A microbially produced AhR ligand promotes a Tph1-driven tolerogenic program in multiple sclerosis.

Multiple sclerosis is a debilitating autoimmune disease, characterized by chronic inflammation of the central nervous system. While the significance of the gut microbiome on multiple sclerosis pathogenesis is established, the underlining mechanisms are unknown. We found that serum levels of the microbial postbiotic tryptophan metabolite indole-3-carboxaldehyde (3-IAld) inversely correlated with disease duration in multiple sclerosis patients. Much like the host-derived tryptophan derivative L-Kynurenine, 3-IAld would bind and activate the Aryl hydrocarbon Receptor (AhR), which, in turn, controls endogenous tryptophan catabolic pathways. As a result, in peripheral lymph nodes, microbial 3-IAld, affected mast-cell tryptophan metabolism, forcing mast cells to produce serotonin via Tph1. We thus propose a protective role for AhR-mast-cell activation driven by the microbiome, whereby natural metabolites or postbiotics will have a physiological role in immune homeostasis and may act as therapeutic targets in autoimmune diseases.

Clinical correlates of state and trait anxiety in multiple sclerosis.

BACKGROUND: Anxiety represents one of the most prevalent psychiatric symptoms in multiple sclerosis (MS), impacting the overall disease burden and quality of life. This psychopathological feature can be expressed as state (S-ANX) and trait (T-ANX) anxiety, but few studies specifically evaluated these two components in MS. The present study was aimed at investigating the prevalence and specific correlates of S-ANX and T-ANX in a cohort of people with MS (PwMS). METHODS: 88 in- and out-patients with MS were consecutively recruited. S-ANX and T-ANX were evaluated with the two subscales of the State and Trait Anxiety Inventory. Bivariate analyses were performed to compare PwMS who displayed clinically significant S-ANX and T-ANX and those who did not. Two logistic regression models were run in order to identify variables significantly associated with S-ANX and T-ANX. RESULTS: S-ANX and T-ANX presented a prevalence of 42% and 45.5%, respectively. S-ANX was more frequent in subjects hospitalized due to recent MS onset. PwMS and S-ANX more frequently had a recent relapse, as well as evidence of disease activity on brain magnetic resonance imaging. Subjects with T-ANX were more often females and displayed higher severity of fatigue. Depressive features at the Beck Depression Inventory were more severe in both S-ANX and T-ANX subjects. PwMS with S-ANX reported a higher prevalence of T-ANX and vice versa. At the logistic regressions, depression severity displayed a significant association with S-ANX and T-ANX. We also detected positive associations between S-ANX and inpatient status, as well as between T-ANX and female sex. CONCLUSION: Both S-ANX and T-ANX are highly prevalent features in PwMS. These two components of anxiety should be adequately identified and discriminated in the clinical practice. The higher severity of depression in PwMS with clinically significant anxiety should not be neglected.

Impact of post-contrast MRI in the definition of active multiple sclerosis.

BACKGROUND: For multiple sclerosis (MS) phenotypes classification, the presence of "disease activity" can be defined by clinical relapses and/or by magnetic resonance imaging (MRI) through gadolinium-enhancing (Gd+) lesions or new/enlarged T2 lesions. Recent MRI and pathology findings have demonstrated Gd deposition in the brain, suggesting to avoid Gd administration when dispensable. In this scenario, we aimed to evaluate the contribution of post-contrast MRIs to the definition of "active" MS phenotype. METHODS: We retrospectively selected 84 "active" relapsing-remitting MS (RRMS) patients according to Lublin 2013, calculating both the number of Gd+ lesions not detectable as new/unequivocally enlarged on T2 images and the proportion of patients who would be still correctly classified as "active" without Gd administration. RESULTS: 13 out of 164 (7.9%) Gd+ lesions did not correspond to a new/enlarged T2 lesion. Gd administration did not modify the classification of MS as "active" in 83 out of 84 subjects (98.8%). CONCLUSION: The contribution of Gd+ lesions to the correct classification of RRMS patients as "active" is marginal, thus limiting the need of routine Gd administration for this scope. Further studies are warranted to support these conclusions.

Cognitive impairment in multiple sclerosis: lessons from cerebrospinal fluid biomarkers.

Cognitive impairment is a common clinical manifestation of multiple sclerosis, but its pathophysiology is not completely understood. White and grey matter injury together with synaptic dysfunction do play a role. The measurement of biomarkers in the cerebrospinal fluid and the study of their association with cognitive impairment may provide interesting in vivo evidence of the biological mechanisms underlying multiple sclerosis-related cognitive impairment. So far, only a few studies on this topic have been published, giving interesting results that deserve further investigation. Cerebrospinal fluid biomarkers of different pathophysiological mechanisms seem to reflect different neuropsychological patterns of cognitive deficits in multiple sclerosis. The aim of this review is to discuss the studies that have correlated cerebrospinal fluid markers of immune, glial and neuronal pathology with cognitive impairment in multiple sclerosis. Although preliminary, these findings suggest that cerebrospinal fluid biomarkers show some correlation with cognitive performance in multiple sclerosis, thus providing interesting insights into the mechanisms underlying the involvement of specific cognitive domains.

Cerebrospinal fluid free light chains compared to oligoclonal bands as biomarkers in multiple sclerosis.

