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Human genetics and preclinical studies have identified key contributions of TREM2 to several neurodegenerative conditions, inspiring efforts to modulate TREM2 therapeutically. Here, we characterize the activities of three TREM2 agonist antibodies in multiple mixed-sex mouse models of Alzheimer's disease (AD) pathology and remyelination. Receptor activation and downstream signaling are explored in vitro, and active dose ranges are determined in vivo based on pharmacodynamic responses from microglia. For mice bearing amyloid-ß (Aß) pathology (PS2APP) or combined Aß and tau pathology (TauPS2APP), chronic TREM2 agonist antibody treatment had limited impact on microglia engagement with pathology, overall pathology burden, or downstream neuronal damage. For mice with demyelinating injuries triggered acutely with lysolecithin, TREM2 agonist antibodies unexpectedly disrupted injury resolution. Likewise, TREM2 agonist antibodies limited myelin recovery for mice experiencing chronic demyelination from cuprizone. We highlight the contributions of dose timing and frequency across models. These results introduce important considerations for future TREM2-targeting approaches.
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Doença de Alzheimer , Glicoproteínas de Membrana , Microglia , Esclerose Múltipla , Receptores Imunológicos , Animais , Receptores Imunológicos/agonistas , Receptores Imunológicos/metabolismo , Receptores Imunológicos/genética , Glicoproteínas de Membrana/agonistas , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Camundongos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Feminino , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Anticorpos/farmacologia , Humanos , Peptídeos beta-Amiloides/metabolismo , Proteínas tau/metabolismoRESUMO
In multiple sclerosis (MS), persisting disability can occur independent of relapse activity or development of new central nervous system (CNS) inflammatory lesions, termed chronic progression. This process occurs early and it is mostly driven by cells within the CNS. One promising strategy to control progression of MS is the inhibition of the enzyme Bruton's tyrosine kinase (BTK), which is centrally involved in the activation of both B cells and myeloid cells, such as macrophages and microglia. The benefit of BTK inhibition by evobrutinib was shown as we observed reduced pro-inflammatory activation of microglia when treating chronic experimental autoimmune encephalomyelitis (EAE) or following the adoptive transfer of activated T cells. Additionally, in a model of toxic demyelination, evobrutinib-mediated BTK inhibition promoted the clearance of myelin debris by microglia, leading to an accelerated remyelination. These findings highlight that BTK inhibition has the potential to counteract underlying chronic progression of MS.
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Tirosina Quinase da Agamaglobulinemia , Encefalomielite Autoimune Experimental , Microglia , Bainha de Mielina , Piperidinas , Pirimidinas , Animais , Feminino , Camundongos , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/metabolismo , Compostos de Bifenilo/farmacologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/patologia , Camundongos Endogâmicos C57BL , Microglia/patologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Bainha de Mielina/patologia , Bainha de Mielina/metabolismo , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Remielinização/fisiologia , Remielinização/efeitos dos fármacosRESUMO
BACKGROUND: Evobrutinib - an oral, central nervous system (CNS)-penetrant, and highly selective Bruton's tyrosine kinase inhibitor - has shown efficacy in a 48-week, double-blind, Phase II trial in patients with relapsing MS. OBJECTIVE: Report results of the Phase II open-label extension (OLE; up to week 192 from randomisation) and a cerebrospinal fluid (CSF) sub-study. METHODS: In the 48-week double-blind period (DBP), patients received evobrutinib 25 mg once-daily, 75 mg once-daily, 75 mg twice-daily or placebo (switched to evobrutinib 25 mg once-daily after week 24). Patients could then enter the OLE, receiving evobrutinib 75 mg once-daily (mean (± standard deviation (SD)) duration = 50.6 weeks (±6.0)) before switching to 75 mg twice-daily. RESULTS: Of 164 evobrutinib-treated patients who entered the OLE, 128 (78.0%) completed ⩾192 weeks of treatment. Patients receiving DBP evobrutinib 75 mg twice-daily: annualised relapse rate at week 48 (0.11 (95% confidence interval (CI) = 0.04-0.25)) was maintained with the OLE twice-daily dose up to week 192 (0.11 (0.05-0.22)); Expanded Disability Status Scale score remained stable; serum neurofilament light chain fell to levels like a non-MS population (Z-scores); T1 gadolinium-enhancing lesion numbers remained low. No new safety signals were identified. In the OLE, evobrutinib was detected in the CSF of all sub-study patients. CONCLUSION: Long-term evobrutinib treatment was well tolerated and associated with a sustained low level of disease activity. Evobrutinib was present in CSF at concentrations similar to plasma.
