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Disease-modifying therapies (DMTs) impact the cellular immune response to severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) vaccines in patients with multiple sclerosis (pwMS). In this study, we aim to elucidate the characteristics of the involved antigen-specific T cells via the measurement of broad cytokine profiles in pwMS on various DMTs. We examined SARS-CoV-2-specific T cell responses in whole blood cultures characterized by the release of interleukin (IL)-2, IL-4, IL-5, IL-10, IL-13, IL-17A, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α), as well as antibodies (AB) targeting the SARS-CoV-2 spike protein in pwMS following either two or three doses of mRNA or viral vector vaccines (VVV). For mRNA vaccination non-responders, the NVX-CoV2373 protein-based vaccine was administered, and immune responses were evaluated. Our findings indicate that immune responses to SARS-CoV-2 vaccines in pwMS are skewed towards a Th1 phenotype, characterized by IL-2 and IFN-γ. Additionally, a Th2 response characterized by IL-5, and to a lesser extent IL-4, IL-10, and IL-13, is observed. Therefore, the measurement of IL-2 and IL-5 levels could complement traditional IFN-γ assays to more comprehensively characterize the cellular responses to SARS-CoV-2 vaccines. Our results provide a comprehensive cytokine profile for pwMS receiving different DMTs and offer valuable insights for designing vaccination strategies in this patient population.
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Background: The primary treatment for acute relapses in multiple sclerosis (MS) is the intravenous administration of high-dose methylprednisolone (IVMP). However, the mechanisms through which corticosteroid treatment impacts acute neuroinflammation in people with MS (pwMS) remain not fully understood. In particular, the changes induced by glucocorticoids (GCs) on cells of the innate immune system and the differences between patients with distinct immunotherapies have received little attention to date. Methods: We conducted immunophenotyping using flow cytometry on peripheral blood mononuclear cells of pwMS who received IVMP treatment during a relapse. We compared the impact of an IVMP treatment on a broad variety of immune cell subsets within three groups: twelve patients who were treatment-naïve to disease modifying therapies (wDMT) to ten patients on platform therapies (PT) and eighteen patients on fingolimod therapy (FTY). Results: We observed pronounced interindividual short- and intermediate-term effects of IVMP on distinct immune cells subsets. In addition to the well-documented decrease in T-helper cells (Th cells), we detected significant alterations after the first IVMP infusion within the innate immune response among neutrophil, eosinophil and basophil granulocytes, monocytes and plasmacytoid dendritic cells (pDCs). When comparing patients wDMT to the PT and FTY cohorts, we found that IVMP had a similar impact on innate immune cells across all treatment groups. However, we did not observe a significant further decline in T lymphocyte counts during IVMP in patients with pre-existing lymphopenia under FTY treatment. Although T cell apoptosis is considered the main mechanism of action of GCs, patients with FTY still reported symptom improvement following IVMP treatment. Conclusion: In addition to T cell suppression, our data suggests that further immunoregulatory mechanisms of GC, particularly on cells of the innate immune response, are of greater significance than previously understood. Due to the regulation of the adaptive immune cells by DMTs, the impact of GC on these cells varies depending on the underlying DMT. Additional studies involving larger cohorts and cerebrospinal fluid samples are necessary to gain a deeper understanding of the immune response to GC in pwMS with different DMTs during relapse to define and explain differences in clinical response profiles.
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Esclerosis Múltiple , Humanos , Femenino , Masculino , Adulto , Persona de Mediana Edad , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/inmunología , Clorhidrato de Fingolimod/uso terapéutico , Clorhidrato de Fingolimod/administración & dosificación , Inmunidad Innata/efectos de los fármacos , Metilprednisolona/uso terapéutico , Metilprednisolona/administración & dosificación , Inmunofenotipificación , Leucocitos Mononucleares/inmunología , Corticoesteroides/uso terapéutico , Corticoesteroides/administración & dosificación , Inmunosupresores/uso terapéutico , Glucocorticoides/uso terapéutico , Glucocorticoides/administración & dosificaciónRESUMEN
Multiple sclerosis (MS) as a chronic, degenerative autoimmune disease of the central nervous system has a longitudinal and heterogeneous course with increasing treatment options and risk profiles requiring constant monitoring of a growing number of parameters. Despite treatment guidelines, there is a lack of strategic and individualised monitoring pathways, including respective quality indicators (QIs). To address this, we systematically developed transparent, traceable, and measurable QIs for MS monitoring. Through literature review, expert discussions, and consensus-building, existing QIs were identified and refined. In a two-stage online Delphi process involving MS specialists (on average 53 years old and with 25 years of professional experience), the QIs were evaluated for content, clarity, and intelligibility, resulting in a set of 24 QIs and checklists to assess the quality of care. The final QIs provide a structured approach to document, monitor, and enhance the quality of care for people with MS across their treatment journey.
