Cerebrospinal fluid, brain, and spinal cord levels of L-aspartate signal excitatory neurotransmission abnormalities in multiple sclerosis patients and experimental autoimmune encephalomyelitis mouse model

The neuroinflammatory process characterizing multiple sclerosis (MS) is associated with changes in excitatory synaptic transmission and altered central concentrations of the primary excitatory amino acid, L-glutamate (L-Glu). Recent findings report that cerebrospinal fluid (CSF) levels of L-Glu positively correlate with pro-inflammatory cytokines in MS patients. However, to date, there is no evidence about the relationship between the other primary excitatory amino acid, L-aspartate (L-Asp), its derivative D-enantiomer, D-aspartate, and the levels of pro-inflammatory and anti-inflammatory cytokines in the CSF of MS. In the present study, we measured by HPLC the levels of these amino acids in the cortex, hippocampus, cerebellum, and spinal cord of mice affected by experimental autoimmune encephalomyelitis (EAE). Interestingly, in support of glutamatergic neurotransmission abnormalities in neuroinflammatory conditions, we showed reduced L-Asp levels in the cortex and spinal cord of EAE mice and increased D-aspartate/total aspartate ratio within the cerebellum and spinal cord of these animals. Additionally, we found significantly decreased CSF levels of L-Asp in both relapsing-remitting (n = 157) MS (RR-MS) and secondary progressive/primary progressive (n = 22) (SP/PP-MS) patients, compared to control subjects with other neurological diseases (n = 40). Importantly, in RR-MS patients, L-Asp levels were correlated with the CSF concentrations of the inflammatory biomarkers G-CSF, IL-1ra, MIP-1β, and Eotaxin, indicating that the central content of this excitatory amino acid, as previously reported for L-Glu, reflects a neuroinflammatory environment in MS. In keeping with this, we revealed that CSF L-Asp levels were positively correlated with those of L-Glu, highlighting the convergent variation of these two excitatory amino acids under inflammatory synaptopathy occurring in MS

Evidence confirms an anthropic origin of Amazonian Dark Earths.

Arising from: Silva et al. Nature Communications https://doi.org/10.1038/s41467-020-20184-2 (2021

The Saracá longhouse: a cultural boundary in the Pre-Colonial Middle Amazon from an house perspective

Esta pesquisa pretende contribuir para o entendimento da formação e da manutenção de uma fronteira cultural no contexto do médio Amazonas, durante o período pré-colonial tardio. O objeto de estudo insere-se no âmbito do ápice demográfico na Amazônia central, decorrente da convergência de movimentos populacionais em larga escala, associados à expansão das duas últimas grandes tradições culturais pré-coloniais: a Polícroma da Amazônia e a Inciso-Ponteada. Tal período foi descrito ressaltando a ocorrência de fortes conflitos em um processo de reconfiguração cultural. Através de uma abordagem que considera as fronteiras como processos históricos, propomos que na região do baixo rio Urubu (AM), a partir do ano 1000 d. C., a penetração de elementos exógenos faça de contrapeso à formação de um estilo local, a tradição Saracá, capaz de incorporar tais elementos e naturaliza-los sobre a base de uma ideologia de persistência cultural. Portanto, a hipótese com a qual trabalhamos vira ao avesso a visão tradicional, ao sustentar que à base da formação dessa fronteira persistente tenhamos que admitir o desenvolvimento e a afirmação de uma política interacionista. Com o objetivo de testar tal hipótese, investigamos o contexto de uma casa, localizada no sítio arqueológico Bom Socorro (Itacoatiara-AM); partindo do pressuposto que o âmbito doméstico possa ser altamente informativo das relações que se instauram entre o nível local e o nível regional. A escavação de tal estrutura possibilitou inserir a variabilidade artefatual dentro da dimensão social de uma comunidade circunscrita. Os resultados apontam para um período de ocupação do sítio entre 1430 e 1650 AD, quando, a interação entre diferentes grupos na região tem levado a formação de grandes assentamentos, compostos por casas comunais dispostas segundo fileiras paralelas. No setor central da maloca foi encontrada uma área de consumo de alimentos, possivelmente associada ao âmbito político-convivial. As cerâmicas desse contexto condensam toda a variabilidade estilística regional, revelando a ocorrência de relações sociais que perpassam as fronteiras culturais. O estudo das relações estilísticas entre a cerâmica Saracá e os outros conjuntos demostra que essa tradição local compartilha muitos traços diagnósticos também com os estilos mais antigos; inclusive, é evidente uma forte semelhança iconográfica com a arte rupestre regional. Tais elementos apontam para a produção de um estilo local fortemente embasado na tradição, que possivelmente reflete a intenção de reificar uma fronteira social.This research aims to understand the formation and maintenance of a cultural frontier in the context of Middle Amazonas, during the late pre-contact period. The scope of this research is focused on the demographic peak period of central Amazonia, due to large population movements, along with the spread of the two last important traditions of pre-contact period: Polychrome and Incised and Punctate. This period has been characterized by heavy conflicts in a context of culture change. If we consider the frontier as an historical process, we argue that in this region, from 1000 AD onward, exogenous cultural elements are coexistent with a local style, Saracá tradition, which was able to include these items on a pre-existing ideological conservativism. Because of this, we argue the opposite of customary approach, stressing that at the very basis of this cultural frontier a cultural interchange has been developed and strengthened. In order to test this hypothesis, from the standpoint that domestic context is highly informative, we studied a communal house of Bom Socorro archaeological site (Amazonas state, Brazil). The excavation of this domestic structure made possible the contextualization of this artefactual variability in the social dimension of a small community, showing the connections of different cultural traditions with extra-frontier social bonds. Results point to an occupation period which extends between 1430 and 1650 AD, when the interaction between different groups lead to formation of large settlements made by large communal houses placed in parallel lines. In the central area of the house a feeding area has been recovered, possibly associated to a political or religious function. Ceramic production from this context is a synthesis of the entire regional stylistic variability, pointing to social relationships crossing cultural frontiers. The study of stylistic relationship between Saraca ceramics and other groups demonstrates that this local tradition shares many specific traits with the oldest stylistic assemblages. A strong iconographic relationship with regional rock art is also evident. All these elements point to the production of a local style deeply rooted into the tradition, maybe reflecting the aim of stressing a real social frontier

