Novel approaches to assessing upper motor neuron dysfunction in motor neuron disease/amyotrophic lateral sclerosis: IFCN handbook chapter.

Identifying upper motor neuron (UMN) dysfunction is fundamental to the diagnosis and understanding of disease pathogenesis in motor neuron disease (MND). The clinical assessment of UMN dysfunction may be difficult, particularly in the setting of severe muscle weakness. From a physiological perspective, transcranial magnetic stimulation (TMS) techniques provide objective biomarkers of UMN dysfunction in MND and may also be useful to interrogate cortical and network function. Single, paired- and triple pulse TMS techniques have yielded novel diagnostic and prognostic biomarkers in MND, and have provided important pathogenic insights, particularly pertaining to site of disease onset. Cortical hyperexcitability, as heralded by reduced short interval intracortical inhibition (SICI) and increased short interval intracortical facilitation, has been associated with the onset of lower motor neuron degeneration, along with patterns of disease spread, development of specific clinical features such as the split hand phenomenon, and may provide an indication about the rate of disease progression. Additionally, reduction of SICI has emerged as a potential diagnostic aid in MND. The triple stimulation technique (TST) was shown to enhance the diagnostic utility of conventional TMS measures in detecting UMN dysfunction in MND. Separately, sophisticated brain imaging techniques have uncovered novel biomarkers of neurodegeneration that have bene associated with progression. The present review will discuss the utility of TMS and brain neuroimaging derived biomarkers of UMN dysfunction in MND, focusing on recently developed TMS techniques and advanced neuroimaging modalities that interrogate structural and functional integrity of the corticomotoneuronal system, with an emphasis on pathogenic, diagnostic, and prognostic utility.

The ALSFRS-R Summit: a global call to action on the use of the ALSFRS-R in ALS clinical trials.

The Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) was developed more than 25 years ago as an instrument to monitor functional change over time in patients with ALS. It has since been revised and extended to meet the needs of high data quality in ALS trials (ALSFRS-R), however a full re-validation of the scale was not completed. Despite this, the scale has remained a primary outcome measure in clinical trials. We convened a group of clinical trialists to discuss and explore opportunities to improve the scale and propose alternative measures. In this meeting report, we present a call to action on the use of the ALSFRS-Revised scale in clinical trials, focusing on the need for (1) harmonization of the ALSFRS-R administration globally, (2) alignment on a set of recommendations for clinical trial design and statistical analysis plans (SAPs), and (3) use of additional outcome measures.

Effects of tofersen treatment in patients with SOD1-ALS in a "real-world" setting - a 12-month multicenter cohort study from the German early access program.

Background: In April 2023, the antisense oligonucleotide tofersen was approved by the U.S. Food and Drug Administration (FDA) for treatment of SOD1-amyotrophic lateral sclerosis (ALS), after a decrease of neurofilament light chain (NfL) levels had been demonstrated. Methods: Between 03/2022 and 04/2023, 24 patients with SOD1-ALS from ten German ALS reference centers were followed-up until the cut-off date for ALS functional rating scale revised (ALSFRS-R), progression rate (loss of ALSFRS-R/month), NfL, phosphorylated neurofilament heavy chain (pNfH) in cerebrospinal fluid (CSF), and adverse events. Findings: During the observation period, median ALSFRS-R decreased from 38.0 (IQR 32.0-42.0) to 35.0 (IQR 29.0-42.0), corresponding to a median progression rate of 0.11 (IQR -0.09 to 0.32) points of ALSFRS-R lost per month. Median serum NfL declined from 78.0 pg/ml (IQR 37.0-147.0 pg/ml; n = 23) to 36.0 pg/ml (IQR 22.0-65.0 pg/ml; n = 23; p = 0.02), median pNfH in CSF from 2226 pg/ml (IQR 1061-6138 pg/ml; n = 18) to 1151 pg/ml (IQR 521-2360 pg/ml; n = 18; p = 0.02). In the CSF, we detected a pleocytosis in 73% of patients (11 of 15) and an intrathecal immunoglobulin synthesis (IgG, IgM, or IgA) in 9 out of 10 patients. Two drug-related serious adverse events were reported. Interpretation: Consistent with the VALOR study and its Open Label Extension (OLE), our results confirm a reduction of NfL serum levels, and moreover show a reduction of pNfH in CSF. The therapy was safe, as no persistent symptoms were observed. Pleocytosis and Ig synthesis in CSF with clinical symptoms related to myeloradiculitis in two patients, indicate the potential of an autoimmune reaction. Funding: No funding was received towards this study.

