rho = 0.39, P = 0.018) and was significantly greater in those with worsening after diagnosis than in those without worsening (P < 0.001). CONCLUSIONS: Brain atrophy rate appears as a promising marker of neurodegeneration in Wilson's disease. © 2022 International Parkinson and Movement Disorder Society.

Serum Neurofilament Light Chain as a Biomarker of Brain Injury in Wilson's Disease: Clinical and Neuroradiological Correlations.

BACKGROUND: Clinical scales and neuroimaging are used to monitor nervous system injury in Wilson's disease, while data on serum markers are scarce. OBJECTIVE: To investigate whether serum concentrations of neurofilament light chain (sNfL) correlate with brain injury in Wilson's disease patients. METHODS: In 61 treatment-naïve patients, the Unified Wilson's Disease Rating Scale and a validated semiquantitative brain magnetic resonance imaging scale were compared with concentrations of sNfL. RESULTS: Concentrations of sNfL were significantly higher in patients with neurological disease compared with patients presenting with other forms (39.7 ± 73.4 pg/mL vs. 13.3 ± 9.2 pg/mL; P < 0.01). Moreover, the sNfL concentration positively correlated with neurological severity scores and with acute and chronic brain damage based on the neuroimaging scale. CONCLUSIONS: Neurofilament light chain concentrations may be used as a marker of brain injury in Wilson's disease, in addition to the clinical and neuroimaging disease severity scales. © 2022 International Parkinson and Movement Disorder Society.

Autoimmunity and long-term safety and efficacy of alemtuzumab for multiple sclerosis: Benefit/risk following review of trial and post-marketing data.

Does preexisting or treatment-emergent autoimmunity increase the risk of subsequent autoimmune disease in individuals with relapsing-remitting multiple sclerosis (MS) after alemtuzumab? In the extended phase 2/3 trials, 34/96 (35.4%) patients with and 395/1120 (35.3%) without preexisting autoimmunity developed non-MS autoimmunity. Thyroid autoimmunity after alemtuzumab courses 1 or 2 did not increase subsequent non-thyroid autoimmune adverse events. Therefore, autoimmune disease before or after alemtuzumab treatment does not predict autoimmunity after further courses, so should not preclude adequate alemtuzumab dosing to control MS. Finally, post-marketing safety data contribute toward a full record of the alemtuzumab benefit/risk profile for the MS field.