Intrinsic blood-brain barrier dysfunction contributes to multiple sclerosis pathogenesis.

Blood-brain barrier (BBB) breakdown and immune cell infiltration into the CNS are early hallmarks of multiple sclerosis (MS). The mechanisms leading to BBB dysfunction are incompletely understood and generally thought to be a consequence of neuroinflammation. Here, we have challenged this view and asked if intrinsic alterations in the BBB of MS patients contribute to MS pathogenesis. To this end, we made use of human induced pluripotent stem cells derived from healthy controls and MS patients and differentiated them into brain microvascular endothelial cell (BMEC)-like cells as in vitro model of the BBB. MS-derived BMEC-like cells showed impaired junctional integrity, barrier properties and efflux pump activity when compared to healthy controls. Also, MS-derived BMEC-like cells displayed an inflammatory phenotype with increased adhesion molecule expression and immune cell interactions. Activation of Wnt/ß-catenin signalling in MS-derived endothelial progenitor cells enhanced barrier characteristics and reduced the inflammatory phenotype. Our study provides evidence for an intrinsic impairment of BBB function in MS patients that can be modelled in vitro. Human iPSC-derived BMEC-like cells are thus suitable to explore the molecular underpinnings of BBB dysfunction in MS and will assist in the identification of potential novel therapeutic targets for BBB stabilization.

[Neurology 2019]. / Neurologie.

New studies confirm the possibility of late thrombolysis. Meta-analyses have confirmed that CGRP inhibitors are efficacious for migraines. Cladribine is a new oral treatment for relapsing-remitting multiple sclerosis. Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a new clinical entity accounting for cognitive decline in old patients. The timing of levodopa introduction has no effect on the long-term course of idiopathic Parkinson's disease. Hypophosphatemia helps distinguish between seizures and syncopes in the emergency department. A second course of intravenous immunoglobulins provides no benefit for severe Guillain Barre syndrome. Outdoor therapy improves clinical scales in patients with disorder of consciousness. Ultrasound guided lumbar puncture improves the yield of the procedure.

De nouvelles études confirment la possibilité de thrombolyse tardive. Les méta-analyses confirment l'effet bénéfique des inhibiteurs du CGRP (calcitonin gene-related peptide) pour la migraine. La cladribine est un nouveau traitement oral pour la sclérose en plaque de type poussée-rémission. L'encéphalopathie à TDP-43 à prédominance limbique est une nouvelle entité en lien avec des troubles cognitifs de la personne âgée. Le délai d'introduction de la lévodopa n'a pas d'influence sur l'évolution à long terme de la maladie de Parkinson. L'hypophosphatémie aide à différencier les crises d'épilepsie des syncopes. Une deuxième cure d'immunoglobulines n'apporte pas de bénéfice dans le traitement du syndrome de Guillain-Barré. Les patients avec troubles de l'état de conscience bénéficient des thérapies à l'air libre. L'ultrason améliore le rendement de la ponction lombaire.

The "central vein sign" in patients with diagnostic "red flags" for multiple sclerosis: A prospective multicenter 3T study.

BACKGROUND: The central vein sign (CVS) has been shown to help in the differential diagnosis of multiple sclerosis (MS), but most prior studies are retrospective. OBJECTIVES: To prospectively assess the diagnostic predictive value of the CVS in diagnostically difficult cases. METHODS: In this prospective multicenter study, 51 patients with suspected MS who had clinical, imaging, or laboratory "red flags" (i.e. features atypical for MS) underwent 3T fluid-attenuated inversion recovery (FLAIR*) magnetic resonance imaging (MRI) for CVS assessment. After the diagnostic work-up, expert clinicians blinded to the results of the CVS assessment came to a clinical diagnosis. The value of the CVS to prospectively predict an MS diagnosis was assessed. RESULTS: Of the 39 patients who received a clinical diagnosis by the end of the study, 27 had MS and 12 received a non-MS diagnosis that included systemic lupus erythematosus, sarcoidosis, migraine, Sjögren disease, SPG4-spastic-paraparesis, neuromyelitis optica, and Susac syndrome. The percentage of perivenular lesions was higher in MS (median = 86%) compared to non-MS (median = 21%; p < 0.0001) patients. A 40% perivenular lesion cutoff was associated with 97% accuracy and a 96% positive/100% negative predictive value. CONCLUSION: The CVS detected on 3T FLAIR* images can accurately predict an MS diagnosis in patients suspected to have MS, but with atypical clinical, laboratory, and imaging features.

Multicontrast connectometry: a new tool to assess cerebellum alterations in early relapsing-remitting multiple sclerosis.

BACKGROUND: Cerebellar pathology occurs in late multiple sclerosis (MS) but little is known about cerebellar changes during early disease stages. In this study, we propose a new multicontrast "connectometry" approach to assess the structural and functional integrity of cerebellar networks and connectivity in early MS. METHODS: We used diffusion spectrum and resting-state functional MRI (rs-fMRI) to establish the structural and functional cerebellar connectomes in 28 early relapsing-remitting MS patients and 16 healthy controls (HC). We performed multicontrast "connectometry" by quantifying multiple MRI parameters along the structural tracts (generalized fractional anisotropy-GFA, T1/T2 relaxation times and magnetization transfer ratio) and functional connectivity measures. Subsequently, we assessed multivariate differences in local connections and network properties between MS and HC subjects; finally, we correlated detected alterations with lesion load, disease duration, and clinical scores. RESULTS: In MS patients, a subset of structural connections showed quantitative MRI changes suggesting loss of axonal microstructure and integrity (increased T1 and decreased GFA, P < 0.05). These alterations highly correlated with motor, memory and attention in patients, but were independent of cerebellar lesion load and disease duration. Neither network organization nor rs-fMRI abnormalities were observed at this early stage. CONCLUSION: Multicontrast cerebellar connectometry revealed subtle cerebellar alterations in MS patients, which were independent of conventional disease markers and highly correlated with patient function. Future work should assess the prognostic value of the observed damage.