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Esclerose Múltipla , Piperidinas , Pirimidinas , Humanos , Esclerose Múltipla/tratamento farmacológico , Seguimentos , Recidiva , Método Duplo-Cego , Resultado do TratamentoRESUMO
Factor XIII is a transglutaminase enzyme that plays a crucial role in hemostasis and wound healing. It crosslinks fibrin strands, stabilizing clots and promoting clot resistance to fibrinolysis. Additionally, Factor XIII has been found to have multiple other functions that extend beyond coagulation, including the regulation of inflammation and tissue repair processes. Emerging evidence suggests that Factor XIII may also have differential roles in acute myocardial infarction and ischemic stroke, two common cardiovascular events with significant morbidity and mortality. In acute myocardial infarction, Factor XIII has been implicated in promoting clot stability and reducing the risk of re-occlusion. In ischemic stroke, Factor XIII may also contribute to the pathogenesis of cerebral ischemia by promoting clot formation and exacerbating neuronal damage. Several studies have investigated the association between Factor XIII and these cardiovascular events, using various approaches such as genetic polymorphism analysis, animal models, and clinical data analysis. These studies have provided important insights into the role of Factor XIII in acute myocardial infarction and ischemic stroke, highlighting its potential as a therapeutic target for interventions aimed at improving outcomes in these conditions. In this review, we will summarize the current understanding of Factor XIII's role in acute myocardial infarction and ischemic stroke.
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A major therapeutic goal in the treatment of multiple sclerosis (MS) is to prevent the accumulation of disability over an often decades-long disease course. Disability progression can result from acute relapses as well as from CNS intrinsic parenchymal disintegration without de novo CNS lesion formation. Research focus has shifted to progression not associated with acute inflammation, as it is not sufficiently controlled by currently available treatments. This review outlines how recent advances in the understanding of the pathogenesis of progressive MS have been facilitated by the development of more precise, less static pathogenetic concepts of progressive MS, as well as by new techniques for the analysis of region-specific proteomic and transcriptomic signatures in the human CNS. We highlight key drivers of MS disease progression and potential targets in its treatment.
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Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Humanos , Esclerose Múltipla/tratamento farmacológico , Proteômica , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Esclerose Múltipla Crônica Progressiva/patologia , Progressão da DoençaRESUMO
Objective: Prospective cohort study to test the real-life feasibility of longitudinal patient-reported outcome measurement PROM (Integrated Palliative Outcome Scale IPOS, and NCCN Distress Thermometer DT) required for outpatients with non-curable lung or prostate cancer in comprehensive cancer centers. Methods: Assessment with paper-based IPOS and DT was observed for 15 months. We analyzed response to patients' distress (requests for supportive and palliative services) following PROM. Focus groups to comprehensively explore the user experience of patients, informal caregivers and health care professionals (HCP) supplemented the analysis. Results: Ninety-seven percent (125/129) of the patients received a questionnaire once, but quarterly assessment as recommended by certification committees was achieved only in 50% and 31% of prostate and lung cancer patients. Although both instruments were well accepted, only IPOS showed a high content validity, because some patients had difficulties in understanding the DT. Patients felt comfortable with completing the PROM, and HCP found PROM helped to structure the patient encounter. Due to organizational deficiencies in the handling of the instruments and operationalization of reactions to identified distress, the referrals to supportive and palliative services were rare. Conclusion: To facilitate consequences from PROM it should be a standardized intervention rather than assessment alone. Innovation: The patient perspective improves the implementation of PROM under real-life clinical conditions.
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We present a novel internet of things (IoT) sensing platform that uses helical propagation paths of ultrasonic guided waves (UGWs) for structural health monitoring. This wireless sensor network comprises multiple identical sensor units that communicate with a host PC. The units have dedicated hardware to both generate and receive ultrasonic signals, as well as RF signals for use in triggering the sensors. The system was developed for monitoring and sensing pipelines and similar structures in real-time to facilitate interactive sensing. For accurate sensing with a limited number of arbitrarily scattered sensors, we obtain information from all sensor pairs and analyze helical propagation paths in addition to the commonly used shortest paths. UGWs can propagate long distances along the walls of pipelines, and their propagation velocity depends directly on the thickness of the waveguide, and is affected by energy leakage and mass loading. In this paper, we evaluated the network by utilizing it to detect fouling. The network could be adapted for further ultrasonic measurement tasks, e.g., measuring wall thicknesses or monitoring defects with pulse-echo methods.
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The advancement of technologies for producing chemicals and materials from non-fossil resources is of critical importance. An illustrative example is the dehydrogenation of glucose, to yield gluconic acid, a specialty chemical. In this study, we propose an innovative production route for gluconic acid while generating H2 as a co-product. Our concept involves a dual-function membrane, serving both as a catalyst for glucose dehydrogenation into gluconic acid and as a means to efficiently remove the produced H2 from the reaction mixture. To achieve this two membranes were developed, one catalytically active and one dense aimed at H2 removal. The catalytic membrane showed significant activity, yielding 16 % gluconic acid (t=120â min) with a catalyst selectivity of 93 % and stable performance over five consecutive cycles. Incorporating the H2 separating membrane showed the significance of H2 removal in driving the reaction forward. Its inclusion led to a twofold increase in gluconic acid yield, aligning with Le Chatelier's principles. As a future prospect the two layers can be combined into a dual-layer membrane which opens the way for a new production route to simultaneously produce gluconic acid and H2, using high-throughput reactors such as hollow-fiber systems.
