Serum neurofilament light chain at time of diagnosis is an independent prognostic factor of survival in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: The prognostic value of serum neurofilament light chain (sNfL), a biomarker of neurodegeneration, compared to other prognostic factors of amyotrophic lateral sclerosis (ALS) at the time of diagnosis, remains unclear. METHODS: Sera from ALS patients were prospectively collected at the first diagnostic visit in our centre. sNfL levels were determined by single molecule array in 207 ALS patients and in 21 healthy controls. The prognostic value of sNfL was compared with that of other known clinical prognostic factors using a Cox regression model and multivariate analysis. RESULTS: Serum neurofilament light chain levels were higher in ALS patients than in controls (P < 0.0001). Seven parameters were predictive of death in ALS: older age, bulbar onset, higher ALS Functional Rating Scale revised (ALSFRS-R) score, greater weight loss, lower maximal inspiratory pressure, forced vital capacity and higher sNfL levels. A Cox regression model showed that sNfL (P < 0.0001), weight loss (P = 0.040) and site at onset (P = 0.048) were independent predictive factors of death. In a sub-cohort restricted to 139 patients with complete spirometry data, sNfL level (P < 0.005) and forced vital capacity (P = 0.022) were independent factors predictive of death. In a subgroup of 142 patients in whom ALSFRS-R score was available at several time points, sNfL levels positively correlated with ALSFRS-R rate of decline (r = 0.571, P < 10-12 ). CONCLUSIONS: Higher sNfL concentration is a strong and independent prognostic factor of death in ALS as early as the time of diagnosis.

mu-Opioid receptor modulates peptide release from rat neurohypophysial terminals by inhibiting Ca(2+) influx.

The activation of opioid receptors in neurones of the central nervous system leads to a variety of effects including the modulation of diuresis and parturition, processes that are directly controlled by the hypothalamic-neurohypophysial system (HNS). The effects of mu-opioid receptor activation on peptide release, voltage-gated Ca2+ currents and intracellular calcium levels ([Ca2+]i) were studied in isolated nerve terminals of the HNS. The mu-receptor agonist, DAMGO ([d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin) inhibited high K+-induced peptide release in a dose-dependent manner, with oxytocin release being more sensitive to block than vasopressin release at all concentrations tested. The addition of the mu-receptor antagonist CTOP (d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr amide) was able to overcome the inhibitory effects of DAMGO. By contrast to previous results, voltage-gated Ca2+ currents were sensitive to blockage by DAMGO and this inhibition was also prevented by CTOP. Furthermore, [Ca2+]i measurements with Fura-2 corroborated the inhibition by DAMGO of calcium entry and its reversal by the micro -receptor antagonist in these nerve terminals. Thus, the decrease in neuropeptide release, particularly for oxytocin, induced by the activation of mu-opioid receptors in neurohypophysial terminals is mediated, at least in part, by a corresponding decrease in Ca2+ entry due to the inhibition of voltage-gated Ca2+ channels.