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Background and Objectives To determine the relative importance of global or regional MRI and blood markers of neurodegeneration and neuroaxonal injury in predicting cognitive performance for recently diagnosed patients with multiple sclerosis (MS). Methods Thirty-five newly diagnosed patients with relapsing-remitting MS (RRMS) and 23 healthy controls (HCs) simultaneously completed a full clinical and neuropsychological assessment, structural brain MRI, and serum neurofilament light chain (sNfL) level test. Linear regression analyses were performed to determine which global or regional measures of gray matter (GM) atrophy and cortical thickness (CT), in combination with sNfL levels and clinical scores, are most strongly related to neuropsychological impairment. Results Compared with HCs, patients with MS showed bilateral thalamic GM atrophy (left, p = 0.033; right, p = 0.047) and diminished CT, particularly in the right superior and transverse temporal gyri (p = 0.045; p = 0.037). Regional atrophy failed to add predictive variance, whereas anxiety symptoms, sNfL, and global CT were the best predictors (R-2 = 0.404; p < 0.001) of cognitive outcomes, with temporal thickness accounting for greater variance in cognitive deficits than global CT. Discussion Thalamic GM atrophy and thinning in temporal regions represent a distinctive MRI trait in the early stages of MS. Although sNfL levels alone do not clearly differentiate HCs and patients with RRMS, in combination with global and regional CT, sNfL levels can better explain the presence of underlying cognitive deficits. Hence, cortical thinning and sNfL increases can be considered 2 parallel neurodegenerative markers in the pathogenesis of progression in newly diagnosed patients with MS., This work was supported by the European Regional Development Fund and the Spanish Ministry of Science, Innovation and Universities (grant: RTI2018-096951-A-I00) and the Ministry of Economy and Competitiveness (grant: RYC-2015-18467).

[Introduction] Stroke is a serious public health problem, given it is a major cause of disability worldwide despite the spread of recanalisation therapies. Enhancement of brain plasticity with stem cell administration is a promising innovative therapy to reduce sequelae in these patients., [Methods and analysis] We have developed a phase IIb, multicentre, randomised, double-blind, placebo-controlled clinical trial protocol to evaluate the safety and efficacy of intravenous administration of allogeneic adipose tissue-derived mesenchymal stem cells (AD-MSCs) in patients with acute ischaemic stroke, concurrently with conventional stroke treatment. Thirty patients will be randomised on a 1:1 basis to receive either intravenous placebo or allogeneic AD-MSCs as soon as possible within the first 4 days from stroke symptom onset. Patients will be followed up to 24 months after randomisation. The primary objective is the safety assessment of early intravenous administration of allogeneic AD-MSCs by reporting all adverse events and neurological or systemic complications in both treatment groups. Secondary objectives assess efficacy of early intravenous AD-MSC treatment in acute ischaemic stroke by evaluating changes in the modified Rankin Scale and the National Institutes of Health Stroke Scale throughout the follow-up period. In addition, brain repair biomarkers will be measured at various visits., [Ethics and dissemination] This clinical trial has been approved by the Clinical Research Ethics Committee of La Paz University Hospital (Madrid, Spain) and by the Spanish Agency of Medication and Health Products and has been registered in Eudra CT (2019-001724-35) and ClinicalTrials.gov (NCT04280003). Study results will be disseminated through peer-reviewed publications in Open Access format and at conference presentations., This clinical trial has been promoted by the La Paz University Hospital Institute for Health Research—IdiPAZ (La Paz University Hospital—Universidad Autónoma de Madrid) and sponsored from a competitive grant from the Carlos III Health Institute Healthcare Research Fund, and cofunded by the European Regional Development Fund (ERDF) 'A way to make Europe'/'Investing in your future' (PIC18/00016). This clinical trial has been supported by Plataforma Española de Investigación Clínica y Ensayos Clínicos, SCReN (Spanish Clinical Research Network), funded by Carlos III Health Institute-General Subdirection for Evaluation and Promotion of Research, research PT17/0017/0013; State Plan for Scientific Investigation, Technology and Innovation (2017–2020) and cofunded by European Regional Development Fund/European Social fund 'A way to make Europe'/'Investing in your future' (grant ID PT17/0017/0013).