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OBJECTIVES: To assess neurofilament light chain serum (sNfL) levels in patients with secondary progressive multiple sclerosis (SP-MS). METHODS: Using a single molecule array, we analyzed sNfL levels in a cross-sectional cohort study of 153 patients with SP-MS hospitalized for rehabilitation in a clinic specialized in the care for patients with multiple sclerosis (MS). In addition, we investigated the correlation of disease activity with sNfL levels in 36 patients with relapsing-remitting MS (RR-MS). RESULTS: Mean sNfL levels in patients with SP-MS were consistently elevated when compared with age-matched controls and patients with RR-MS. In SP-MS, age dependency of sNfL levels was pronounced, whereas patients with RR-MS younger than 41 years without recent disease activity were not distinguishable from age-matched healthy controls. In a multivariate analysis, clinical disability was a risk factor for elevated sNfL levels in SP-MS, whereas no correlation with comorbidities, such as cardiovascular disease, diabetes mellitus, smoking status, or vitamin D serum levels, could be detected. DISCUSSION: These findings highlight that measurement of sNfL levels represents a useful tool to assess the extent of neuroaxonal damage as a surrogate for clinical progression in patients with SP-MS, when age and disease activity as major confounders are taken into account.
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Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla Recidivante-Remitente , Proteínas de Neurofilamentos , Humanos , Estudos Transversais , Masculino , Feminino , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/sangue , Esclerose Múltipla Crônica Progressiva/fisiopatologia , Adulto , Proteínas de Neurofilamentos/sangue , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Idoso , Fatores Etários , Estudos de Coortes , Avaliação da Deficiência , Biomarcadores/sangueRESUMO
Importance: Biomarkers distinguishing nonrelapsing progressive disease biology from relapsing biology in multiple sclerosis (MS) are lacking. Cerebrospinal fluid (CSF) is an accessible fluid that most closely reflects central nervous system biology. Objective: To identify CSF biological measures associated with progressive MS pathobiology. Design, Setting, and Participants: This cohort study assessed data from 2 prospective MS cohorts: a test cohort provided serial CSF, clinical, and imaging assessments in a multicenter study of patients with relapsing MS (RMS) or primary progressive MS (PPMS) who were initiating anti-CD20 treatment (recruitment: 2016-2018; analysis: 2020-2023). A single-site confirmation cohort was used to assess CSF at baseline and long-term (>10 year) clinical follow-up (analysis: 2022-2023). Exposures: Test-cohort participants initiated standard-of-care ocrelizumab treatment. Confirmation-cohort participants were untreated or received standard-of-care disease-modifying MS therapies. Main Outcomes and Measures: Twenty-five CSF markers, including neurofilament light chain, neurofilament heavy chain, and glial fibrillary acid protein (GFAP); 24-week confirmed disability progression (CDP24); and brain magnetic resonance imaging measures reflecting focal injury, tissue loss, and progressive biology (slowly expanding lesions [SELs]). Results: The test cohort (n = 131) included 100 patients with RMS (mean [SD] age, 36.6 [10.4] years; 68 [68%] female and 32 [32%] male; Expanded Disability Status Scale [EDSS] score, 0-5.5), and 31 patients with PPMS (mean [SD] age, 44.9 [7.4] years; 15 [48%] female and 16 [52%] male; EDSS score, 3.0-6.5). The confirmation cohort (n = 68) included 41 patients with RMS and 27 with PPMS enrolled at diagnosis (age, 40 years [range, 20-61 years]; 47 [69%] female and 21 [31%] male). In the test cohort, GFAP was correlated with SEL count (r = 0.33), greater proportion of T2 lesion volume from SELs (r = 0.24), and lower T1-weighted intensity within SELs (r = -0.33) but not with acute inflammatory measures. Neurofilament heavy chain was correlated with SEL count (r = 0.25) and lower T1-weighted intensity within SELs (r = -0.28). Immune markers correlated with measures of acute inflammation and, unlike GFAP, were impacted by anti-CD20. In the confirmation cohort, higher baseline CSF GFAP levels were associated with long-term CDP24 (hazard ratio, 2.1; 95% CI, 1.3-3.4; P = .002). Conclusions and Relevance: In this study, activated glial markers (in particular GFAP) and neurofilament heavy chain were associated specifically with nonrelapsing progressive disease outcomes (independent of acute inflammatory activity). Elevated CSF GFAP was associated with long-term MS disease progression.