Cerebrospinal fluid (CSF) free light chains (FLC) may be an alternative biomarker to oligoclonal bands (OCB) in multiple sclerosis (MS). Herein, we compared the diagnostic accuracy of CSF OCB and FLC and we tested the prognostic value of FLC in a cohort of 64 MS patients and 106 controls. A κ-index >7.83 was more sensitive but less specific than OCB in discriminating MS patients from controls. Additionally, a κ-index >10.61 performed better than OCB in the discrimination between MS and controls with inflammatory neurological diseases (p < .001). In clinically isolated syndrome (CIS) patients, a κ-index >10.61 significantly predicted time to conversion to MS (p = .020). κ-index might be a valid alternative to OCB as a diagnostic biomarker for MS and might also be a prognostic marker in CIS.

Cerebrospinal fluid neurofilament light chain predicts disease activity after the first demyelinating event suggestive of multiple sclerosis.

BACKGROUND: The prediction of disease activity in patients with a first demyelinating event suggestive of multiple sclerosis (MS) is of high clinical relevance. Cerebrospinal fluid (CSF) neurofilament light chain (NfL) has shown to have prognostic value in MS patients. In this work, we measured CSF NfL in patients at the first demyelinating event in order to find a cut-off value able to discriminate patients who will have disease activity from those who will remain stable during the follow-up. METHODS: We included CSF samples collected within 30 days after the onset of the first demyelinating event from 32 patients followed-up for 3.8 ±â€¯2.5 years. CSF NfL was measured with a newly developed in-house enzyme linked immunosorbent assay (ELISA). RESULTS: At the first demyelinating event, patients with subsequent disease activity had significantly higher baseline CSF NfL values compared to clinically and radiologically stable patients (median 812.5 pg/mL, range 205-2359 pg/mL vs 329.5 pg/mL, range 156-3492 pg/mL, p = 0.002). A CSF NfL cut-off value of 500 pg/mL significantly discriminated these two groups of patients with a 90% sensitivity and an 83.3% specificity. CONCLUSION: Our results confirm that CSF NfL is a prognostic marker in the very early phases of MS. The validation of a cut-off value of 500 pg/mL could provide clinicians with a dichotomous variable that can simplify the prognostic assessment of patients at the first demyelinating event.

Cerebrospinal fluid neurofilament light chain tracks cognitive impairment in multiple sclerosis.

BACKGROUND: Cognitive impairment (CI) is a disabling symptom of multiple sclerosis (MS). Axonal damage disrupts neural circuits and may play a role in determining CI, but its detection and monitoring are not routinely performed. Cerebrospinal fluid (CSF) neurofilament light chain (NfL) is a promising marker of axonal damage in MS. OBJECTIVE: To retrospectively examine the relationship between CSF NfL and CI in MS patients. METHODS: CSF NfL concentration was measured in 28 consecutive newly diagnosed MS patients who underwent a neuropsychological evaluation with the Brief Repeatable Battery of Neuropsychological tests (BRBN). RESULTS: CSF NfL was higher in patients with overall CI (947.8 ± 400.7 vs 518.4 ± 424.7 pg/mL, p < 0.01), and with impairment in information processing speed (IPS) (820.8 ± 413.6 vs 513.6 ± 461.4 pg/mL, p < 0.05) and verbal fluency (1292 ± 511 vs 582.8 ± 395.4 pg/mL, p < 0.05), and it positively correlated with the number of impaired BRBN tests (r = 0.48, p = 0.01) and cognitive domains (r = 0.47, p = 0.01). Multivariate analyses taking into account potential confounders confirmed these findings. CONCLUSION: CSF NfL is higher in MS patients with CI and impaired IPS and verbal fluency. Large myelinated axons injury, causing neural disconnection, may be an important determinant of CI in MS and can be reliably measured through CSF NfL.

Treatment of multiple sclerosis relapses with high-dose methylprednisolone reduces the evolution of contrast-enhancing lesions into persistent black holes.

INTRODUCTION: The MRI evidence of persistent black holes (pBHs) on T1-weighted images reflects brain tissue loss in multiple sclerosis (MS). The evolution of contrast-enhancing lesions (CELs) into pBHs probably depends on the degree and persistence of focal brain inflammation. The aim of our retrospective study was to evaluate the effect of a single cycle of intravenous methylprednisolone (IVMP), as for MS relapse treatment, on the risk of CELs' evolution into pBHs. PATIENTS AND METHODS: We selected 57 patients with CELs on the baseline MRI scan. We evaluated the evolution of CELs into pBHs on a follow-up MRI scan performed after ≥ 6 months in patients exposed and not exposed to IVMP for the treatment of relapse after the baseline MRI. RESULTS: In our cohort, 182 CELs were identified in the baseline MRI and 57 of them (31.3%) evolved into pBHs. In the multivariate analysis, the exposure of CELs to IVMP resulted to be a significant independent protective factor against pBHs' formation (OR 0.28, 95% CI 0.11-0.766, p = 0.005), while ring enhancement pattern and the fact of being symptomatic were significant risk factors for CELs' conversion into pBHs (OR 6.42, 95% CI 2.55-17.27, p < 0.001 and OR 13.19, 95% CI 1.56-288.87, p = 0.037). CONCLUSIONS: The exposure of CELs to a cycle of IVMP as for relapse treatment is associated with a lower risk of CELs' evolution into pBHs. Future studies are required to confirm the potential independent protective effect of IVMP on CELs' evolution into pBHs.

Visual pathway involvement in multiple sclerosis: Look straight in the eyes.

Visual symptoms are a common clinical manifestation of multiple sclerosis (MS) and are frequently due to acute optic neuritis (ON). However, the entire visual pathway can be involved throughout the disease course. We describe the case of a young MS patient who experienced visual symptoms that were eventually found to be caused by retinal periphlebitis, an inflammatory process of the anterior visual pathway, which is common during MS, but rarely symptomatic. This case reinforces the concept that in all MS patients complaining visual symptoms, a complete work-up should be performed in order to rule out possible ON mimicries.