In-depth analysis of data from the RAS-ALS study reveals new insights in rasagiline treatment for amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: In 2016, we concluded a randomized controlled trial testing 1 mg rasagiline per day add-on to standard therapy in 252 amyotrophic lateral sclerosis (ALS) patients. This article aims at better characterizing ALS patients who could possibly benefit from rasagiline by reporting new subgroup analysis and genetic data. METHODS: We performed further exploratory in-depth analyses of the study population and investigated the relevance of single nucleotide polymorphisms (SNPs) related to the dopaminergic system. RESULTS: Placebo-treated patients with very slow disease progression (loss of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised [ALSFRS-R] per month before randomization of ≤0.328 points) showed a per se survival probability after 24 months of 0.85 (95% confidence interval = 0.65-0.94). The large group of intermediate to fast progressing ALS patients showed a prolonged survival in the rasagiline group compared to placebo after 6 and 12 months (p = 0.02, p = 0.04), and a reduced decline of ALSFRS-R after 18 months (p = 0.049). SNP genotypes in the MAOB gene and DRD2 gene did not show clear associations with rasagiline treatment effects. CONCLUSIONS: These results underline the need to consider individual disease progression at baseline in future ALS studies. Very slow disease progressors compromise the statistical power of studies with treatment durations of 12-18 months using clinical endpoints. Analysis of MAOB and DRD2 SNPs revealed no clear relationship to any outcome parameter. More insights are expected from future studies elucidating whether patients with DRD2CC genotype (Rs2283265) show a pronounced benefit from treatment with rasagiline, pointing to the opportunities precision medicine could open up for ALS patients in the future.

Impairment of oculomotor functions in patients with early to advanced amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) can result into an incomplete locked in state (iLIS), in which communication depends on eye tracking computer devices. Oculomotor function impairments in ALS have been reported, but there is little research, particularly with respect to patients in iLIS. In the present study, we compared reflexive and executive oculomotor function by means of an eye tracking test battery between three groups: advanced ALS patients in iLIS (n = 22), patients in early to middle ALS stages (n = 44) and healthy subjects (n = 32). Patients with ALS showed significant deteriorations in oculomotor functions, with stronger impairments in iLIS. More specifically, ALS patients produced visually guided prosaccades with longer latencies and more frequent hypometria compared to healthy subjects. Longest latencies were obtained in iLIS patients, with a stronger prolongation for vertical than for horizontal prosaccades. ALS patients made more antisaccade errors and generated antisaccades with longer latencies. Smooth pursuit was also impaired in ALS. In the earlier ALS stages, bulbar onset patients presented stronger antisaccade and smooth pursuit deficits than spinal onset patients. Our findings reveal a relevant deterioration of important oculomotor functions in ALS, which increases in iLIS. It includes impairments of reflexive eye movements to loss of executive inhibitory control, indicating a progressing pathological involvement of prefrontal, midbrain and brainstem areas. The assessment of oculomotor functions may therefore provide clinically relevant bio- and progression marker, particularly in advanced ALS.

Cluster Analysis to Explore Clinical Subphenotypes of Eosinophilic Granulomatosis With Polyangiitis.

OBJECTIVE: Previous studies suggested that distinct phenotypes of eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg-Strauss syndrome) could be determined by the presence or absence of antineutrophil cytoplasmic antibodies (ANCA), reflecting predominant vasculitic or eosinophilic processes, respectively. This study explored whether ANCA-based clusters or other clusters can be identified in EGPA. METHODS: This study used standardized data of 15 European centers for patients with EGPA fulfilling widely accepted classification criteria. We used multiple correspondence analysis, hierarchical cluster analysis, and a decision tree model. The main model included 10 clinical variables (musculoskeletal [MSK], mucocutaneous, ophthalmological, ENT, cardiovascular, pulmonary, gastrointestinal, renal, central, or peripheral neurological involvement); a second model also included ANCA results. RESULTS: The analyses included 489 patients diagnosed between 1984 and 2015. ANCA were detected in 37.2% of patients, mostly perinuclear ANCA (85.4%) and/or antimyeloperoxidase (87%). Compared with ANCA-negative patients, those with ANCA had more renal (P < 0.001) and peripheral neurological involvement (P = 0.04), fewer cardiovascular signs (P < 0.001), and fewer biopsies with eosinophilic tissue infiltrates (P = 0.001). The cluster analyses generated 4 (model without ANCA) and 5 clusters (model with ANCA). Both models identified 3 identical clusters of 34, 39, and 40 patients according to the presence or absence of ENT, central nervous system, and ophthalmological involvement. Peripheral neurological and cardiovascular involvement were not predictive characteristics. CONCLUSION: Although reinforcing the known association of ANCA status with clinical manifestations, cluster analysis does not support a complete separation of EGPA in ANCA-positive and -negative subsets. Collectively, these data indicate that EGPA should be regarded as a phenotypic spectrum rather than a dichotomous disease.

