Appropriate immune response following COVID-19 vaccination is important in the context of disease-modifying treatments (DMTs). In a prospective cross-sectional study, we determined SARS-COV-2 IgG response up to 6 months following PfizerBNT162b2 vaccination in 414 multiple sclerosis (MS) patients and 89 healthy subjects. Protective response was demonstrated in untreated MS patients ( N = 76, 100%), treated with Cladribine ( N = 48, 100%), Dimethyl fumarate ( N = 35, 100%), Natalizumab ( N = 32, 100%), and Teriflunomide ( N = 39, 100%), similarly to healthy subjects ( N = 89, 97.8%). Response was decreased in Fingolimod ( N = 42, 9.5%), Ocrelizumab ( N = 114, 22.8%) and Alemtuzumab ( N = 22, 86.4%) treated patients. IgG response can help tailor adequate vaccine guidelines for MS patients under various DMTs.

Abstract:We analyzed biochemically and temporally the molecular events that occur in the programmed cell death of mouse cerebellar granule neurons deprived of high potassium levels. An hour after switching the neurons to a low extracellular Kconcentration ([K~] 0),a significant part of the genomic DNA was already cleaved to highmolecular-weight fragments. This phenomenon was intensified with the progression of the death process. Addition of cycloheximide to the neurons 4 h after high [K~]0 deprivation resulted in no cell loss and complete recovery of the damaged DNA. DNA margination and nuclearfragmentation as assessed by 4,6-diaminodiphenyl-2-phenylindole staining were observable in a few cells beginning .-~4 h after the removal of high [K~]0and developed to nuclear condensation 4 h later. Six hours after high [K~]0 deprivation, the DNA was fragmented into oligonucleosome-sized fragments. Within 6 h after removal of the extracellular K~, 50% of the neurons were committed to die and lost their ability to be rescued by readministration of 25 mM [K~]0. Similar to high [K~]0 deprivation, inhibition of RNA or protein synthesis failed to halt neuronal degeneration of a similar percentage of cells 6 h after the onset of the death process. Mitochondrial function steadily decreased after [K~]0 removal. An~-~40% decrease in RNA and protein synthesis was detected by 6 h of [K~]0removal during the period of cell death commitment; rates continued to decline gradually thereafter. The temporal characteristics of the DNA damage and recovery, DNA cleavage to oligonucleosome-sized fragments, and the reduction in mitochondrial activityevents that occurred within the critical time-may indicate that these processes have an important part in the mechanism that committed the neurons to die.

The neurotransmitter dopamine is capable of inducing apoptosis in postmitotic sympathetic neurons via its oxidative metabolites. To detect genes whose expression is transcriptionally regulated during the early stages of dopamine-triggered apoptosis, we applied the differential display method to cultured sympathetic neurons. One of the up-regulated genes was identified as cyclin B2, which exhibited two waves of induction and destruction, both at the mRNA and protein levels, resembling the sequential oscillations typical of two successive mitotic events in proliferating cells. The time window between the two waves was characterized by a change in expression of other cell-cycle stage-specific genes, and oscillations in proliferating cell nuclear antigen and alterations in cyclin A were observed. Cyclin Dl and cyclindependent kinases were undetected and no sign of active DNA synthesis could be observed, indicating that activation of cell-cycle components is incomplete. In comparison with a normal cell cycle, temporal expression profile of these mediators was unsynchronized. Whereas the first wave of cell-cycle changes occurred prior to the commitment of the cells to the death process and could be tolerated by the cells, the second wave of changes coincided with the death commitment point. Our findings indicate that inappropriate and incomplete activation of some cell cycle-related genes in postmitotic neurons occurs during dopamine-triggered neuronal apoptosis.

Apoptosis is an active, intrinsic cell suicide program. We recently suggested that it may have a role in the death of nigrostriatal dopaminergic neurons in Parkinson's disease (PD). We now report that levodopa, the current major therapy for PD, is a potent inducer of apoptosis in cultured postmitotic chick sympathetic neurons. Levodopa, in a concentration range of 0.01-0.3 mM, caused the characteristic apoptotic cascade of cell shrinkage, massive membrane blebbing, and nuclear fragmentation, as evident by nuclear flow cytometry and fluorescence microscopy. Levodopa-induced apoptosis was inhibited by antioxidants, indicating that it may be mediated by autooxidation-reactive species. Levodopa treatment for PD may therefore constitute an additional challenge for the defective apoptosis-inhibiting systems in the nigrostriatal neurons. Despite reassuring data from some, but not all, previous studies, these findings suggest that the possible in vivo toxic effects of levodopa on the survival of the remaining nigral neurons should be further explored.

Summary. Parkinson 's disease (PD) is a progressive neurological disorder caused by rather selective degeneration of the dopaminergic (DA) neurons in the substantia nigra . Though subject to intensive research, the etiology of this nigral neuronal loss is still enigmatic and treatment is basically symptomatic. The current major hypothesis suggests that nigraI neuronal death in PD is due to excessive oxidative stress generated by auto-and enzymatic oxidation of the endogenous neurotransmitter dopamine (DA ), the formation of neuromelanin and presence of high concentrations of iron.We have found that DA toxicity is mediated through its oxidative metabolites. Whereas thiol-containing antioxidants provided marked protection against DA toxicity, ascorbic acid accelerated DA-induced death. Using the differential display approach, we sought to isolate and characterize genes whose expression is altered in response to DA toxicity. We found an upregulation of the collapsin response mediator protein (CRM) and TCP-lb in sympathetic neurons, which undergo dopamine-induced apoptosis. The isolation of these genes led us to examine the expression and activity of CRM and TCP-lb related genes. Indeed, we found a significant induction of mRNAs of the secreted collapsin-l and the mitochondrial stress protein HSP60. Antibodies directed against collapsin -l provided marked and prolonged protection of several neuronal cell types from dopamine-induced apoptosis. In a parallel study, using antisense technology, we found that inhibition of TCP-lb expression significantly reduced DA-induced neuronal death. These findings suggest a functional role for collapsin-l and TCP-lb as positive mediators of DA-induced neuronal apoptosis.