Introduction/Aims: Serum cardiac troponin T (cTnT) levels are elevated in the majority of amyotrophic lateral sclerosis (ALS) patients and increase over time. Neurofilament light chain (NfL) is an established therapy response biomarker in ALS as superoxide dismutase 1 (SOD1)-ALS patients treated with the antisense oligonucleotide tofersen show a decrease in NfL. In this study we assess the course of cTnT levels in SOD1-ALS at baseline and during tofersen treatment. Methods: Serum cTnT was analyzed at baseline and during tofersen treatment in 23 SOD1-ALS patients at two specialized ALS centers in Germany and compared to a control cohort of 74 ALS patients without SOD1-mutations and not treated with tofersen. Results: cTnT levels increased in the control ALS-cohort over time (p<0.0001) but not in the tofersen group (p=0.36). CK, and CK-MB levels did not show relevant changes over time. The median monthly increase of cTnT was 0.045 points (IQR 0.02-0.08) in the control ALS cohort and 0.01 points (IQR -0.01-0.03) in the tofersen group (p=0.0013). The fold change in cTnT levels of the tofersen- treated cohort (median 1.2; IQR 0.77-1.59) was significantly less and even showed a reduction in some patients compared to the control group (median 1.89; IQR 1.35-2.75) (p=0.0003). Discussion: In this study, we find a response signal of cTnT to tofersen treatment, which supports the value of cTnT as an independent biomarker in ALS. These results contribute to the notion that cTnT may provide additional value as a progression and treatment response biomarker in ALS complementary to NfL and warrant further investigations. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study is a retrospective analysis using clinical routine data (Bonn) and data from the "APST-registry study", and "NfL-ALS"-study in Berlin. As the laboratory measurements were part of the routine clinical work-up and retrospectively analysed in Bonn, no formal consent was needed per statement of our institutional ethics review board of Bonn University Hospital (Ethics Board decision letter 324/20; ethical approval was waived). The study protocol "APST registry study" was approved by the Medical Ethics Committee of Charité-Universitätsmedizin Berlin, Germany, under numbers EA2/168/20 and EA1/219/15 (for the sub-study of platform-based sNfL data management, "NfL-ALS"). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the author

In amyotrophic lateral sclerosis (ALS), heterogeneity of motor phenotypes is a fundamental hallmark of the disease. Distinct ALS phenotypes were associated with a different progression and survival. Despite its relevance for clinical practice and research, there is no broader consensus on the classification of ALS phenotypes. An expert consensus process for the classification of ALS motor phenotypes was performed from May 2023 to December 2024. A three-determinant anatomical classification was proposed which is based on the (1) region of onset (O), (2) the propagation of motor symptoms (P), and (3) the degree of upper (UMN) and/or lower motor neuron (LMN) dysfunction (M). Accordingly, this classification is referred to as the “OPM classification”. Onset phenotypes differentiate the site of first motor symptoms: O1) head onset; O2d) distal arm onset; O2p) proximal arm onset; O3r) trunk respiratory onset; O3a) trunk axial onset; O4d) distal leg onset; O4p) proximal leg onset. Propagation phenotypes differentiate the temporal propagation of motor symptoms from the site of onset to another, vertically distant body region: PE) earlier propagation (within 12 months of symptom onset); PL) later propagation (without propagation within 12 months of symptom onset), including the established phenotypes of “progressive bulbar paralysis” (O1, PL), “flail-arm syndrome” (O2p, PL), and “flail-leg syndrome” (O4d, PL); PN) propagation not yet classifiable as time since symptom onset is less than 12 months. Phenotypes of motor neuron dysfunction differentiate the degree of UMN and/or LMN dysfunction: M0) balanced UMN and LMN dysfunction; M1d) dominant UMN dysfunction; M1p) pure UMN dysfunction (“primary lateral sclerosis”, PLS); M2d) dominant LMN dysfunction; M2p) pure LMN dysfunction (“progressive muscle atrophy”, PMA); M3) dissociated motor neuron dysfunction with dominant LMN and UMN dysfunction of the arms and legs (“brachial amyotrophic spastic paraparesis”), respectively. This consensus process aimed to standardize the clinical description of ALS motor phenotypes in clinical practice and research – based on the onset region, propagation pattern, and motor neuron dysfunction. This “OPM classification” contributes to specifying the prognosis, to defining the inclusion or stratification criteria in clinical trials and to correlate phenotypes with the underlying disease mechanisms of ALS.