Amyotrophic Lateral Sclerosis: Advances and Prospects.

The JCM Topical Collection "Amyotrophic Lateral Sclerosis: Latest Advances and Prospects" started in 2020 and currently includes 11 publications reflecting a broad range of clinical research areas in the ALS field [...].

Guideline "Motor neuron diseases" of the German Society of Neurology (Deutsche Gesellschaft für Neurologie).

INTRODUCTION: In 2021, the Deutsche Gesellschaft für Neurology published a new guideline on diagnosis and therapy of motor neuron disorders. Motor neuron disorders affect upper motor neurons in the primary motor cortex and/or lower motor neurons in the brain stem and spinal cord. The most frequent motor neuron disease amyotrophic lateral sclerosis (ALS) is a rapidly progressive disease with an average life expectancy of 2-4 years with a yearly incidence of 3.1/100,000 in Central Europe (Rosenbohm et al. in J Neurol 264(4):749-757, 2017. https://doi.org/10.1007/s00415-017-8413-3 ). It is considered a rare disease mainly due to its low prevalence as a consequence of short disease duration. RECOMMENDATIONS: These guidelines comprise recommendations regarding differential diagnosis, neuroprotective therapies and multidisciplinary palliative care including management of respiration and nutrition as well as provision of assistive devices and end-of-life situations. CONCLUSION: Diagnostic and therapeutic guidelines are necessary due the comparatively high number of cases and the aggressive disease course. Given the low prevalence and the severe impairment of patients, it is often impossible to generate evidence-based data so that ALS guidelines are partially dependent on expert opinion.

Spectrum and frequency of genetic variants in sporadic amyotrophic lateral sclerosis.

Therapy of motoneuron diseases entered a new phase with the use of intrathecal antisense oligonucleotide therapies treating patients with specific gene mutations predominantly in the context of familial amyotrophic lateral sclerosis. With the majority of cases being sporadic, we conducted a cohort study to describe the mutational landscape of sporadic amyotrophic lateral sclerosis. We analysed genetic variants in amyotrophic lateral sclerosis-associated genes to assess and potentially increase the number of patients eligible for gene-specific therapies. We screened 2340 sporadic amyotrophic lateral sclerosis patients from the German Network for motor neuron diseases for variants in 36 amyotrophic lateral sclerosis-associated genes using targeted next-generation sequencing and for the C9orf72 hexanucleotide repeat expansion. The genetic analysis could be completed on 2267 patients. Clinical data included age at onset, disease progression rate and survival. In this study, we found 79 likely pathogenic Class 4 variants and 10 pathogenic Class 5 variants (without the C9orf72 hexanucleotide repeat expansion) according to the American College of Medical Genetics and Genomics guidelines, of which 31 variants are novel. Thus, including C9orf72 hexanucleotide repeat expansion, Class 4, and Class 5 variants, 296 patients, corresponding to ∼13% of our cohort, could be genetically resolved. We detected 437 variants of unknown significance of which 103 are novel. Corroborating the theory of oligogenic causation in amyotrophic lateral sclerosis, we found a co-occurrence of pathogenic variants in 10 patients (0.4%) with 7 being C9orf72 hexanucleotide repeat expansion carriers. In a gene-wise survival analysis, we found a higher hazard ratio of 1.47 (95% confidence interval 1.02-2.1) for death from any cause for patients with the C9orf72 hexanucleotide repeat expansion and a lower hazard ratio of 0.33 (95% confidence interval 0.12-0.9) for patients with pathogenic SOD1 variants than for patients without a causal gene mutation. In summary, the high yield of 296 patients (∼13%) harbouring a pathogenic variant and oncoming gene-specific therapies for SOD1/FUS/C9orf72, which would apply to 227 patients (∼10%) in this cohort, corroborates that genetic testing should be made available to all sporadic amyotrophic lateral sclerosis patients after respective counselling.

