Objective Elevated levels of neurofilament light (NfL) and heavy (NfH) chain in amyotrophic lateral sclerosis (ALS) cerebrospinal fluid (CSF) and serum reflect neuro-axonal degeneration and are used as diagnostic biomarkers. However, studies comparing the differential diagnostic potential for ALS of all four parameters are missing. Here, we measured serum NfL/NfH and CSF NfL/NfH in a large cohort of ALS and other neurological disorders and analysed the differential diagnostic potential. Methods In total CSF and serum of 294 patients were analysed. The diagnostic groups comprised: ALS (n=75), frontotemporal lobar degeneration (FTLD) (n=33), Alzheimer’s disease (n=20), Parkinson’s disease (dementia) (n=18), Creutzfeldt-Jakob disease (n=11), non-neurodegenerative controls (n=77) (Con) and 60 patients who were seen under the direct differential diagnosis of a patient with ALS (Con.DD). Results CSF and serum NfL and NfH showed significantly increased levels in ALS (p<0.0001) compared with Con and Con.DD. The difference between ALS and FTLD was markedly stronger for NfH than for NfL. CSF and serum NfL demonstrated a stronger correlation (r=0.84 (95% CI 0.80 to 0.87), p<0.001) than CSF and serum NfH (r=0.68 (95% CI 0.61 to 0.75), p<0.0001). Comparing ALS and Con.DD, receiver operating characteristic analysis revealed the best area under the curve (AUC) value for CSF NfL (AUC=0.94, 95% CI 0.91 to 0.98), followed by CSF NfH (0.93, 95% CI 0.88 to 0.98), serum NfL (0.93, 95% CI 0.89 to 0.97) and serum NfH (0.88, 95% CI 0.82 to 0.94). Conclusion Our results demonstrate that CSF NfL and NfH as well as serum NfL are equally suited for the differential diagnosis of ALS, whereas serum NfH appears to be slightly less potent.

Objective: Neurofilament light chains (NfL) and phosphorylated neurofilament heavy chains (pNfH), established as diagnostic and prognostic biomarkers in hospital‐based amyotrophic lateral sclerosis (ALS) cohorts, are now surrogate markers in clinical trials. This study extends their evaluation to a population level, with the aim of advancing their full establishment and assessing the transferability of biomarker findings from controlled cohorts to real‐world ALS populations.Methods: We measured serum NfL and pNfH levels in all ALS patients (n = 790) and general population controls (n = 570) with available baseline samples participating in the epidemiological ALS Registry Swabia, providing platform‐specific (ELLA™) reference data and Z‐scores for controls, as well as reference data, disease‐specific Z‐scores and longitudinal data in ALS. We evaluated the diagnostic and prognostic utility of neurofilaments and quantified the impact of ALS‐related factors and non‐ALS confounders.Results: Neurofilaments showed high diagnostic and prognostic utility at the population level, with NfL superior to pNfH. The novel concept of a population‐based ALS Z‐score significantly improved the prognostic utility compared to absolute raw values. Both biomarkers increased more strongly with age in controls than in ALS, and age adjustment improved diagnostic accuracy. Our data show that disease progression rates, ALS phenotype, body mass index (BMI), and renal function need to be considered when interpreting neurofilament levels; longitudinal neurofilament levels were generally stable in individual patients, especially when adjusted for age and baseline levels.Interpretation: Population‐based assessment enhances the utility of particularly serum NfL as a diagnostic and prognostic biomarker in ALS and improves the translation of findings from controlled cohorts to real‐world populations. ANN NEUROL 2024;96:1040–1057

The social and medical impact of rare diseases is increasingly recognized. Amyotrophic lateral sclerosis (ALS) is the most prevalent of the motor neuron diseases. It is characterized by rapidly progressive damage to the motor neurons with a survival of 2–5 years for the majority of patients. The objective of this work is to describe the study protocol and the implementation steps of the amyotrophic lateral sclerosis (ALS) registry Swabia, located in the South of Germany.