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The SARS-CoV-2 pandemic profoundly impacted people with multiple sclerosis (pwMS). Disease-related aspects and demographic factors may influence vaccination rates, infection susceptibility, and severity. Despite prior research, comprehensive real-world data obtained throughout the pandemic remain limited. We investigated SARS-CoV-2 vaccination and infection patterns in a large monocentric real-world cohort. We collected prospective data from medical visits at the MS Center Dresden, Germany, from the pandemic's beginning until 31 May 2022. Logistic regression and rank correlation analyses were used to explore associations between SARS-CoV-2 outcomes and patient characteristics. Of 2115 pwMS assessed (mean age 46.5, SD ± 12.9; median expanded disability status scale 2.5), 77.9% were under disease-modifying treatment (DMT), primarily B-cell depletion (25.4%). A total of 35.5% reported SARS-CoV-2 infections, and 77.4% were fully vaccinated. PwMS with increased disability, older age, and comorbidities were associated with higher vaccination rates, possibly due to the awareness of these populations regarding complications of SARS-CoV-2 infections. Infections were more common in younger females, people with a lower degree of disability, those with relapsing MS, and those who were not vaccinated. PwMS on B-cell depletion reported more infections than untreated pwMS and those receiving other types of disease-modifying therapy, despite higher vaccination rates. Most infections were mild, with no severity differences according to demographic or disease-related factors, except for gender. Notably, all fatal cases occurred in unvaccinated pwMS. Our studies suggest that demographic and disease-related factors, especially age and the use of B-cell depletion, significantly influenced SARS-CoV-2 vaccination and infection rates in our cohort. These factors may be considered in future preventive campaigns in further pandemics.
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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.
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OBJECTIVE: Repeated intravenous administration of anti-CD20 depleting monoclonal antibodies 6 months apart is among the highly effective treatment options in multiple sclerosis (MS). Here, we aimed to investigate peripheral immune cell subset depletion kinetics following either rituximab (RTX) or ocrelizumab (OCR) infusions in people with MS (pwMS). METHODS: We studied pwMS treated de-novo with either RTX (n = 7) or OCR (n = 8). The examinations were scheduled before the initiation of anti-CD20 therapy and every 12 weeks for up to 15 months. Immunophenotyping of immune cell subsets in peripheral blood was performed by multiparametric fluorescence cytometry. RESULTS: A significant, persistent decrease of CD19+ B cells was observed already with the first anti-CD20 infusion (p < 0.0001). A significant proportional reduction of memory B cells within the B-cell pool was achieved only after two treatment cycles (p = 0.005). We observed a proportional increase of immature (p = 0.04) and naive B cells (p = 0.004), again only after the second treatment cycle. As for the peripheral T-cell pool, we observed a continuous proportional increase of memory T helper (TH) cells/central memory TH cells (p = 0.02/p = 0.008), while the number of regulatory T cells (Treg) decreased (p = 0.007). The percentage of B-cell dependent TH17.1 central memory cells dropped after the second treatment cycle (p = 0.02). No significant differences in the depletion kinetics between RTX and OCR were found. INTERPRETATION: Peripheral immune cell profiling revealed more differentiated insights into the prompt and delayed immunological effects of repeated intravenous anti-CD20 treatment. The observation of proportional changes of some pathogenetically relevant immune cell subsets only after two infusion cycles deserves further attention.