Safety and efficacy of rozanolixizumab in patients with generalised myasthenia gravis (MycarinG): a randomised, double-blind, placebo-controlled, adaptive phase 3 study.

BACKGROUND: Generalised myasthenia gravis is a chronic, unpredictable, and debilitating autoimmune disease. New treatments for this disease are needed because conventional therapies have limitations, such as side-effects (eg, increased infection risk) or inadequate control of symptoms. Rozanolixizumab is a neonatal Fc receptor blocker that might provide a novel therapeutic option for myasthenia gravis. We aimed to assess the safety and efficacy of rozanolixizumab for generalised myasthenia gravis. METHODS: MycarinG is a randomised, double-blind, placebo-controlled, adaptive phase 3 study done at 81 outpatient centres and hospitals in Asia, Europe, and North America. We enrolled patients (aged ≥18 years) with acetylcholine receptor (AChR) or muscle-specific kinase (MuSK) autoantibody-positive generalised myasthenia gravis (Myasthenia Gravis Foundation of America class II-IVa), a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 3 (non-ocular symptoms), and a quantitative myasthenia gravis score of at least 11. Patients were randomly assigned (1:1:1) to receive subcutaneous infusions once a week for 6 weeks of either rozanolixizumab 7 mg/kg, rozanolixizumab 10 mg/kg, or placebo. Randomisation was stratified by AChR and MuSK autoantibody status. Investigators, patients, and people assessing outcomes were masked to random assignments. The primary efficacy endpoint was change from baseline to day 43 in MG-ADL score, assessed in the intention-to-treat population. Treatment-emergent adverse events (TEAEs) were assessed in all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03971422) and EudraCT (2019-000968-18); an open-label extension study has been completed (NCT04124965; EudraCT 2019-000969-21) and another is underway (NCT04650854; EudraCT 2020-003230-20). FINDINGS: Between June 3, 2019, and June 30, 2021, 300 patients were assessed for eligibility, of whom 200 were enrolled. 66 (33%) were randomly assigned to rozanolixizumab 7 mg/kg, 67 (34%) to rozanolixizumab 10 mg/kg, and 67 (34%) to placebo. Reductions in MG-ADL score from baseline to day 43 were greater in the rozanolixizumab 7 mg/kg group (least-squares mean change -3·37 [SE 0·49]) and in the rozanolixizumab 10 mg/kg group (-3·40 [0·49]) than with placebo (-0·78 [0·49]; for 7 mg/kg, least-squares mean difference -2·59 [95% CI -4·09 to -1·25], p<0·0001; for 10 mg/kg, -2·62 [-3·99 to -1·16], p<0·0001). TEAEs were experienced by 52 (81%) of 64 patients treated with rozanolixizumab 7 mg/kg, 57 (83%) of 69 treated with rozanolixizumab 10 mg/kg, and 45 (67%) of 67 treated with placebo. The most frequent TEAEs were headache (29 [45%] patients in the rozanolixizumab 7 mg/kg group, 26 [38%] in the rozanolixizumab 10 mg/kg group, and 13 [19%] in the placebo group), diarrhoea (16 [25%], 11 [16%], and nine [13%]), and pyrexia (eight [13%], 14 [20%], and one [1%]). Five (8%) patients in the rozanolixizumab 7 mg/kg group, seven (10%) in the rozanolixizumab 10 mg/kg group, and six (9%) in the placebo group had a serious TEAE. No deaths occurred. INTERPRETATION: Rozanolixizumab showed clinically meaningful improvements in patient-reported and investigator-assessed outcomes in patients with generalised myasthenia gravis, for both 7 mg/kg and 10 mg/kg doses. Both doses were generally well tolerated. These findings support the mechanism of action of neonatal Fc receptor inhibition in generalised myasthenia gravis. Rozanolixizumab represents a potential additional treatment option for patients with generalised myasthenia gravis. FUNDING: UCB Pharma.

Clinical and genetic features of amyotrophic lateral sclerosis patients with C9orf72 mutations.