Neutrophils are immune cells specialized in producing large amounts of reactive oxygen species (ROS) to kill microbes. However, the mechanisms by which these cells regulate the balance of different ROS species and mitigate oxidative stress remain unclear. Here, we demonstrate that superoxide dismutase 1 (SOD1) plays a crucial role in ROS formation and antimicrobial activity in neutrophils. Our findings reveal that SOD1 modulates the ratio of superoxide (O2-) to hydrogen peroxide (H2O2) during the ROS burst, thereby supporting myeloperoxidase (MPO) enzymatic activity. By employing biochemical, cell biological, and genetic approaches, we show that SOD1 is crucial for ROS formation during NETosis and microbial infections, as it reduces oxidative stress and enables complete neutrophil activation. Impairment of SOD1 activity increases cysteine oxidation and lipid peroxidation. Neutrophils isolated from a patient with a SOD1 mutation exhibit decreased ROS production and impaired neutrophil extracellular trap (NET) formation. Our findings suggest that SOD1 is a novel regulatory factor in the oxidative burst that enables the full immunological response of neutrophils.

INTRODUCTION/AIMS:Cardiac troponin T (cTnT) levels are elevated in the majority of persons with amyotrophic lateral sclerosis (ALS) and increase over time. Neurofilament light chain (NfL) is an established therapy response biomarker in ALS as superoxide dismutase1 (SOD1)-ALS patients treated with the antisense oligonucleotide tofersen show a decrease in NfL. In this study, we assess cTnT levels in SOD1-ALS at baseline and during tofersen treatment. METHODS:cTnT was analyzed at baseline and during tofersen treatment in 23 SOD1-ALS patients at two specialized ALS centers in Germany and compared to a control cohort of 74 ALS patients without SOD1 variants. RESULTS:cTnT levels increased in the control ALS cohort over time (p < 0.0001) but not in the tofersen group (p = 0.36). Creatine kinase (CK) and CK-MB levels did not show significant changes over time. The median monthly increase of cTnT was 0.045 points (IQR 0.02-0.08) in the control ALS cohort and 0.01 points (IQR -0.01-0.03) in the tofersen group (p = 0.0013). A significantly lower fold change in cTnT levels was observed in the tofersen-treated cohort (median 1.2; IQR 0.77-1.59) relative to the control group (median 1.89; IQR 1.35-2.75) (p = 0.0003). Nine (39%) patients treated with tofersen experienced a reduction in cTnT levels. DISCUSSION:In this study, we describe a response signal of cTnT to tofersen treatment, which supports the value of cTnT as an independent biomarker in ALS. These results contribute to the notion that cTnT may provide additional value as a progression and treatment response biomarker in ALS complementary to NfL and warrant further investigation.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease predominantly affecting motor neurons resulting in substantial, progressive disability. The amyotrophic lateral sclerosis functional rating scale - revised (ALSFRS-R) is commonly used to assess and monitor functional status in patients with ALS. Additionally, it is the current regulatory accepted primary outcome measure documenting functional status in ALS clinical trials. The ALSFRS-R was originally designed to be administered to a patient by a trained professional. But over time it has been adapted to be performed independently by patients or their caregivers without assistance. Several different versions of the self-administered ALSFRS-R have been created over the past two decades, each with subtle but important differences. Some of these differences are related to language used in item wording or the platform for which the scale was intended to be administered (e.g. digitally). These differences across versions of the self-administered scale may be problematic as they could increase the heterogeneity of data collected across clinical trials or complicate interpretation of results across trials. Therefore, we highlight the need for a harmonized version of the self-administered ALSFRS-R to be used across all clinics and clinical trial sites internationally.

We present an electronic data capture (EDC) system based on Near Field Communication (NFC). NFC is an easy way for self-reporting of health status information. As traditional paper-based questionnaires are time- and cost-consuming and may be affected by low patient compliance, our EDC system allows patient monitoring and electronic data acquisition directly from the patient's home. It enables real time representation and analysis of patient data and thus allows direct medical intervention by physicians. The results of a field test indicate that NFC is almost as simple as filling out a paper-based questionnaire. During the study patients used the prototype autonomously and with minimal errors. Further, NFC technology was perceived as very intuitive and the information quality of each patient's health status could be improved. Based on the findings we derive recommendations for future research and applications of NFC based electronic data capture systems.

