Objective To identify preferred neurofilament assays and clinically validate serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) as prognostic and potential pharmacodynamic biomarkers relevant to amyotrophic lateral sclerosis (ALS) therapy development. Methods In this prospective, multicenter, longitudinal observational study of patients with ALS (n = 229), primary lateral sclerosis (n = 20), and progressive muscular atrophy (n = 11), biological specimens were collected, processed, and stored according to strict standard operating procedures (SOPs). Neurofilament assays were performed in a blinded manner by independent contract research organizations. Results For serum NfL and pNfH measured using the Simoa assay, there were no missing data (i.e., technical replicates below the lower limit of detection were not encountered). For the Iron Horse and Euroimmun pNfH assays, such missingness was encountered in ∼4% and ∼10% of serum samples, respectively. Mean coefficients of variation for NfL in serum and CSF were both ∼3%. Mean coefficients of variation for pNfH in serum and CSF were ∼4%–5% and ∼2%–3%, respectively, in all assays. Baseline serum NfL concentration, but not pNfH, predicted the future Revised ALS Functional Rating Scale (ALSFRS-R) slope and survival. Incorporation of baseline serum NfL into mixed effects models of ALSFRS-R slopes yields an estimated sample size saving of ∼8%. Depending on the method used to estimate effect size, use of serum NfL (and perhaps pNfH) as pharmacodynamic biomarkers, instead of the ALSFRS-R slope, yields significantly larger sample size savings. Conclusions Serum NfL may be considered a clinically validated prognostic biomarker for ALS. Serum NfL (and perhaps pNfH), quantified using the Simoa assay, has potential utility as a pharmacodynamic biomarker of treatment effect.

Amyotrophic lateral sclerosis (ALS) is a progressive, degenerative neuromuscular disease with limited treatment options. The diagnosis of ALS can be challenging for numerous reasons, resulting in delays that may compromise optimal management and enrollment into clinical trials. Several studies have examined the process and challenges regarding the clinical diagnosis of ALS. Twenty-one studies that were almost exclusively from the English literature published between 1990 and 2020 were identified via PubMed using relevant search terms and included patient populations from the United States, Canada, Japan, Egypt, and several countries in South America and Europe. Probable or definitive ALS patients were identified using El Escorial or revised El Escorial/Airlie House Criteria. Time to diagnosis or diagnostic delay was defined as mean or median time from patient-reported first symptom onset to formal diagnosis by a physician, as recorded in medical records. The typical time to diagnosis was 10-16 months from symptom onset. Several points of delay in the diagnosis course were identified, including specialist referrals and misdiagnoses, often resulting in unnecessary procedures and surgeries. Bulbar onset was noted to significantly reduce time to ALS diagnosis. Future interventions and potential research opportunities were reviewed.

To compare the effect of riluzole on median survival in population studies of patients with amyotrophic lateral sclerosis (ALS) with that observed in clinical trials. Methods: Two independent PubMe...

Objective: To determine whether short echo-time (TE) proton magnetic resonance spectroscopic imaging (¹H-MRSI) can detect in vivo differences in signal intensities of specific metabolites in the medulla of patients with ALS compared with healthy individuals and whether these metabolites could be useful surrogate markers of disease. Background: ¹H-MRSI can detect N-acetylaspartate +N-acetylaspartylglutamate (abbreviated NAx), which is localized to neurons, and glutamate (Glu) + glutamine (Gln), abbreviated Glx, which may be important in ALS pathogenesis. The medulla is an ideal region to study ALS because of its high density of nuclei and fiber tracts that frequently undergo degeneration, even when more rostral brain regions show minimal pathology. Methods: Ten patients with ALS and seven healthy control subjects underwent short TE ¹H-MRSI on a 1.5 T clinical imaging system. Signal intensities of NAx and Glx were normalized to creatine–phosphocreatine and compared between groups. Results: Compared with normal subjects, the medulla of patients with ALS had 17% lower NAx (p = 0.03) and 55% higher Glx (p = 0.02) signals. Bulbar symptoms, represented by the ALS Functional Rating Scale, correlated with Glx (r = −0.68, p = 0.03) but not NAx (r = 0.22, p = 0.53). Conclusion: There is in vivo ¹H-MRSI evidence of neuronal degeneration or loss and excess Glu + Gln in the medulla of patients with ALS. Although this cross-sectional study cannot identify which change occurred first, the higher Glx signal in the medulla of patients with more dysarthria and dysphagia is consistent with the hypothesis of Glu excitotoxicity in ALS pathogenesis. Longitudinal ¹H-MRSI studies of the medulla (and other brain regions) in more patients with ALS are required to confirm these findings and to determine whether such metabolite changes will be useful in monitoring disease progression, in clinical diagnosis, and in understanding the pathogenesis of ALS.