Over half of multiple sclerosis (MS) patients experience cognitive deficits, including learning and memory dysfunction, and the mechanisms underlying these deficits remain poorly understood. Neuronal injury and synaptic loss have been shown to occur within the hippocampus in other neurodegenerative disease models, and these pathologies have been correlated with cognitive impairment. Whether hippocampal abnormalities occur in MS models is unknown. Using experimental autoimmune encephalomyelitis (EAE), we evaluated hippocampal neurodegeneration and inflammation during disease. Hippocampal pathology began early in EAE disease course, and included decreases in CA1 pyramidal layer volume, loss of inhibitory interneurons and increased cell death of neurons and glia. It is interesting to note that these effects occurred in the presence of chronic microglial activation, with a relative paucity of infiltrating blood-borne immune cells. Widespread diffuse demyelination occurred in the hippocampus, but there was no significant decrease in axonal density. Furthermore, there was a significant reduction in pre-synaptic puncta and synaptic protein expression within the hippocampus, as well as impaired performance on a hippocampal-dependent spatial learning task. Our results demonstrate that neurodegenerative changes occur in the hippocampus during autoimmune-mediated demyelinating disease. This work establishes a preclinical model for assessing treatments targeted toward preventing hippocampal neuropathology and dysfunction in MS.

Over 50% of multiple sclerosis (MS) patients experience cognitive deficits, and hippocampal-dependent memory impairment has been reported in over 30% of these patients. While post-mortem pathology studies and in vivo magnetic resonance imaging (MRI) demonstrate that the hippocampus is targeted in MS, the neuropathology underlying hippocampal dysfunction remains unknown. Furthermore, there are no treatments available to date to effectively prevent neurodegeneration and associated cognitive dysfunction in MS. We have recently demonstrated that the hippocampus is also targeted in experimental autoimmune encephalomyelitis (EAE), the most widely used animal model of MS. The objective of this study was to assess whether a candidate treatment (testosterone) could prevent hippocampal synaptic dysfunction and underlying pathology when administered in either a preventative or a therapeutic (post-disease induction) manner. Electrophysiological studies revealed impairments in basal excitatory synaptic transmission that involved both AMPA receptor-mediated changes in synaptic currents, and faster decay rates of NMDA receptor-mediated currents in mice with EAE. Neuropathology revealed atrophy of the pyramidal and dendritic layers of hippocampal cornu ammonis 1 (CA1), decreased pre (Synapsin-1) and post (postsynaptic density 95; PSD-95) synaptic staining, diffuse demyelination, and microglial activation. Testosterone treatment administered either before or after disease induction restores excitatory synaptic transmission as well as pre- and postsynaptic protein levels within the hippocampus. Furthermore, cross-modality correlations demonstrate that fluctuations in excitatory postsynaptic potentials are significantly correlated to changes in postsynaptic protein levels and suggest that PSD-95 is a neuropathological substrate to impaired synaptic transmission in the hippocampus during EAE. This is the first report demonstrating that testosterone is a viable therapeutic treatment option that can restore both hippocampal function and disease-associated pathology that occur during autoimmune disease.

Cognitive deficits occur in over half of multiple sclerosis patients, with hippocampal-dependent learning and memory commonly impaired. Data from in vivo MRI and post-mortem studies in MS indicate that the hippocampus is targeted. However, the relationship between structural pathology and dysfunction of the hippocampus in MS remains unclear. Hippocampal neuropathology also occurs in experimental autoimmune encephalomyelitis (EAE), the most commonly used animal model of MS. Although estrogen treatment of EAE has been shown to be anti-inflammatory and neuroprotective in the spinal cord, it is unknown if estrogen treatment may prevent hippocampal pathology and dysfunction. In the current study we examined excitatory synaptic transmission during EAE and focused on pathological changes in synaptic protein complexes known to orchestrate functional synaptic transmission in the hippocampus. We then determined if estriol, a candidate hormone treatment, was capable of preventing functional changes in synaptic transmission and corresponding hippocampal synaptic pathology. Electrophysiological studies revealed altered excitatory synaptic transmission and paired-pulse facilitation (PPF) during EAE. Neuropathological experiments demonstrated that there were decreased levels of pre-and post-synaptic proteins in the hippocampus, diffuse loss of myelin staining and atrophy of the pyramidal layers of hippocampal cornu ammonis 1 (CA1). Estriol treatment prevented decreases in excitatory synaptic transmission and lessened the effect of EAE on PPF. In addition, estriol treatment prevented several neuropathological alterations that occurred in the hippocampus during EAE. Cross-modality correlations revealed that deficits in excitatory synaptic transmission were significantly correlated with reductions in trans-synaptic protein binding partners known to modulate excitatory synaptic transmission. To our knowledge, this is the first report describing a functional correlate to hippocampal neuropathology in any MS model. Furthermore, a treatment was identified that prevented both deficits in synaptic function and hippocampal neuropathology. More than 50% of MS patients experience cognitive deficits, 1,2 and hippocampal-dependent learning and memory is often impaired.3,4 Hippocampal atrophy has been shown in MS patients using in vivo MRI, 5,6 and this atrophy was correlated with impaired performance on visuospatial memory testing, a hippocampal-dependent function.7 Data from postmortem studies in MS have demonstrated that hippocampal demyelination and neuropathology occur. 8,9 This demyelination has been associated with changes in molecules modulating synaptic integrity, axonal transport and glutamate homeostasis.10 Although evidence from both in vivo MRI and post-mortem pathological studies indicates that hippocampal pathology occurs during MS, the relationship between such pathology and dysfunction remains unclear. Moreover, there are currently no treatments available to prevent hippocampal dysfunction during MS.Demyelination, axonal los...