Neurological facilities are traditionally centered in academic hospitals and often far away from the patients’ living area. Both, the transfer of patients to remote hospitals and inpatient treatment are associated with high energy consumption. Numbers of patients with neurological diseases are expected to increase along with the demographical changes and the environmental impact of neurological treatment should become a target for health policy, therefore. Positive effects have been demonstrated for the use of telemedicine by improving inpatient treatment in local community hospitals or avoiding hospital admissions via monitoring of complex diseases in outpatient settings. We discuss the potentials of telemedicine in the field of in- and outpatient neurological care as well as the need for more scientific evaluation on environmental impacts.

Basal cell carcinoma (BCC) is the most frequent cancer among the white population, representing 75% of all skin cancers [1]. The incidence of BCC cases is increasing, probably because of changes of leisure activities and migration to regions with higher solar radiation. BCCs rarely metastasize (<0.1%), and mortality rates are low; however, some tumors grow aggressively and may cause extensive tissue damage. Aggressive growth of BCC correlates with histological subtypes. Nodular and superficial BCC, representing 60% and 25% of all BCC, respectively, are usually considered less aggressive than morpheaform, infiltrative, micronodular, and metatypic BCC, which are associated with a higher rate of local recurrences [2, 3]. Several risk factors for the development of BCC have been described, which include physical characteristics, exposures to environmental carcinogens, immunosuppression, and genetic predisposition. Other genetic changes, acquired subsequently and affecting cell proliferation and apoptosis, may also be involved in tumorigenesis. In the following sections, some recently identified molecular mechanisms are described that are involved in BCC development and which potentially represent targets of new pharmacologic treatment modalities.

Chlamydia trachomatis is the most common sexually transmitted organism In Industrialized countries. Nucleic acid amplification testing, using non-invasively collected specimens, is considered to be the method of choice for diagnosis of chlamydial infections of the urethra and the lower genital tract. Serological testing has the potential to circumvent the problem of specimen sampling in invasive C. trachomatis infections of the upper genital tract. However, only a few defined chlamydial antigens have been used in a standardized diagnostic assay format. In this study, we used serological two-dimensional proteomic analysis to broaden the spectrum of diagnostically relevant C. trachomatis proteins. The genes encoding an assortment of already known chlamydial antigens, as well as immunogenic proteins that have not been described before, were cloned, and the recombinant proteins were purified in order to compare their diagnostic usefulness in parallel with a newly developed line immunoassay. With 189 sera collected from patients with and without C. trachomatis infection, recombinant major outer membrane protein (MOMP), chlamydial protease-like activity factor (CPAF), outer membrane protein 2 (OMP2), translocated actin-recruiting protein, and polymorphic membrane protein D (PmpD) showed the highest level of diagnostic sensitivity and specificity. In patients suffering from ascending and invasive C. trachomatis infections, such as pelvic inflammatory disease and lymphogranuloma venereum, the sensitivity reached with these proteins ranged between 71% (PmpD) and 94% (OMP2), and the specificity ranged between 82% (PmpD) and 100% (MOMP and OMP2). Recombinant thio-specific antioxidant peroxidase, ribosomal protein S1 (RpsA) and hypothetical protein 17 showed lower sensitivity but comparably high specificity, ranging from 94% to 100%. The novel line immunoassay based on defined recombinant antigens has promise for improved serodiagnosis in severe and invasive C. trachomatis infections.

We report a patient with Guillain–Barré syndrome (GBS), characterized by severe tetraparesis, bulbar syndrome, and ophthalmoparesis. The nadir was reached within 1 day, followed by respiratory insufficiency requiring mechanical ventilation. Molecular analysis revealed a duplication at chromosome 17p11.2‐12, which is a known genetic cause of Charcot–Marie–Tooth disease type 1A (CMT1A). We suggest that this genotype may comprise a previously unrecognized genetic risk factor for GBS. Muscle Nerve, 2007

The authors present a 50-year-old patient with adult-onset amyotrophic lateral sclerosis (ALS) that was rapidly progressing. Screening of the spastin gene revealed a heterozygous missense change S44L. We excluded the involvement of the ALS-linked gene for copper/zinc superoxide dismutase (SOD1). This unusual phenotype shows that allelic variants of spastin may predispose bearers to a greater spectrum of motor neuron disorders including ALS.

