Jorge Correale

Cellular Elements of the Blood-Brain Barrier

The Blood-brain-barrier (BBB) provides both anatomical and physiological protection for the central nervous system (CNS), shielding the brain for toxic substances in the blood, supplying brain tissues with nutrients and filtering harmful compounds from the brain back to the bloodstream. The BBB is composed of four main cellular elements: endothelial cells (ECs), astrocyte end-feet, microglial cells, and perycites. Transport across the BBB is limited by both physical and metabolic barriers (enzymes, and different transport systems). Tight junctions (TJs) present between ECs form an important barrier against diffusion, excluding most blood-borne substances for entering the brain.

Argentine Patagonia: prevalence and clinical features of multiple sclerosis

There are few studies reporting multiple sclerosis prevalence rates in the Buenos Aires region, Argentina (latitude 34°S) (between 12–18.5/100 000 inhabitants), and no studies have been performed in the larger region between parallels 36° and 55°S. The aim of this study is to determine the prevalence rates and clinical features of multiple sclerosis in residents of the Argentine Patagonia. Four cities from the region were selected for this study, giving a sample population of 417 666 inhabitants (~24% of the total Patagonia population). 1st March 2002 was determined as prevalence day. Patients were ascertained using multiple case-finding methods. The point prevalence rate was 17.2/100 000 (17.2 age-adjusted to the world population). Prevalence rates were higher for women than for men, 22.1 versus 12.2/100 000 inhabitants (21.4 versus 12.7 sex-adjusted to the world population). The study population was mainly of European descent and mestizoes. Clinical features were similar to those reported in other countries. This study shows that Argentine Patagonia is a medium-risk area with no south–north gradient between parallels 55° and 36°S. The Patagonia population shows recent internal migration that makes it difficult to determine whether the exposure to potential risk factors has been long enough to modify the disease incidence.

Myosin Light Chain Kinase Inhibitors Induce Retraction of Mature Oligodendrocyte Processes

Mature oligodendrocytes emit numerous myelinating processes. Force generating molecules are required for process outgrowth and spreading. We have analyzed the effect of the myosin II light chain kinase inhibitors ML-7 and ML-9 in cultured oligodendrocytes. Both drugs affect oligodendrocyte cell shape, provoking a retraction of high order processes. Our results suggest that the adhesion of the myelinating processes to the substrate depends on MLC phosphorylation, thus likely implicating myosin IIA.

Increasing prevalence of multiple sclerosis in Buenos Aires, Argentina.

UNLABELLED In 1996, the prevalence of multiple sclerosis (MS) for the metropolitan area of Buenos Aires using the capture-recapture method was estimated to be between 14 and 19.8 cases per 100,000 inhabitants. The aim of this study was to update the prevalence to 2014 following the same methodology. METHODS Gran Buenos Aires is the denomination that refers to the megalopolis comprised by the autonomous city of Buenos Aires and the surrounding conurbation of the province of Buenos Aires. The study was carried out taking December 2014 as the prevalence month. We used the capture-recapture method to estimate the prevalence of MS cross-matching registries from 6 MS Centers from the metropolitan area of Buenos Aires. Log-linear model Poisson regression was used to estimate the number of affected MS patients not detected by any of the 6 sources considered. RESULTS 1035 registries were obtained from the 6 lists from 910 different patients detected. The population of the area based on 2010 census was 12,806,866, the number of MS cases estimated amongst source interactions were 4901. The estimated prevalence was 38.2 per 100,000 inhabitants (95% CI 36.1-41.2). CONCLUSION The study is an update almost 20 years after the first one in the area showing a significant increase in the previous reported prevalence. Our findings are in line with previous studies performed in other regions of the world.