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Esclerosis Múltiple , Humanos , Rituximab/farmacología , Rituximab/uso terapéutico , Anticuerpos Monoclonales/farmacología , Linfocitos B , Antígenos CD19/metabolismo , Antígenos CD19/farmacologíaRESUMEN
Different stages of Parkinson's disease (PD) are defined by clinical criteria, while late-stage PD is marked by the onset of morbidity milestones and rapid clinical deterioration. Based on neuropathological evidence, degeneration in the dopaminergic system occurs primarily in the early stage of PD, raising the question of what drives disease progression in late-stage PD. This study aimed to investigate whether late-stage PD is associated with increased neurodegeneration dynamics rather than functional decompensation using the blood-based biomarker serum neurofilament light chain (sNfL) as a proxy for the rate of neurodegeneration. The study included 118 patients with PD in the transition and late-stage (minimum disease duration 5 years, mean (SD) disease duration 15 (±7) years). The presence of clinical milestones (hallucinations, dementia, recurrent falls, and admission to a nursing home) and mortality were determined based on chart review. We found that sNfL was higher in patients who presented with at least one clinical milestone and increased with a higher number of milestones (Spearman's ρ = 0.66, p < 0.001). Above a cutoff value of 26.9 pg/ml, death was 13.6 times more likely during the follow-up period (95% CI: 3.53-52.3, p < 0.001), corresponding to a sensitivity of 85.0% and a specificity of 85.7% (AUC 0.91, 95% CI: 0.85-0.97). Similar values were obtained when using an age-adjusted cutoff percentile of 90% for sNfL. Our findings suggest that the rate of ongoing neurodegeneration is higher in advanced PD (as defined by the presence of morbidity milestones) than in earlier disease stages. A better understanding of the biological basis of stage-dependent neurodegeneration may facilitate the development of neuroprotective means.
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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 0.05â¯ng/L, a lower limit of quantification (LLoQ) of 0.8â¯ng/L, and between-laboratory imprecision <10â¯% 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.
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Filamentos Intermedios , Neuronas , Humanos , Reproducibilidad de los Resultados , Inmunoensayo , Proteínas de Neurofilamentos , Biomarcadores , Pruebas HematológicasRESUMEN
OBJECTIVES: To examine the agreement between published reference resources for neurofilament light chain (NfL) applied to a large population of people with multiple sclerosis (MS). METHODS: Six published reference resources were used to classify NfL in participants in the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network as elevated or normal and to derive age-specific NfL Z-scores. NfL values were classified as elevated if they exceeded the >95th percentile (i.e., Z-score >1.645) of the age-specific reference range. Furthermore, age-specific NfL Z-scores could be derived for 4 of 6 reference resources. RESULTS: NfL measurements were assessed from 12,855 visits of 6,687 people with MS (median 2 samples per individual [range 1-7]). The mean ± SD age was 47.1 ± 11.7 years, 72.1% of participants were female, disease duration was 15.0 ± 10.6 years, body mass index was 28.6 ± 6.9 kg/m2, and serum NfL was 12.87 ± 12.86 pg/mL. Depending on the selection of the reference resource, the proportion of NfL measurements classified as elevated varied from 3.7% to 30.9%. The kappa coefficient across the 6 reference resources used was 0.576 (95% CI 0.571-0.580) indicating moderate agreement. Spearman correlations between Z-scores derived from the various reference resources exceeded 0.90; however, concordance coefficients were lower, ranging from 0.72 to 0.89. DISCUSSION: Interpretation of blood NfL values may vary markedly depending on the selection of the reference resource. Borderline elevated values should be interpreted with caution, and future studies should focus on standardizing NfL measurement and reporting across laboratories/platforms, better characterizing the effects of confounding/influencing factors, and defining the performance of NfL (including as part of multimodal predictive algorithms) for prediction of disease-specific outcomes.
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Esclerosis Múltiple , Humanos , Femenino , Adulto , Persona de Mediana Edad , Masculino , Esclerosis Múltiple/diagnóstico , Filamentos Intermedios , Proteínas de Neurofilamentos , BiomarcadoresRESUMEN
Our objective was to analyze longitudinal cellular and humoral immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in people with multiple sclerosis (pwMS) on B-cell depleting treatment (BCDT) compared to pwMS without immunotherapy. We further evaluated the impact of COVID-19 infection and vaccination timing. PwMS (n = 439) on BCDT (ocrelizumab, rituximab, ofatumumab) or without immunotherapy were recruited for this prospective cohort study between June 2021 and June 2022. SARS-CoV-2 spike-specific antibodies and interferon-γ release of CD4 and CD8 T-cells upon stimulation with spike protein peptide pools were analyzed at different timepoints (after primary vaccination, 3 and 6 months after primary vaccination, after booster vaccination, 3 months after booster). Humoral response to SARS-CoV-2 was consistently lower whereas T-cell response was higher in patients with BCDT compared to controls. Cellular and humoral responses decreased over time after primary vaccination and increased again upon booster vaccination, with significantly higher antibody titers after booster than after primary vaccination in both untreated and B-cell-depleted pwMS. COVID-19 infection further led to a significant increase in SARS-CoV-2-specific responses. Despite attenuated B-cell responses, a third vaccination for patients with BCDT seems recommendable, since at least partial protection can be expected from the strong T-cell response. Moreover, our data show that an assessment of T-cell responses may be helpful in B-cell-depleted patients to evaluate the efficacy of SARS-CoV-2 vaccination.