In the teaching of biology and science the understanding of macroscopic morphology prioritizes the two-dimensional view, much more for logistic than pedagogical factors. Such a view, offered by textbooks, is the most important limiting factor for mastering these skills. Good quality three-dimensional models are costly. Biological materials of known origin and ethics are also infrequent, their preparation and preservation require skilled labor, constant curation and even require chemicals in their preparation that are irritating, toxic or with potential for abuse, e.g. formaldehyde, alcohol, chloroform. The need to bring the student closer to the content taught in the classroom enriching the didactics and improving the teaching-learning process leads to a search for new ways and materials that help the teacher in this development. The action protocol for the production of didactic material for the teaching of anatomy, using semifin slices of vertebrate brain, fixed and later included in polyester acrylic resin facilitates the real contact of the student with the theoretically exposed, disconnecting from the need for a science and biology lab, since resin is a lightweight, non-toxic, long-lasting material that can be taken into the classroom. The choice of neuroanatomy (brain) pieces is interesting because of their structural and nomenclature complexity that, when viewed and handled, facilitates the student's theoretical-practical correlation. No ensino de Biologia e Ciências a compreensão da morfologia macroscópica prioriza a visão bidimensional, muito mais por fatores logísticos do que pedagógicos. Tal visão, oferecida pelos livros didáticos, é o fator limitante mais importante para o domínio destas competências. Modelos tridimensionais de boa qualidade são de custo elevado. Materiais biológicos de procedência conhecida e ética também são infrequentes, sua preparação e conservação exigem mão de obra especializada, curadoria constante e ainda requerem substâncias químicas no seu preparo que são irritantes, tóxicas ou com potencial de abuso, e.g. formol, álcool, clorofórmio. A necessidade de aproximar o estudante do conteúdo ministrado em sala de aula enriquecendo a didática e melhorando o processo ensino-aprendizagem faz com que haja uma busca de novas maneiras e materiais que auxiliem o professor neste desenvolvimento. O protocolo de ação para a produção de material didático, para o ensino de Anatomia, fazendo uso de fatias semifinas de encéfalo de vertebrados, fixado e posteriormente incluídas em resina acrílica de poliéster facilita o contato real do estudante com o exposto teoricamente, desvinculando da necessidade de um laboratório de Ciências e Biologia, uma vez que a resina é um material leve, atóxico, de grande durabilidade e que pode ser levado para dentro da sala de aula. A escolha de peças da neuroanatomia (encéfalos) se mostra interessante devido a sua complexidade estrutural e de nomenclatura que, ao ser vista e manuseada, facilita ao estudante a correlação teórico-prática.

Objective: To compare fetuses with intrauterine growth restriction (IUGR) and those with normal growth, in terms of skull and brain measurements obtained by magnetic resonance imaging (MRI). Materials and Methods: This was a prospective cohort study including 26 single fetuses (13 with IUGR and 13 with normal growth), evaluated from 26 to 38 weeks of gestation. Using MRI, we measured skull and brain biparietal diameters (BPDs); skull and brain occipitofrontal diameters (OFDs); corpus callosum length and area; transverse cerebellar diameter; extracerebral cerebrospinal fluid (eCSF); and right and left interopercular distances (IODs). Results: The following were significantly smaller in IUGR fetuses than in control fetuses: skull BPD (76.9 vs. 78.2 mm; p = 0.0029); brain BPD (67.8 vs. 71.6 mm; p = 0.0064); skull OFD (93.6 vs. 95 mm; p = 0.0010); eCSF (5.5 vs. 8.2 mm; p = 0.0003); right IOD (9.8 vs. 13.9 mm; p = 0.0023); and left IOD (11.8 vs. 16.3 mm; p = 0.0183). The skull BPD/eCSF, brain BPD/eCSF, skull OFD/eCSF, and brain OFD/eCSF ratios were also lower in IUGR fetuses. Conclusion: IUGR fetuses had smaller OFD and BPD, both skull and brain, and less eCSF when compared to normal growth fetuses. Resumo Objetivo: Comparar medidas do crânio e encéfalo por meio da ressonância magnética (RM) de fetos com restrição do crescimento intrauterino (RCIU) e com crescimento adequado. Materiais e Métodos: Realizou-se um estudo de coorte prospectivo com 13 fetos com RCIU e 13 controles entre 26 e 38 semanas. Foram realizadas as seguintes medidas por RM: diâmetro biparietal (DBP) e