The objective of this study was to investigate the potential involvement of cardiac structure and function by cardiac magnetic resonance (CMR) imaging in amyotrophic lateral sclerosis (ALS) patients. Our study included 35 patients with ALS without a history of cardiac disease and an age and gender matched healthy control group (n=34). All subjects received a CMR in a 1.5T whole-body scanner. Patients were also screened with Holter monitoring, echocardiography and a blood test of cardiac markers. Myocardial mass in ALS hearts were reduced compared to the control group, and ejection volumes in the left and right heart were severely decreased in ALS patients, as shown by echocardiography and CMR. The myocardium showed increased T1 enhancement in 77% of the patients compared to 27% of controls (p=0.0001). A trend towards late gadolinium enhancement patterns consistent with myocardial fibrosis was observed in 23.5% of the patients (9.1% of controls). Holter monitoring was normal in all patients as well as troponin T. Cardiac involvement seems to be present in ALS patients without clinical cardiac symptoms and with a normal cardiac routine assessment. Structural myocardial defects in CMR may be due to sympathetic dysfunction and may account for reported cardiac deaths in late-stage ALS patients.

Background and Objectives: Whether physical activity (PA) is a risk factor for amyotrophic lateral sclerosis (ALS) is controversial since data on life-long PA are rare. The main objective of this study is to provide insight in PA as a potential risk factor for ALS, reporting data on cumulative PA, leisure time PA and occupational PA. This study also aims at gathering evidence on the role of PA as a prognostic factor in disease course. Methods: Lifetime PA values collected by questionnaires addressing work and leisure time were quantified into metabolic equivalents (MET). A population-based case-control study embedded in the ALS Registry Swabia served to calculate odds ratio (OR) of ALS by PA in different time intervals and prognosis. Results: In ALS cases (393 cases, 791 age- and sex-matched controls), we observed reduced total PA at interview and up to 5 years before interview compared to controls. Total PA was not associated with ALS risk 5-55 years before interview. Heavy occupational work intensity was associated with increased ALS risk (OR=1.97, 95%-CI (1.34, 2.89)). Total PA levels were associated with survival in a nonlinear manner: inactive patients and highest activity levels (25 METh/week) revealed the worst survival time of 15.4/19.3 months, respectively. Best median survival with 29.8 months was seen at 10.5 METh/week after adjusting for other prognostic factors. Discussion: Lifetime combined PA sharply decreased several years before disease onset compared to controls. The risk of developing ALS was not associated with former total PA levels 5-55 years before interview in contrast to occupational PA, probably reflecting work associated exposures. We found a strong nonlinear association of current and pre-diagnostic PA level and survival in ALS cases with the best survival with moderate PA. PA intensity may be a disease modifying factor with an unfavourable outcome in sedentary and hyperactive behaviour. Classification of evidence: This study provides Class III evidence that physical activity was not associated with the development of ALS.

Background: Cardiac involvement has been described in idiopathic inflammatory myopathies (IIM), including non-specific ECG and echocardiographic findings. Aim of our study was to evaluate myocardial deformation parameters in IIM and to correlate them with late gadolinium enhancement (LGE) findings using cardiac magnetic resonance imaging (CMR). Methods: Forty-seven consecutive patients with histologically proven IIM were included into our study. Twenty-five healthy volunteers were used as a control group. All patients and controls underwent CMR examination using a 1.5 T scanner including functional cine and LGE imaging. After a mean follow-up of 234.7 ± 79.5 days a second CMR examination was performed in IIM patients. Results: In comparison to healthy volunteers, IIM patients had lower left ventricular mass and left ventricular global radial, circumferential and longitudinal strain. There was no significant difference in left ventricular ejection fraction. Patients with LGE (N = 28) had lower left ventricular ejection fraction (p = 0.016), global right and left ventricular longitudinal strain (p = 0.014 and p = 0.005) and global left ventricular diastolic longitudinal strain rate (p = 0.001) compared to patients without LGE (N = 19). In IIM patients, a significant decrease of left ventricular ejection fraction, left ventricular mass and all measured deformation parameters was observed between baseline and follow-up CMR. Conclusion: Cardiac involvement in IIM is frequent. Impairment of systolic and diastolic deformation parameters and a worsening over time can be observed. CMR is a useful tool for cardiac diagnostic work-up of these patients.