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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.
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Estado de Salud , Linfocitos , Recuento de Células , Citometría de Flujo , InmunomodulaciónRESUMEN
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.
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COVID-19 , Esclerosis Múltiple , Moduladores de los Receptores de fosfatos y esfingosina 1 , Humanos , Vacunas contra la COVID-19 , SARS-CoV-2 , Receptores de Esfingosina-1-Fosfato , Estudios Longitudinales , COVID-19/prevención & control , Anticuerpos Antivirales , VacunaciónRESUMEN
Introduction: Given its wide availability and cost-effectiveness, multidimensional flow cytometry (mFC) became a core method in the field of immunology allowing for the analysis of a broad range of individual cells providing insights into cell subset composition, cellular behavior, and cell-to-cell interactions. Formerly, the analysis of mFC data solely relied on manual gating strategies. With the advent of novel computational approaches, (semi-)automated gating strategies and analysis tools complemented manual approaches. Methods: Using Bayesian network analysis, we developed a mathematical model for the dependencies of different obtained mFC markers. The algorithm creates a Bayesian network that is a HC tree when including raw, ungated mFC data of a randomly selected healthy control cohort (HC). The HC tree is used to classify whether the observed marker distribution (either patients with amyotrophic lateral sclerosis (ALS) or HC) is predicted. The relative number of cells where the probability q is equal to zero is calculated reflecting the similarity in the marker distribution between a randomly chosen mFC file (ALS or HC) and the HC tree. Results: Including peripheral blood mFC data from 68 ALS and 35 HC, the algorithm could correctly identify 64/68 ALS cases. Tuning of parameters revealed that the combination of 7 markers, 200 bins, and 20 patients achieved the highest AUC on a significance level of p < 0.0001. The markers CD4 and CD38 showed the highest zero probability. We successfully validated our approach by including a second, independent ALS and HC cohort (55 ALS and 30 HC). In this case, all ALS were correctly identified and side scatter and CD20 yielded the highest zero probability. Finally, both datasets were analyzed by the commercially available algorithm 'Citrus', which indicated superior ability of Bayesian network analysis when including raw, ungated mFC data. Discussion: Bayesian network analysis might present a novel approach for classifying mFC data, which does not rely on reduction techniques, thus, allowing to retain information on the entire dataset. Future studies will have to assess the performance when discriminating clinically relevant differential diagnoses to evaluate the complementary diagnostic benefit of Bayesian network analysis to the clinical routine workup.
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Esclerosis Amiotrófica Lateral , Citometría de Flujo , Citometría de Flujo/clasificación , Citometría de Flujo/métodos , Teorema de Bayes , Algoritmos , Esclerosis Amiotrófica Lateral/diagnóstico , Humanos , Modelos Teóricos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más AñosRESUMEN
Objective: This pilot study explores the influence of acute alcohol exposure on cell mechanical properties of steady-state and activated leukocytes conducted with real-time deformability cytometry. Methods: Nineteen healthy male volunteers were enrolled to investigate the effect of binge drinking on biophysical properties and cell counts of peripheral blood leukocytes. Each participant consumed an individualized amount of alcohol to achieve a blood alcohol concentration of 1.2 as a mean peak. In addition, we also incubated whole blood samples from healthy donors with various ethanol concentrations and performed stimulation experiments using lipopolysaccharide and CytoStim™ in the presence of ethanol. Results: Our findings indicate that the biophysical properties of steady-state leukocytes are not significantly affected by a single episode of binge drinking within the first two hours. However, we observed significant alterations in relative cell counts and a shift toward a memory T cell phenotype. Moreover, exposure to ethanol during stimulation appears to inhibit the cytoskeleton reorganization of monocytes, as evidenced by a hindered increase in cell deformability. Conclusion: Our observations indicate the promising potential of cell mechanical analysis in understanding the influence of ethanol on immune cell functions. Nevertheless, additional investigations in this field are warranted to validate biophysical properties as biomarkers or prognostic indicators for alcohol-related changes in the immune system.
