Dysferlin Is a New Marker for Leaky Brain Blood Vessels in Multiple Sclerosis

Abstract

Dysferlin is a muscle protein involved in cell membrane repair and its deficiency is associated with muscular dystrophy. We describe that dysferlin is also expressed in leaky endothelial cells. In the normal central nervous system (CNS), dysferlin is only present in endothelial cells of circumventricular organs. In the inflamed CNS of patients with multiple sclerosis (MS) or in animals with experimental autoimmune encephalomyelitis, dysferlin reactivity is induced in endothelial cells and the expression is associated with vascular leakage of serum proteins. In MS, dysferlin expression in endothelial cells is not restricted to vessels with inflammatory cuffs but is also present in noninflamed vessels. In addition, many blood vessels with perivascular inflammatory infiltrates lack dysferlin expression in inactive lesions or in the normal-appearing white matter. In vitro, dysferlin can be induced in endothelial cells by stimulation with tumor necrosis factor-alpha. Hence, dysferlin is not only a marker for leaky brain vessels, but also reveals dissociation of perivascular inflammatory infiltrates and blood-brain barrier disturbance in multiple sclerosis.

In vitro investigation of poor cerebrospinal fluid suppression on fluid‐attenuated inversion recovery images in the presence of a gadolinium‐based contrast agent

“…Subtraction techniques or quantification of SI variations of CSF on FLAIR images obtained after contrast injection might be necessary when investigating patients affected by diseases that at some stages are characterized by subtle, diffuse BBB leakage. For example these postanalysis steps could be useful in advanced, chronic stages of multiple sclerosis, in which the conventional MR technique (i.e., contrast-enhanced T 1 -weighted images) might only par- tially detect neuropathologically evident BBB disturbance (12).…”

The molecular basis of neurodegeneration in multiple sclerosis

“…While clinical disease is highly variable between patients with relapsing MS, the clinical course of the disease is surprisingly uniform in patients who have entered the progressive phase. Furthermore, onset of steady disease progression, both in patients with primary or secondary progressive disease, occurs around the same age (age [40][41][42][43][44][45][46][47][48][49][50], irrespective of previous disease severity or course [21,22].…”

Multiple sclerosis shrinks intralesional, and enlarges extralesional, brain parenchymal veins

“…Studies have reported leakage of serum proteins outside discrete areas of demyelination and inflammation, 19,20 as well as subtle blood-brain barrier disruption in nonenhancing lesions. 21 However, 3 factors render this explanation unlikely: 1) intralesional veins, where this effect should be most prominent, were narrowed rather than enlarged; 2) veins within actively enhancing lesions, where the blood-brain barrier is most widely open, did not further narrow once the contrast enhancement resolved; and 3) images were acquired during injection of gadolinium, so subtle leakage, which is likely to be slow, should only have a minor effect on apparent diameter.…”