Disease onset in familial and sporadic multiple sclerosis in Argentina

UNLABELLED The present study was carried out to assess if there is an anticipation of age at onset in younger generations of familial multiple sclerosis (FMS) vs. sporadic MS (SMS) in Argentina. METHODS multicenter study that included patients from 14 MS Centers of Argentina. Patients were considered as FMS if they had in their family at least one relative of first or second degree diagnosed with MS; otherwise, patients were considered to have SMS. We compared the age at onset between familial and sporadic cases as well as the age at onset between relatives from different generations in FMS vs. SMS. RESULTS 1333 patients were included, 97 of them were FMS (7.3%). A lower age at onset in the younger generations of FMS cases was found compared with older generations of FMS as well as. SMS cases (24.1±3.7 years vs. 30.3±5.7 years, and 32.4±9.4 respectively; p<0.001). No differences were observed between older generations of FMS vs. SMS cases (p=0.12). CONCLUSION we observed an anticipation of age at onset of MS in younger generations of patients with FMS vs. older generations of FMS and SMS.

Iron Availability Compromises Not Only Oligodendrocytes But Also Astrocytes and Microglial Cells

When disrupted, iron homeostasis negatively impacts oligodendrocyte (OLG) differentiation and impairs myelination. To better understand myelin formation and OLG maturation, in vivo and in vitro studies were conducted to evaluate the effect of iron deficiency (ID) not only on OLG maturation but also on astrocytes (AST) and microglial cells (MG). In vivo experiments in an ID model were carried out to describe maturational events during OLG and AST development and the reactive profile of MG during myelination when iron availability is lower than normal. In turn, in vitro assays were conducted to explore proliferating and maturational states of each glial cell type derived from control or ID conditions. Studies targeted NG2, PDGFRα, CNPAse, CC1, and MBP expression in OLG, GFAP and S100 expression in AST, and CD11b, ED1, and cytokine expression in MG, as well as BrDU incorporation in the three cell types. Our results show that ID affected OLG development at early stages, not only reducing their maturation capacity but also increasing their proliferation and affecting their morphological complexity. AST ID proliferated more than control ones and were more immature, much like OLG. Cytokine expression in ID animals reflected an anti-inflammatory state which probably influenced OLG maturation. These results show that ID conditions alter all glial cells and may impact myelin formation, which could be regulated by a mechanism involving a cross talk between AST, MG, and oligodendrocyte progenitors (OPC).

Gender ratio trends over time in multiple sclerosis patients from Argentina

Several studies in multiple sclerosis (MS) suggest a trend of increasing disease frequency in women during the last decades. A direct comparison of gender ratio trends among MS populations from Argentina remains to be carried out. The objective of the study was to compare gender ratio trends, over a 50-year span in MS populations from Argentina. METHODS multicenter study that included patients from 14 MS Centers of Argentina. Patients with definite MS with birth years ranging from 1940 to 1989 were included. Gender ratios were calculated by five decades based on year of birth and were adjusted for the F/M born-alive ratio derived from the Argentinean national registry of births. The F/M ratios were calculated using a multivariate logistic regression per five decades by the year of birth approach. Analyses were performed using Stata 10.1. RESULTS 1069 patients were included. Gender ratios showed a significant increase from the first to the last decade in the whole MS sample (from 1.8 to 2.7; p value for trend=0.023). The Gender ratio did not show differences considering MS subtype. CONCLUSION our study showed a modest increase of the F/M ratio (from 1.8 to 2.7) over time among patients affected by MS in Argentina.

Combined effects of transferrin and thyroid hormone during oligodendrogenesis In vitro

Thyroid hormones (THs) and transferrin (Tf) are factors capable of favoring myelination due to their positive effects on oligodendroglial cell (OLG) differentiation. The first notion of a combined effect of apotransferrin (aTf) and TH emerged from experiments conducted in young hyperthyroid animals, which showed a seven‐fold increase in the expression of Tf mRNA and precocious myelination when compared with control animals. The mechanism underlying this phenomenon in young hyperthyroid rats could consist of an increase in Tf synthesis, which in the CNS is almost exclusively produced by OLG. Overall, our results show that, during the initial stages of OLG differentiation, Tf synthesis triggers thyroid hormone receptor alpha 1 (TRα1) expression in the subventricular zone (SVZ) and promotes proliferating cells to become responsive to this trophic factor. Exposure to TH could then regulate Tf expression through TRα1 and promote the induction of thyroid hormone receptor beta (TRβ) expression, which mediates TH effects on myelination through the activation of final OLG differentiation. This regulation of the combined effects of Tf and THs implies that both factors are fundamental actors during oligodendrogenesis. GLIA 2016;64:1879–1891