Amyloid-β Homeostasis Bridges Inflammation, Synaptic Plasticity Deficits and Cognitive Dysfunction in Multiple Sclerosis

Cognitive deficits are frequently observed in multiple sclerosis (MS), mainly involving processing speed and episodic memory. Both demyelination and gray matter atrophy can contribute to cognitive deficits in MS. In recent years, neuroinflammation is emerging as a new factor influencing clinical course in MS. Inflammatory cytokines induce synaptic dysfunction in MS. Synaptic plasticity occurring within hippocampal structures is considered as one of the basic physiological mechanisms of learning and memory. In experimental models of MS, hippocampal plasticity is profoundly altered by proinflammatory cytokines. Although mechanisms of inflammation-induced hippocampal pathology in MS are not completely understood, alteration of Amyloid-beta (A beta) metabolism is emerging as a key factor linking together inflammation, synaptic plasticity and neurodegeneration in different neurological diseases. We explored the correlation between concentrations of A beta(1-42) and the levels of some proinflammatory and anti-inflammatory cytokines (interleukin-1 beta (IL-1 beta), IL1-ra, IL-8, IL-10, IL-12, tumor necrosis factor alpha (TNF alpha), interferon gamma (IFN gamma)) in the cerebrospinal fluid (CSF) of 103 remitting MS patients. CSF levels of A beta(1-42) were negatively correlated with the proinflammatory cytokine IL-8 and positively correlated with the anti-inflammatory molecules IL-10 and interleukin-1 receptor antagonist (IL-1ra). Other correlations, although noticeable, were either borderline or not significant. Our data show that an imbalance between proinflammatory and anti-inflammatory cytokines may lead to altered A beta homeostasis, representing a key factor linking together inflammation, synaptic plasticity and cognitive dysfunction in MS. This could be relevant to identify novel therapeutic approaches to hinder the progression of cognitive dysfunction in MS

Inflammation and Corticospinal Functioning in Multiple Sclerosis: A TMS Perspective

Transcranial magnetic stimulation (TMS) has been employed in multiple sclerosis (MS) to assess the integrity of the corticospinal tract and the corpus callosum and to explore some physiological properties of the motor cortex. Specific alterations of TMS measures have been strongly associated to different pathophysiological mechanisms, particularly to demyelination and neuronal loss. Moreover, TMS has contributed to investigate the neurophysiological basis of MS symptoms, particularly those not completely explained by conventional structural damage, such as fatigue. However, variability existing between studies suggests that alternative mechanisms should be involved. Knowledge of MS pathophysiology has been enriched by experimental studies in animal models (i.e., experimental autoimmune encephalomyelitis) demonstrating that inflammation alters synaptic transmission, promoting hyperexcitability and neuronal damage. Accordingly, TMS studies have demonstrated an imbalance between cortical excitation and inhibition in MS. In particular, cerebrospinal fluid concentrations of different proinflammatory and anti-inflammatory molecules have been associated to corticospinal hyperexcitability, highlighting that inflammatory synaptopathy may represent a key pathophysiological mechanism in MS. In this perspective article, we discuss whether corticospinal excitability alterations assessed with TMS in MS patients could be useful to explain the pathophysiological correlates and their relationships with specific MS clinical characteristics and symptoms. Furthermore, we discuss evidence indicating that, in MS patients, inflammatory synaptopathy could be present since the early phases, could specifically characterize relapses, and could progressively increase during the disease course