Inflammatory intrathecal profiles and cortical damage in multiple sclerosis

Abstract

A common pattern of intrathecal (meninges and CSF) inflammatory profile strongly correlates with increased cortical pathology, both at the time of diagnosis and at death. These results suggest a role for detailed CSF analysis combined with MRI as a prognostic marker for more aggressive MS. Ann Neurol 2018 Ann Neurol 2018;83:739-755.

Influencia de la infección SARS-CoV-2 sobre enfermedades neurodegenerativas y neuropsiquiátricas: ¿una pandemia demorada?

“…Similar patrón proinflamatorio incluyendo niveles de CXCL13, TNF, IFNγ, CXCL12, IL6, IL8, e IL10, se ha detectado en el LCR de pacientes de EM con alto nivel de daño en sustancia gris en el momento del diagnostico. De alguna manera estos datos apoyarían el papel de la Neuroinflamación en la fase de neurodegeneración de esta enfermedad [24].…”

MRI of cortical lesions and its use in studying their role in MS pathogenesis and disease course

“…In order to verify this hypothesis, a combined neuropathology, molecular and imaging study on post-mortem MS cases and in MS patients at the time of diagnosis has been performed demonstrating that a common pattern of intrathecal (meninges and CSF) inflammatory profile strongly correlates with increased cortical pathology, both at time of the diagnosis and of death. In particular, increased expression of pro-inflammatory cytokines (IFNγ, TNF, IL2 and IL22) and molecules related to sustained B-cell activity and lymphoid-neogenesis (CXCL13, CXCL10, LTα, IL6, IL10) was detected in paired meninges and CSF of rapidly progressive post-mortem MS cases with high levels of meningeal inflammation and GM demyelination (45). Significant (P < 0.0001) positive correlation was, in fact, detected non only between degree of meningeal inflammation and percentage of cortical demyelination (r = 0.968), but also specifically between degree of meningeal inflammation and CSF levels of CXCL13 (r = 0.943), IFNγ (r = 0.718), IL10 (r = 0.627), CCL22 (r = 0.603), IL16 (r = 0.568) and TNF (r = 0.553) in post-mortem progressive MS patients ( Figure 2).…”

Localized calcium accumulations prime synapses for phagocyte removal in cortical neuroinflammation

“…To induce neuroinflammation in the mouse cortex, we adapted previous targeted models of cortical MS pathology from rats (Gardner et al, 2013;Merkler et al, 2006). We stereotactically injected interferon gamma (IFN) and tumor necrosis factor alpha (TNF), pro-inflammatory 5 cytokines highly expressed in the meninges of progressive MS patients (Gardner et al, 2013;Magliozzi et al, 2018), into the somatosensory cortex of mice that were previously immunized with myelin-oligodendrocyte glycoprotein (MOG, Figure 1A). This resulted in the formation of cortical lesions that extended subpially to both hemispheres (Figure 1B) thus mimicking the widespread cortical pathology in progressive MS. Like their counterparts in humans 10 (Lagumersindez- Denis et al, 2017;Lucchinetti et al, 2011), these cortical lesions were characterized by phagocyte activation and modest T cell infiltration causing extensive myelin loss with relative preservation of axons (Figure S1).…”

“…While the c-MS model involves only one episode of locally triggered neuroinflammation, driven by a single injection of cytokines, in MS sustained sources of such proinflammatory signaling exist, e.g. originating from lymphoid aggregates in the meninges, 5 which correlate with increased levels of proinflammatory cytokines in the cerebrospinal fluid of corresponding patients (Magliozzi et al, 2018). However, such cytokines might well have complex effects, as for example TNF can potentiate existing synaptic connections, and hence contribute to transient hyperactivity of cortical circuits, e.g.…”