Neuroprotective Effects of Inflammation in the Nervous System

Abstract Inflammation in the nervous system is widely recognized as contributing to a number of neurological conditions. However, the central nervous system (CNS) has also been classically recognized as occupying a privileged site with respect to immune-related phenomena. This dichotomy is widely understood to be a functional manifestation of known CNS and peripheral nervous system (PNS) barriers, in addition to the variable immunocompetence of certain CNS and PNS cells. Moreover, the variable capacities of, for example, CNS cells to produce cytokines and/or induce neurotrophic factors in certain disease states or after trauma are also recognized as contributing. In light of these considerations, this chapter explores the damage-to-benefit ratio for several classes of cells and their secretory products after CNS and PNS lesions, trauma, and diseases. Included are an evaluation of macrophage, microglial, and Schwann cell activation, as well as T-lymphocyte responses during several experimental pathophysiological models and disease states. These cellular activities range from being protective to pathogenic factors. The contributions of autoreactive antibodies (Abs) to disease processes and nervous system repair are also considered for their effects that categorically parallel described cellular responses. However, in experimental model systems involving myelination, overall observations point to Abs synthesized following CNS injuries as being potentially therapeutic, and these examples are reviewed. Moreover, data presented from the studies of cytokines in experimental and natural disease states demonstrate that certain cytokines have the capacity to generate multiple and opposite effects including producing damage, protection, or regeneration. Examples are described involving tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and interferon (IFN)-γ. Ultimately, our understanding of the inflammatory processes that protect versus those that contribute to neuronal damage will be a prerequisite to designing effective new therapies for diseases affecting the nervous system.

Clinical and imaging features distinguishing Susac syndrome from primary angiitis of the central nervous system

INTRODUCTION To assess clinical and/or imaging features useful to distinguish between Susac syndrome (SuS) and primary angiitis of central nervous system (PACNS). METHODS Multicenter retrospective analysis of two cohorts of Argentine patients diagnosed with SuS and PACNS. RESULTS 13 patients diagnosed with SuS (6 women and 7 men, mean age 35 ± 10 years) and 15 with PACNS (10 women and 5 men, mean age 44 ± 18 years) were analyzed. Cognitive impairment (11 out of 13 patients vs. 5 out of 15, p = .006), ataxia (7 out of 13 vs. 2 out of 15, p = .042) and auditory disturbances (7 out of 13 vs. 0 out of 15, p = .003) were more frequent in SuS patients; whereas seizures were more frequent in PACNS patients (8 out of 15 vs. 1 out of 13, p = .035). On MRI, corpus callosum (CC) involvement was observed more often in SuS, with abnormalities in CC genu, in 13 out of 13 SuS patients vs. only 2 out of 15 PACNS patients (p < .001); in CC body these were present in 13 out of 13 SuS patients vs. 1 out of 15 PACNS patients, (p < .001); and in CC splenium in 12 out of 13 Sus patients vs. 1 of 15 PACNS, p < .001). Cortical lesions were more frequent in PACNS patients (10 out of 15 vs. 3 out of 13 SuS patients, p = .02), as were hemorrhages (5 out of 15 vs. 0 out of 13 SuS, p = .04) and multiple basal ganglia infarcts (7 out of 15 vs. 1 out of 13 Sus, p = .037). CONCLUSION Specific clinical and/or MRI findings may help distinguish SuS from PACNS with potential therapeutic implications.