These data demonstrate that GC resistance during autoimmune neuroinflammation is dynamically regulated. This has implications for the timing of steroid treatments and provides a putative pathway to explain the observed association between psychological stress and exacerbation of autoimmune diseases.

Objective Serum neurofilament light (sNfL) is a promising new biomarker in multiple sclerosis (MS). We explored the relationship between sNfL and health outcomes and resource use in MS patients. Methods MS patients with serum samples and health‐outcome measurements collected longitudinally between 2011 and 2016 were analyzed. sNfL values were evaluated across age and gender. Data were analyzed using correlation with log‐transformed sNfL values. Results A total of 304 MS patients with a mean age of 32.9 years, average EDSS of 1.6 (SD = 1.5) and baseline sNfL of 8.8 (range 1.23–78.3) pg/mL were studied. Baseline sNFL values increased with age and were higher in females. Baseline sNfL correlated with baseline Multiple Sclerosis Quality of Life physical composite (mean = 49.4 (9.1), P = 0.035) and baseline EDSS (P = 0.002). Other PRO measures at baseline did not show a significant relationship with baseline sNfL. Average of baseline and follow‐up sNfL correlated with MSQoL physical‐role limitations (mean = 48.9 (10.8), P = 0.043) and social‐functioning (mean = 52.3 (7), P = 0.034) at 24‐month follow‐up. We found a trend for numerically higher sNfL levels in nonpersistent patients compared to those who were persistent to treatment (11.13 vs. 8.53 pg/mL, P = 0.093) measured as average of baseline and 24‐month values. Baseline NfL was associated with number of intravenous steroid infusions (mean = 0.2; SD = 3.0, P = 0.013), whereas the average of baseline and 12 months NfL values related to inpatient stays at 12 months (mean = 0.2; SD = 3.0 P = 0.053). Conclusion Serum NfL is a patient‐centric biomarker that correlated with MS patient health‐outcomes and healthcare utilization measures in a real‐world cohort.

Deshpande (2020) Real-world cost of treatment for multiple sclerosis patients initiating and receiving infused disease-modifying therapies per recommended label in the United States,

ObjectiveTo evaluate lymphocyte counts and incidences of infections in patients with primary progressive MS (PPMS) receiving fingolimod 0.5 mg/d or placebo over 5 years during the INFORMS study, to assess infection rates with longer-term treatment.MethodsINFORMS was a randomized, multicenter, double-blind, placebo-controlled, parallel-group, phase 3 study of the sphingosine 1-phosphate receptor modulator fingolimod in patients with PPMS. Lymphocyte counts and incidences of infections were compared in patients receiving fingolimod or placebo. Infection rates were assessed in patients receiving fingolimod according to nadir and mean absolute lymphocyte count (ALC).ResultsOverall, 336 patients received fingolimod 0.5 mg/d (total exposure: 908.1 patient-years), and 487 received placebo (1,423.5 patient-years). In patients receiving fingolimod, mean ALC decreased by approximately 70% in the 2 weeks following treatment initiation and remained stable throughout the study. The incidences of all infections in the fingolimod and placebo groups were similar (53.6 vs 51.9 per 100 patient-years). The most common infections in patients receiving fingolimod were urinary tract infections (5.7 per 100 patient-years), upper respiratory tract infections (4.2 per 100 patient-years), and influenza (3.2 per 100 patient-years); incidences were similar in the placebo group (5.9, 4.2, and 3.1 per 100 patient-years, respectively). There was no apparent association between nadir or mean ALC and incidence of infection-related adverse events.ConclusionsIn patients with PPMS, long-term treatment with fingolimod 0.5 mg/d for up to 5 years led to an expected decrease of approximately 70% in mean ALC and did not appear to correlate with increased risk of infection.Classification of evidenceBecause this is a secondary analysis, this study provides Class II evidence that long-term PPMS treatment with fingolimod decreased mean ALC by approximately 70%, but did not significantly increase infection risk.

Background Fingolimod is a sphingosine 1-phosphate receptor modulator approved for relapsing MS. Long-term effects on the immunological profile are not fully understood. Objective Investigate fingolimod's temporal effects on immune cell subsets, and safety outcomes. Methods In FLUENT, a 12-month, prospective, non-randomized, open-label, phase IV study, adult participants received fingolimod 0.5 mg/day. Changes in immune cell subsets, anti-John Cunningham virus (JCV) antibody index, and serum neurofilament levels were assessed. Results 165 fingolimod-naive and 217 participants treated for 2–12 years in routine clinical practice were enrolled. Levels of all monitored peripheral lymphocyte subsets were reduced from month 3 in fingolimod-naive participants. Greatest reductions occurred in naive and central memory CD4+ and CD8+ T cells, and in naive and memory B cells. Most lymphocyte subset levels remained stable in the continuous fingolimod group. Components of the innate immune system remained within reference ranges. No increase in JCV seropositivity was observed. No single cellular subset correlated with anti-JCV antibody index at any time point. Neurofilament levels remained within healthy adult reference limits throughout. No opportunistic infections were reported; no new or unexpected safety signals were observed. Conclusion FLUENT provides insights into the utility of immunological profiling to evaluate therapy response and potential infection risk.