BackgroundCircumventricular organs (CVO) are cerebral areas with incomplete endothelial blood-brain barrier (BBB) and therefore regarded as "gates to the brain". During inflammation, they may exert an active role in determining immune cell recruitment into the brain.MethodsIn a longitudinal study we investigated in vivo alterations of CVO during neuroinflammation, applying Gadofluorine M- (Gf) enhanced magnetic resonance imaging (MRI) in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. SJL/J mice were monitored by Gadopentate dimeglumine- (Gd-DTPA) and Gf-enhanced MRI after adoptive transfer of proteolipid-protein-specific T cells. Mean Gf intensity ratios were calculated individually for different CVO and correlated to the clinical disease course. Subsequently, the tissue distribution of fluorescence-labeled Gf as well as the extent of cellular inflammation was assessed in corresponding histological slices.ResultsWe could show that the Gf signal intensity of the choroid plexus, the subfornicular organ and the area postrema increased significantly during experimental autoimmune encephalomyelitis, correlating with (1) disease severity and (2) the delay of disease onset after immunization. For the choroid plexus, the extent of Gf enhancement served as a diagnostic criterion to distinguish between diseased and healthy control mice with a sensitivity of 89% and a specificity of 80%. Furthermore, Gf improved the detection of lesions, being particularly sensitive to optic neuritis. In correlated histological slices, Gf initially accumulated in the extracellular matrix surrounding inflammatory foci and was subsequently incorporated by macrophages/microglia.ConclusionGf-enhanced MRI provides a novel highly sensitive technique to study cerebral BBB alterations. We demonstrate for the first time in vivo the involvement of CVO during the development of neuroinflammation.

BackgroundA number of studies have investigated cognitive impairment in paediatric patients with multiple sclerosis (MS) but deficits regarding executive functions have not been comprehensively assessed up to now. This study was meant to explore cognitive impairment in German paediatric MS patients with a focus on deficits in executive functions and relate these to clinical disease parameters.Methods and findingsForty paediatric MS patients, which presented at the German centre for MS in childhood and adolescence, were assessed for cognitive deficits applying a very comprehensive battery of cognitive tests including the Wechsler Intelligence scale and subtests of the D-KEFS for executive functions. The performance of MS patients was compared with a group of age and sex matched healthy controls using between-subjects ANOVAs. Paediatric MS patients performed worse in tests assessing verbal comprehension and fluency, processing speed, memory, calculation skills and other executive functions. Arranged by the cognitive domain, group differences were most pronounced regarding verbal comprehension and fluency for the WISC subtests Comprehension (p = 0.000), Vocabulary (p = 0.003) and Information (p = 0.005); regarding processing speed for the written SDMT (p = 0.001) and the WISC subtest Coding (p = 0.005); regarding memory for the VLMT training (p = 0.007) and the BASIC MLT pattern learning training (p = 0.009); regarding executive functions including working memory for the WISC subtest Arithmetics (p = 0.002), the D-KEFS Design Fluency (p = 0.003) and the Corsi block tapping backward task (p = 0.003). Fluid reasoning was largely intact. Relations of cognitive performance and clinical parameters were assessed in MS patients. Disease duration was associated with a reduced performance in tests belonging to the domains verbal comprehension and fluency (WISC Vocabulary: p = 0.034, WISC Information: p = 0.015) and fluid reasoning (WISC Picture Completion: p = 0.003) as well as the WISC Working Memory Index (p = 0.047). Patients with a disease onset between 11 and 14 years performed better in fluid reasoning (WISC matrix reasoning: p = 0.024) than patients with a disease onset at an age above 14. The number of relapses negatively influenced the visual spatial memory performance (BASIC MLT pattern learning training: p = 0.009).ConclusionsThe distribution of cognitive deficits in a representative group German of paediatric MS patients was similar to the pattern known from other European and North-American cohorts. Paediatric MS patients do have cognitive deficits in executive functions and key qualities necessary for successful school performance. Disease duration, age of onset and the number of relapses influence cognitive performance. Cognitive screenings should be implemented on a regular basis for paediatric MS patients, enabling early intervention.