Background: Since 2003, an ongoing outbreak of lymphogranuloma venereum (LGV), caused by Chlamydia trachomatis biovar L2b, has been reported among men who have sex with men. Methods: Twenty-four samples positive for C. trachomatis were analyzed for specific biovars and genovariants by genotyping of the variable segment (VS) 4, VS2 and VS1 regions of the outer membrane protein (omp) A. In addition we assessed the patients’ sociodemographic background and clinical signs and symptoms. Results: Twenty-four men who have sex with men presented with either anorectal or inguinal symptoms and tested positive for C. trachomatis DNA. Of these, the L2 genotype accounted for 15 patients, with a high coinfection rate with HIV (73.3%) and other sexually transmitted infections (53.4%). Analysis of the VS1, VS2, and VS4 regions of the ompA gene revealed the variant L2b in 8 patients. In 4 patients, 3 new L2 sequences were identified with nucleotide changes in the VS1, VS2, and VS4 region, respectively, defining new strains designated L2c, d, e. Conclusions: This outbreak of LGV represents the further spread of C. trachomatis L2 infection. Sequence analysis of ompA regions shows heterogeneity of L2 variants, suggesting more than 1 source of the LGV infections diagnosed in Vienna.

Das klinische und neuropathologische Hauptmerkmal von Motoneuronerkrankungen (MND) ist die selektive Vulnerabilität der Vorderhornzellen im Rückenmark und Hirnstamm sowie der Betz-Zellen im Motorkortex. Ein Tiermodell mit Mutationen im Motorprotein Dynein spiegelt die Selektivität des pathogenetischen Prozesses wieder. Der Multiproteinkomplex Dynactin unterstützt insbesondere im retrograden axonalen Transport funktionell die Funktion des Dyneins.

The molecular mechanisms underlying the co-occurrence of ALS and FTD remain incompletely understood. We report a heterozygous R1101K mutation of the p150 subunit of the molecular motor dynactin (DCTN1) in a family with amyotrophic lateral sclerosis (ALS) and co-occurrence of frontotemporal dementia (FTD). Three members of our kindred were affected with motor neuron disease and two with dementia in an autosomal dominant pattern of inheritance. We excluded the involvement of the ALS and FTD-linked genes for copper/zinc superoxide dismutase (SOD1) and tau. The present study shows that mutations in DCTN1 may result in a wider range of phenotypes than has been previously appreciated. In this case, mutations in DCTN1 may predispose different neuron types to degeneration and then other genetic or external factors are required to produce the variable clinical phenotype. Taken together, our findings contribute to the current concept that familial FTD and ALS represent complex diseases, in which modifying genes and environmental agents can contribute to the risk of disease.

A heterozygous R1101K mutation of the p150 subunit of dynactin (DCTN1) is reported in a family with amyotrophic lateral sclerosis (ALS) and co-occurrence of frontotemporal dementia (FTD). Two members of our kindred were affected with motor neuron disease and two with dementia in an autosomal dominant pattern of inheritance. We excluded the involvement of the ALS and FTD-linked genes for copper/zinc superoxide dismutase (SOD1) and tau. The R1101K sequence alteration of the DCTN1 gene may predispose subjects to ALS and FTD.

Verschiedene Erkrankungen mit Affektion des ersten und zweiten motorischen Neurons zeigen eine selektive Vulnerabilität motorischer Nervenzellen. Ein allgemein gültiger Pathomechanismus ist bislang nicht bekannt, wohl aber scheint der axonale Transport eine nicht unwichtige Rolle zu spielen. Genetische Abnormitäten in Proteinen, die im axonalen Transport entscheidende Funktionen einnehmen, können die Grundlage definierter Motoneuronerkrankungen wie z.B. Varianten der hereditären spastischen Spinalparalyse oder auch der Amyotrophen Lateralsklerose (ALS) sein. Über Ergebnisse aus Tiermodellstudien zum axonalen Transport kristallisierten sich genetische Veränderungen des Multiproteinkomplexes Dynactin als Suszeptibilitätsfaktor bzw. Kandidaten für das Entstehen einer motorischen Systemdegeneration heraus. Ausgehend von Einzelfallberichten von Patienten mit Motoneuronerkrankungen untersuchten wir die p150 Untereinheit des Dynactin 1-Gens (DCTN1) in 552 Motoneuronpatienten. Dabei fanden wir verschiedene missense-Mutationen in Exon 7, 13, 15, 20, 27 und 31 sowie Mutationen im Intron 2 und 28, die zu Veränderungen beim Splicing der DCTN1-prä-mRNA führten. Alle Veränderungen wurden im gleichzeitig analysierten Normalpersonenkollektiv (n=160) nicht gefunden. Zudem wurde eine Mutation im Exon13 detektiert, die auch bei Normalpersonen zu finden war und somit möglicherweise einen Polymorphismus darstellt.