Magnetic resonance imaging of blood–spinal cord barrier disruption in mice with experimental autoimmune encephalomyelitis

Abstract

Inflammation, demyelination, and blood-spinal cord barrier (BSB) breakdown occur in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. The purpose of this study was to evaluate the utility of MRI for detecting lesions and BSB disruption in vivo during EAE in the mouse lumbar spinal cord, to determine how MR features of BSB disruption change during the course of disease, and to relate such changes to clinical signs and histological features of disease. Following induction of EAE in C57BL/6 mice, contrast-enhanced (CE) T 1 -weighted MR images were acquired to detect BSB disruption in the lumbar spinal cord at the early stage of disease, at peak disease, and at remission, and T 2 -weighted images were obtained to monitor spinal cord morphology. Following imaging the spinal cords were assessed in situ for general features of inflammation, BSB leakage, activated macrophages/microglia, and demyelination. No focal lesions were evident on T 2 -weighted MR images. BSB disruption was greatest at the onset of signs of disease, and decreased progressively thereafter. Inflammation and demyelination were pronounced at the initial stage of disease and at peak disease, and were decreased at remission. Nonuniform contrast enhancement indicated that breakdown of the BSB occurred predominantly within the white matter ( Experimental autoimmune encephalomyelitis (EAE) is an animal model of demyelinating disease of the central nervous system (CNS) used to study features of multiple sclerosis (MS). EAE is commonly induced by immunizing with CNS myelin peptides emulsified in complete Freund's adjuvant (CFA) (1) or with myelin-specific Tcells (2). The autoimmune inflammatory responses generated in EAE are similar to events observed in MS, and include the infiltration of macrophages and T cells into the CNS and the breakdown of the blood-brain barrier (BBB) or blood-spinal cord barrier (BSB). Focal areas of inflammatory infiltrates (3,4) and demyelination (5,6) have been observed throughout the CNS in various models of EAE. The autoimmune inflammatory events in EAE are thought to be T-cell-mediated (4), but macrophages are believed to be responsible for the destruction of the myelin sheath that leads to the debilitating features of MS and EAE (6,7).The breakdown of the BBB or BSB may be an important event during the initial stages of EAE. Increased leakage across the BBB may be due to an increase in vesicular transport (8 -11) or the loosening of tight junctions between endothelial cells (12). There are conflicting reports regarding BBB disruption as a consistent component in the development of EAE and in the sequence of events leading to the development of signs of disease. Some studies have indicated that vascular permeability is a distinct event that precedes cellular infiltration (13-15), while other studies found BBB permeability to be present only during inflammation (3,9,16 -18). Though these observations may be dependent on the specific model of EAE, the role of BBB permeability in the initial...

Neutrophils Mediate Blood–Spinal Cord Barrier Disruption in Demyelinating Neuroinflammatory Diseases

“…In the EAE SJL mouse model, it was proposed that the first occurrence of BBB disruption and rabbit IgG leakage occurred in the cerebellum, and then spread to the spinal cord (9). Magnetic resonance imaging in the mouse revealed that BSCB and BBB disruption took place as animals were already displaying acute motor symptoms (10,12). In the brain of EAE mice, Floris et al (10) further observed that monocyte infiltration preceded vascular leakage, although assessments of BBB integrity and cellular infiltration were performed in separate animals that were sacrificed at the end of the imaging session.…”

“…This leads to immune cell invasion, formation of demyelinated lesions, and axonal damage (4,(6)(7)(8). Early breakdown of the BSCB in EAE has been widely documented, but the precise timing and triggers of this disruption are still a matter of debate (9)(10)(11)(12). This has prompted us to look further into the kinetics of BSCB disruption and the putative cellular candidates involved in this process.…”

TRPV1 Gates Tissue Access and Sustains Pathogenicity in Autoimmune Encephalitis

“…While large molecule permeability is dependent on transcytosis, we questioned the permeability of small molecules that normally depend on processes such as diffusion. The blood-spinal cord barrier is normally impermeable to magnetic resonance (MR) contrast agents such as the small (260Da) Gadolinium-DTPA reagent, but in cases of barrier disruption will appear hyperintense in T1-weighted MR images (36). MRI detected CNS edema sensitively but almost equally during EAE in B6 and in protected TRPV1 -/-mice, identifying a shared inflammatory element that is, however, self-limiting and without progressive tissue damage in the absence of TRPV1 ( Figure 6F).…”

Magnetic resonance microimaging of the spinal cord in the SOD1 mouse model of amyotrophic lateral sclerosis detects motor nerve root degeneration

“…In the experimental allergic encephalomyelitis model of multiple sclerosis, contrast changes have been observed in conventional anatomic images (Schellenberg et al, 2007), axial diffusivity has been correlated with axonal damage (Budde et al, 2008;Budde et al, 2007;Budde et al, 2009), and decreased quantitative T2 and magnetic transfer values have been shown (McCreary et al, 2009). Numerous studies have also assessed white matter integrity in mouse models of spinal cord injury, using diffusion tensor imaging Kim et al, 2010;Loy et al, 2007;Tu et al, 2010), T1-and T2-weighted imaging (Gonzalez-Lara et al, 2009;Levene et al, 2008;Nishi et al, 2007), and MRM (Bilgen, 2007).…”