An expansion of the GGGGCC hexanucleotide in the non-coding region of C9orf72 represents the most common cause of familial amyotrophic lateral sclerosis. The objective was to describe and analyse the clinical and genetic features of amyotrophic lateral sclerosis patients with C9orf72 mutations in a large population. Between November 2011 and December 2020, clinical and genetic characteristics of n = 248 patients with amyotrophic lateral sclerosis carrying C9orf72 mutations were collected from the clinical and scientific network of German motoneuron disease centres. Clinical parameters included age of onset, diagnostic delay, family history, neuropsychological examination, progression rate, phosphorylated neurofilament heavy chain levels in CSF and survival. The number of repeats was correlated with the clinical phenotype. The clinical phenotype was compared to n = 84 patients with SOD1 mutations and n = 2178 sporadic patients without any known disease-related mutations. Patients with C9orf72 featured an almost balanced sex ratio with 48.4% (n = 120) women and 51.6% (n = 128) men. The rate of 33.9% patients (n = 63) with bulbar onset was significantly higher compared to sporadic (23.4%, P = 0.002) and SOD1 patients (3.1%, P < 0.001). Of note, 56.3% (n = 138) of C9orf72, but only 16.1% of SOD1 patients reported a negative family history (P < 0.001). The GGGGCC hexanucleotide repeat length did not influence the clinical phenotypes. Age of onset (58.0, interquartile range 52.0-63.8) was later compared to SOD1 (50.0, interquartile range 41.0-58.0; P < 0.001), but earlier compared to sporadic patients (61.0, interquartile range 52.0-69.0; P = 0.01). Median survival was shorter (38.0 months) compared to SOD1 (198.0 months, hazard ratio 1.97, 95% confidence interval 1.34-2.88; P < 0.001) and sporadic patients (76.0 months, hazard ratio 2.34, 95% confidence interval 1.64-3.34; P < 0.001). Phosphorylated neurofilament heavy chain levels in CSF (2880, interquartile range 1632-4638 pg/ml) were higher compared to sporadic patients (1382, interquartile range 458-2839 pg/ml; P < 0.001). In neuropsychological screening, C9orf72 patients displayed abnormal results in memory, verbal fluency and executive functions, showing generally worse performances compared to SOD1 and sporadic patients and a higher share with suspected frontotemporal dementia. In summary, clinical features of patients with C9orf72 mutations differ significantly from SOD1 and sporadic patients. Specifically, they feature a more frequent bulbar onset, a higher share of female patients and shorter survival. Interestingly, we found a high proportion of patients with negative family history and no evidence of a relationship between repeat lengths and disease severity.

Motor unit number index (MUNIX) loss of 50% occurs in half the time of 50% functional loss according to the D50 disease progression model of ALS.

Capturing disease progression in amyotrophic lateral sclerosis (ALS) is challenging and refinement of progression markers is urgently needed. This study introduces new motor unit number index (MUNIX), motor unit size index (MUSIX) and compound muscle action potential (CMAP) parameters called M50, MUSIX200 and CMAP50. M50 and CMAP50 indicate the time in months from symptom onset an ALS patient needs to lose 50% of MUNIX or CMAP in relation to the mean values of controls. MUSIX200 represents the time in months until doubling of the mean MUSIX of controls. We used MUNIX parameters of Musculi abductor pollicis brevis (APB), abductor digiti minimi (ADM) and tibialis anterior (TA) of 222 ALS patients. Embedded in the D50 disease progression model, disease aggressiveness and accumulation were analyzed separately. M50, CMAP50 and MUSIX200 significantly differed among disease aggressiveness subgroups (p < 0.001) regardless of disease accumulation. ALS patients with a low M50 had a significantly shorter survival compared to high M50 (median 32 versus 74 months). M50 preceded the loss of global function (median of about 14 months). M50, CMAP50 and MUSIX200 characterize the disease course in ALS in a new way and may be applied as early measures of disease progression.

Association of the practice of contact sports with the development of amyotrophic lateral sclerosis.