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Neurofilaments (NFs) are not only important for axonal integrity and nerve conduction in large myelinated axons but they are also thought to be crucial for receptor and synaptic functioning. Therefore, NFs may play a critical role in cognitive functions, as cognitive processes are known to depend on synaptic integrity and are modulated by dopaminergic signaling. Here, we present a theory-driven interdisciplinary approach that NFs may link inflammation, neurodegeneration, and cognitive functions. We base our hypothesis on a wealth of evidence suggesting a causal link between inflammation and neurodegeneration and between these two and cognitive decline (see Fig. 1), also taking dopaminergic signaling into account. We conclude that NFs may not only serve as biomarkers for inflammatory, neurodegenerative, and cognitive processes but also represent a potential mechanical hinge between them, moreover, they may even have predictive power regarding future cognitive decline. In addition, we advocate the use of both NFs and MRI parameters, as their synthesis offers the opportunity to individualize medical treatment by providing a comprehensive view of underlying disease activity in neurological diseases. Since our society will become significantly older in the upcoming years and decades, maintaining cognitive functions and healthy aging will play an important role. Thanks to technological advances in recent decades, NFs could serve as a rapid, noninvasive, and relatively inexpensive early warning system to identify individuals at increased risk for cognitive decline and could facilitate the management of cognitive dysfunctions across the lifespan.
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Disfunción Cognitiva , Longevidad , Humanos , Filamentos Intermedios , Cognición , Dopamina , InflamaciónRESUMEN
The acute state of anorexia nervosa (AN) is associated with widespread reductions in cortical gray matter (GM) thickness and white matter (WM) volume, suspected changes in myelin content and elevated levels of the neuronal damage marker neurofilament light (NF-L), but the underlying mechanisms remain largely unclear. To gain a deeper understanding of brain changes in AN, we applied a multimodal approach combining advanced neuroimaging methods with analysis of blood-derived biomarkers. In addition to standard measures of cortical GM thickness and WM volume, we analyzed tissue-specific profiles of brain metabolites using multivoxel proton magnetic resonance spectroscopy, T1 relaxation time as a proxy of myelin content leveraging advanced quantitative MRI methods and serum NF-L concentrations in a sample of 30 female, predominately adolescent patients with AN and 30 age-matched female healthy control participants. In patients with AN, we found a reduction in GM cortical thickness and GM total N-acetyl aspartate. The latter predicted higher NF-L levels, which were elevated in AN. Furthermore, GM total choline was elevated. In WM, there were no group differences in either imaging markers, choline levels or N-acetyl aspartate levels. The current study provides evidence for neuronal damage processes as well as for increased membrane lipid catabolism and turnover in GM in acute AN but no evidence for WM pathology. Our results illustrate the potential of multimodal research including tissue-specific proton magnetic resonance spectroscopy analyses to shed light on brain changes in psychiatric and neurological conditions, which may ultimately lead to better treatments.