diâmetro occipitofrontal (DOF) cerebral e ósseo, comprimento e área do corpo caloso (CPC), diâmetro transverso do cerebelo, líquido cerebroespinhal (LCE) extracerebral e distância interopercular (DIO) direita e esquerda. Resultados: Observaram-se diferenças significativas nas medidas do DBP ósseo (76,9 vs. 78,2 mm; p = 0,0029), DBP cerebral (67,8 vs. 71,6 mm; p = 0,0064) e DOF ósseo (93,6 vs. 95 mm; p = 0,0010) em fetos com RCIU em relação aos fetos com crescimento normal. Observaram-se, ainda, diferenças significativas nas médias do LCE extracerebral (5,5 vs. 8,2 mm; p = 0,0003) e DIO direita (9,8 vs. 13,9 mm; p = 0,0023) e esquerda (11,8 vs. 16,3 mm; p = 0,0183) em fetos com RCIU em relação aos controles. Fetos com RCIU e normais tiveram diferenças entre DBP ósseo/LCE, DBP cerebral/LCE, DOF/LEC, e DOF cerebral/LCE. Conclusão: Fetos com RCIU tiveram menores DBP e DOF, ambos crânio e encéfalo, e menor LCE extracerebral que fetos com crescimento adequado.

Submitted by Charles Hebert Guedes (c.guedes@unesp.br) on 2021-07-05T21:02:39Z No. of bitstreams: 1 Dissertação Charles Hebert Guedes.pdf: 800198 bytes, checksum: e3cc757c146993f188eebf63658724e1 (MD5) Approved for entry into archive by Tais de Almeida (tais.almeida@unesp.br) on 2021-07-06T12:58:04Z (GMT) No. of bitstreams: 1 guedes_ch_me_bot.pdf: 800198 bytes, checksum: e3cc757c146993f188eebf63658724e1 (MD5) Made available in DSpace on 2021-07-06T12:58:04Z (GMT). No. of bitstreams: 1 guedes_ch_me_bot.pdf: 800198 bytes, checksum: e3cc757c146993f188eebf63658724e1 (MD5) Previous issue date: 2021-05-12 A ressonância magnética (RM) tem papel importante na detecção e caracterização das lesões meníngeas, auxiliando assim, um possível diagnóstico clínico ante mortem de doenças intracranianas. O realce meníngeo tem sido descrito como um sinal de múltiplas enfermidades do sistema nervoso central. O objetivo deste estudo foi avaliar o realce meníngeo nas imagens de RM do encéfalo de cães e compilar a associação com diferentes doenças do sistema nervoso central. Foi realizado um estudo retrospectivo de cães submetidos ao exame de ressonância magnética sendo o histórico de déficit neurológico um critério de inclusão para seleção destes animais, os dados foram divididos de acordo com a idade e sexo. Os resultados obtidos na imagem de RM demonstram que entre as doenças observadas a encefalite e a neoplasia apresentaram 22,7% de suspeitas clínicas mais relevantes em relação as outras amostras. Analisado o local de maior incidência foi parietal/temporal/frontal com 27,3%. A descrição e avaliação das frequencias das meninges apresentaram em 90,9% da Pial e Dural e para definição do realce o resultado foi de 59,1% pouco apresentado. O presente estudo possibilitou obter informações específicas e maior compreensão das características de realce meningeal incluindo-se dois padrões de realce meníngeo (pial e dural) e identificar a associação dos valores nas diferentes doenças do sistema nervoso central em cães. Magnetic resonance imaging (MRI) plays an important role in the detection and characterization of meningeal lesions, thus assisting in the clinical diagnosis (ante mortem) of intracranial disease. Meningeal enhancement has been described as a sign of multiple diseases of the central nervous system. The aim of this study was to evaluate whether meningeal enhancement on MRI images of the brain of dogs and to compile the association with diseases of the central nervous system. A retrospective study of dogs submitted to magnetic resonance imaging was conducted and the history of neurological deficit was established as an inclusion criterion for the selection of animals in the study. The data obtained in the exam will be divided according to age and gender, evaluated and computed. The results obtained in the MRI image show that among the diseases observed encephalitis and neoplasia presented 22.7% of clinical suspicions more relevant in relation to the other samples. The site with the greatest finding was parietal/temporal/frontal with 27.3%. The description and evaluation of the frequency of the meninges presented in 90.9% of Pial and Dural and to define the Highlight the result was 59.1% little presented. It was concluded that the present study made it possible to obtain specific information and a greater understanding of the characteristics where it was possible to study the two patterns of meningeous enhancement (pial and dural) and to evaluate that meningeous enhancement through MRI images for different diseases in the brain of dogs there is an association of most values in the varieties of diseases of the nervous system.