Objectives: High-intensity physical activity and sports prone to repetitive injuries of the cervical spine and head (when associated with vigorous practice) have been suggested as possible risk factors for amyotrophic lateral sclerosis (ALS). Our objective was to evaluate the relationship between the practice of contact sports (boxing, hockey, football, rugby) and ALS. Methods: The study included 2247 individuals, 1326 patients and 921 controls from several European countries. Analysis of the effect of contact sports on ALS was conducted in male participants only, as very few women practiced contact sports. Logistic regression models were used with the response variable as the presence or absence of ALS, with α = 0.05 significance level. Results: A relationship between the practice of contact sports and ALS was found, with those practicing contact sports having 76% higher odds of an ALS diagnosis (OR = 1.76, p = 0.001). In addition, univariate analyses for age (higher risk for older people, p < 0.001), smoking status (higher risk for ex-smokers, p = 0.022) and tobacco exposure (higher risk for more exposure, p = 0.038) also indicated that these variables are risk factors for ALS. In multivariate models, in addition to age, the interaction term between practice of contact sports and tobacco exposure was still significant (p = 0.03). Conclusions: This is one of the largest studies on the role of contact sport in ALS development. Our results support the existence of a relationship between the practice of sports with repetitive trauma at the level of the cervical spine and head, and ALS. This risk appears to be enhanced by tobacco exposure.

Performance of serum neurofilament light chain in a wide spectrum of clinical courses of amyotrophic lateral sclerosis-a cross-sectional multicenter study.

BACKGROUND AND PURPOSE: The objective was to assess the performance of serum neurofilament light chain (sNfL) in amyotrophic lateral sclerosis (ALS) in a wide range of disease courses, in terms of progression, duration and tracheostomy invasive ventilation (TIV). METHODS: A prospective cross-sectional study at 12 ALS centers in Germany was performed. sNfL concentrations were age adjusted using sNfL Z scores expressing the number of standard deviations from the mean of a control reference database and correlated to ALS duration and ALS progression rate (ALS-PR), defined by the decline of the ALS Functional Rating Scale. RESULTS: In the total ALS cohort (n = 1378) the sNfL Z score was elevated (3.04; 2.46-3.43; 99.88th percentile). There was a strong correlation of sNfL Z score with ALS-PR (p < 0.001). In patients with long (5-10 years, n = 167) or very long ALS duration (>10 years, n = 94) the sNfL Z score was significantly lower compared to the typical ALS duration of <5 years (n = 1059) (p < 0.001). Furthermore, in patients with TIV, decreasing sNfL Z scores were found in correlation with TIV duration and ALS-PR (p = 0.002; p < 0.001). CONCLUSIONS: The finding of moderate sNfL elevation in patients with long ALS duration underlined the favorable prognosis of low sNfL. The strong correlation of sNfL Z score with ALS-PR strengthened its value as progression marker in clinical management and research. The lowering of sNfL in correlation with long TIV duration could reflect a reduction either in disease activity or in the neuroaxonal substrate of biomarker formation during the protracted course of ALS.

Remote digital assessment of amyotrophic lateral sclerosis functional rating scale - a multicenter observational study.

OBJECTIVE: Remote self-assessment of the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) using digital data capture was investigated for its feasibility as an add-on to ALSFRS-R assessments during multidisciplinary clinic visits. METHODS: From August 2017 to December 2021, at 12 ALS centers in Germany, an observational study on remote assessment of the ALSFRS-R was performed. In addition to the assessment of ALSFRS-R during clinic visits, patients were offered a digital self-assessment of the ALSFRS-R - either on a computer or on a mobile application ("ALS-App"). RESULTS: An estimated multicenter cohort of 4,670 ALS patients received care at participating ALS centers. Of these patients, 971 remotely submitted the ALSFRS-R, representing 21% of the multicenter cohort. Of those who opted for remote assessment, 53.7% (n = 521) completed a minimum of 4 ALSFRS-R per year with a mean number of 10.9 assessments per year. Different assessment frequencies were found for patients using a computer (7.9 per year, n = 857) and mobile app (14.6 per year, n = 234). Patients doing remote assessments were more likely to be male and less functionally impaired but many patients with severe disability managed to complete it themselves or with a caregiver (35% of remote ALSFRS-R cohort in King's Stage 4). CONCLUSIONS: In a dedicated ALS center setting remote digital self-assessment of ALSFRS-R can provide substantial data which is complementary and potentially an alternative to clinic assessments and could be used for research purposes and person-level patient management. Addressing barriers relating to patient uptake and adherence are key to its success.

ALSFRS-R-SE: an adapted, annotated, and self-explanatory version of the revised amyotrophic lateral sclerosis functional rating scale.