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Anorexia Nerviosa , Sustancia Blanca , Adolescente , Humanos , Femenino , Anorexia Nerviosa/diagnóstico por imagen , Anorexia Nerviosa/patología , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Espectroscopía de Resonancia Magnética , Imagen por Resonancia Magnética/métodos , Sustancia Blanca/patología , Biomarcadores , Colina , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patologíaRESUMEN
Importance: Immunological response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is important, especially in people with multiple sclerosis (pwMS) on immunosuppressive therapies. Objective: This study aims to determine whether adjuvanted protein-based vaccine NVX-CoV2373 is able to induce an immune response to SARS-CoV-2 in pwMS with inadequate responses to prior triple mRNA/viral vector vaccination. Design setting and participants: We conducted a single-center, prospective longitudinal cohort study at the MS Center in Dresden, Germany. In total, 65 participants were included in the study in accordance with the following eligibility criteria: age > 18 years, immunomodulatory treatment, and insufficient T-cellular and humoral response to prior vaccination with at least two doses of SARS-CoV-2 mRNA (BNT162b2, mRNA-1273) or viral vector vaccines (AZD1222, Ad26.COV2.S). Interventions: Intramuscular vaccination with two doses of NVX-CoV2373 at baseline and 3 weeks of follow-up. Main outcomes and measures: The development of SARS-CoV-2-specific antibodies and T-cell responses was evaluated. Results: For the final analysis, data from 47 patients on stable treatment with sphingosine-1-phosphate receptor (S1PR) modulators and 17 on ocrelizumab were available. The tolerability of the NVX-CoV2373 vaccination was overall good and comparable to the one reported for the general population. After the second NVX-CoV2373 vaccination, 59% of S1PR-modulated patients developed antispike IgG antibodies above the predefined cutoff of 200 binding antibody units (BAU)/ml (mean, 1,204.37 [95% CI, 693.15, 2,092.65] BAU/ml), whereas no clinically significant T-cell response was found. In the subgroup of the patients on ocrelizumab treatment, 23.5% developed antispike IgG > 200 BAU/ml (mean, 116.3 [95% CI, 47.04, 287.51] BAU/ml) and 53% showed positive spike-specific T-cellular responses (IFN-gamma release to antigen 1: mean, 0.2 [95% CI, 0.11, 0.31] IU/ml; antigen 2: mean, 0.24 [95% CI, 0.14, 0.37]) after the second vaccination. Conclusions: Vaccination with two doses of NVX-CoV2373 was able to elicit a SARS-CoV-2-specific immune response in pwMS lacking adequate immune responses to previous mRNA/viral vector vaccination. For patients receiving S1PR modulators, an increase in anti-SARS-CoV-2 IgG antibodies was detected after NVX-CoV2373 vaccination, whereas in ocrelizumab-treated patients, the increase of antiviral T-cell responses was more pronounced. Our data may impact clinical decision-making by influencing the preference for NVX-CoV2373 vaccination in pwMS receiving treatment with S1PR modulation or anti-CD20 treatment.
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COVID-19 , Esclerosis Múltiple , Vacunas Virales , Humanos , Adulto , Persona de Mediana Edad , Vacunas contra la COVID-19 , Ad26COVS1 , Vacuna BNT162 , ChAdOx1 nCoV-19 , Estudios Longitudinales , Esclerosis Múltiple/tratamiento farmacológico , Estudios Prospectivos , COVID-19/prevención & control , SARS-CoV-2 , Inmunoglobulina G , Anticuerpos Antivirales , Inmunidad CelularRESUMEN
Objective: The study aimed to investigate the effect of exercise on immune cell count and cell mechanical properties in people with multiple sclerosis (pwMS) on different disease-modifying treatments (DMT) vs. healthy controls (HCs). Methods: A cohort of 16 HCs and 45 pwMS, including patients with lymphopenia (alemtuzumab and fingolimod) as well as increased lymphocyte counts (natalizumab), was evaluated for exercise-mediated effects on immune cell counts and lymphocyte deformability. As exercise paradigms, climbing stairs at normal speed or as fast as possible and cycling were used, while blood samples were collected before, immediately, and 20 as well as 60 min post-exercise. Immune cell subtypes and lymphocyte deformability were analyzed using multicolor flow cytometry and real-time deformability cytometry. Results: An increase in lymphocytes and selected subsets was observed following exercise in HCs and all pwMS on different DMTs. Patients with lymphopenia exhibited an increase in absolute lymphocyte counts and immune cell subsets till just below or into the reference range. An increase above the upper limit of the reference range was detected in patients on natalizumab. Exercise-induced alterations were observable even in low and more pronounced in high-intensity physical activities. Lymphocyte deformability was found to be only mildly affected by the investigated exercise regimes. Conclusion: People with multiple sclerosis (PwMS) treated with alemtuzumab, fingolimod, and natalizumab respond to acute exercise with a comparable temporal pattern characterized by the increase of immune cell subsets as HCs. The magnitude of response is influenced by exercise intensity. Exercise-mediated effects should be considered when interpreting laboratory values in patients on immunomodulatory therapy. The impact of exercise on biophysical properties should be further elucidated.