BACKGROUND: The ALS Functional Rating Scale in its revised version (ALSFRS-R) is a disease-specific severity score that reflects motor impairment and functional deterioration in people with amyotrophic lateral sclerosis (ALS). It has been widely applied in both clinical practice and ALS research. However, in Germany, several variants of the scale, each differing slightly from the others, have developed over time and are currently in circulation. This lack of uniformity potentially hampers data interpretation and may decrease item validity. Furthermore, shortcomings within the standard ALSFRS-R questions and answer options can limit the quality and conclusiveness of collected data. METHODS: In a multistage consensus-building process, 18 clinical ALS experts from the German ALS/MND network analyzed the ALSFRS-R in its current form and created an adapted, annotated, and revised scale that closely adheres to the well-established standardized English version. RESULTS: Ten German-language variants of the ALSFRS-R were collected, three of which contained instructions for self-assessment. All of these variants were compiled and a comprehensive linguistic revision was undertaken. A short introduction was added to the resulting scale, comprising general instructions for use and explanations for each of the five reply options per item. This adapted version of the scale, named ALSFRS-R-SE (with the "SE" referring to "self-explanatory"), was carefully reviewed for language and comprehensibility, in both German and English. CONCLUSION: An adapted and annotated version of the ALSFRS-R scale was developed through a multistage consensus process. The decision to include brief explanations of specific scale items and reply options was intended to facilitate ALSFRS-R-SE assessments by both healthcare professionals and patients. Further studies are required to investigate the accuracy and utility of the ALSFRS-R-SE in controlled trials and clinical real-world settings.

Data on medication adherence in adults with neurological disorders: The NeuroGerAd study.

Nonadherence to medication is a common issue that goes along with increased morbidity and mortality and immense health care costs. To improve medication adherence and outcome in ill people, their reasons of not taking their prescribed medication must be known. Here a dataset is presented based on the longitudinal observational NeuroGerAd study in adults with neurological disorders (N = 910). The dataset contains demographic background variables as well as measures of adherence, medication changes after hospital discharge, comprehensive geriatric assessments, personality, patient-physician relationship, and health-related quality of life. As such, the dataset offers unique opportunities to enable a plethora of analyses on personal, social, and institutional factors influencing medication adherence.

Age-dependent increase of cytoskeletal components in sensory axons in human skin.

Aging is a complex process characterized by several molecular and cellular imbalances. The composition and stability of the neuronal cytoskeleton is essential for the maintenance of homeostasis, especially in long neurites. Using human skin biopsies containing sensory axons from a cohort of healthy individuals, we investigate alterations in cytoskeletal content and sensory axon caliber during aging via quantitative immunostainings. Cytoskeletal components show an increase with aging in both sexes, while elevation in axon diameter is only evident in males. Transcriptomic data from aging males illustrate various patterns in gene expression during aging. Together, the data suggest gender-specific changes during aging in peripheral sensory axons, possibly influencing cytoskeletal functionality and axonal caliber. These changes may cumulatively increase susceptibility of aged individuals to neurodegenerative diseases.

Cortical and subcortical grey matter atrophy in Amyotrophic Lateral Sclerosis correlates with measures of disease accumulation independent of disease aggressiveness.

There is a growing demand for reliable biomarkers to monitor disease progression in Amyotrophic Lateral Sclerosis (ALS) that also take the heterogeneity of ALS into account. In this study, we explored the association between Magnetic Resonance Imaging (MRI)-derived measures of cortical thickness (CT) and subcortical grey matter (GM) volume with D50 model parameters. T1-weighted MRI images of 72 Healthy Controls (HC) and 100 patients with ALS were analyzed using Surface-based Morphometry for cortical structures and Voxel-based Morphometry for subcortical Region-Of-Interest analyses using the Computational Anatomy Toolbox (CAT12). In Inter-group contrasts, these parameters were compared between patients and HC. Further, the D50 model was used to conduct subgroup-analyses, dividing patients by a) Phase of disease covered at the time of MRI-scan and b) individual overall disease aggressiveness. Finally, correlations between GM and D50 model-derived parameters were examined. Inter-group analyses revealed ALS-related cortical thinning compared to HC located mainly in frontotemporal regions and a decrease in GM volume in the left hippocampus and amygdala. A comparison of patients in different phases showed further cortical and subcortical GM atrophy along with disease progression. Correspondingly, regression analyses identified negative correlations between cortical thickness and individual disease covered. However, there were no differences in CT and subcortical GM between patients with low and high disease aggressiveness. By application of the D50 model, we identified correlations between cortical and subcortical GM atrophy and ALS-related functional disability, but not with disease aggressiveness. This qualifies CT and subcortical GM volume as biomarkers representing individual disease covered to monitor therapeutic interventions in ALS.