The anatomical study of non-human primates has played an important role in clinical and surgical interventions in veterinary medicine. It is known that the most well-known experimental model in the scientific area is the Macaca mulatta, popularly known as the Rhesus monkey, and what the literature has demonstrated are new experimental models that can supply studies on the central nervous system, making it necessary for these discoveries to deepen greater in the area of comparative anatomy. The purpose of this literature review is to promote a broad view of the anatomical aspects of the brain of human and non-human primates in comparative terms. In this review, some peculiarities were observed in non-human primates regarding the path of blood vessels in the brain, as well as the presence of different venous sinuses of the dura when compared to the human primate. The importance of the morphological study regarding the anatomy of the telencephalon, as well as the mechanisms of lining, cerebral arterial irrigation and drainage of the venous sinuses of the dura mater, provides information on the brain organization of non-human primates, data that are scarce in the literature scientific, but that generate subsidies for understanding other areas of ethological and functional investigations, when compared to the human primate. El estudio anatómico de primates no humanos ha jugado un papel importante en las intervenciones clínicas y quirúrgicas en medicina veterinaria. Se sabe que el modelo experimental más conocido en el área científica es el Macaca mulatta, conocido popularmente como el mono Rhesus, y lo que ha demostrado la literatura son nuevos modelos experimentales que pueden aportar estudios sobre el sistema nervioso central, por lo que es necesario para que estos descubrimientos se profundicen más en el área de la anatomía comparada. El propósito de esta revisión de la literatura es promover una visión amplia de los aspectos anatómicos del cerebro de primates humanos y no humanos en términos comparativos. En esta revisión, se observaron algunas peculiaridades en primates no humanos con respecto al recorrido de los vasos sanguíneos en el cerebro, así como la presencia de diferentes senos venosos de la duramadre en comparación con el primate humano. La importancia del estudio morfológico respecto a la anatomía del telencéfalo, así como los mecanismos de revestimiento, irrigación arterial cerebral y drenaje de los senos venosos de la duramadre, aporta información sobre la organización cerebral de primates no humanos, datos que son escasa en la literatura científica, pero que genera subsidios para comprender otras áreas de las investigaciones etológicas y funcionales, en comparación con el primate humano. O estudo anatômico de primatas não-humanos, tem exercido função importante para intervenções clínicas e cirúrgicas em atendimento da medicina veterinária. Sabe-se que o modelo experimental mais conhecido na área científica é a Macaca mulatta, popularmente conhecido como macaco Rhesus e o que a literatura tem demonstrado são novos modelos experimentais que possam suprir estudos sobre o sistema nervoso central, sendo necessário para essas descobertas um aprofundamento maior na área da anatomia comparativa. O objetivo desta revisão de literatura é promover uma visão ampla sobre os aspectos anatômicos do encéfalo de primatas humanos e não-humanos em termos comparativos. Observou-se nesta revisão algumas particularidades em primatas não-humanos referentes ao trajeto dos vasos sanguíneos no encéfalo, assim como a presença de diferentes seios venosos da dura-máter quando comparados ao primata humano. A importância do estudo morfológico no que se refere a anatomia do telencéfalo, assim como os mecanismos de revestimento, irrigação arterial encefálica e drenagem dos seios venosos da dura-máter, possibilita informações sobre a organização encefálica dos primatas não-humanos, dados esses escassos na literatura científica, mas que geram subsídios para compreensão de outras áreas de investigações etológicas e funcionais, quando comparados ao primata humano.

[spa] Los trastornos neurocognitivos (TNC) son un grupo heterogéneo de entidades clínicas cuya característica principal es el deterioro de todas o algunas de las capacidades funcionales y cognitivas previamente adquiridas por el individuo. Entre ellos encontramos el TNC mayor, tener múltiples etiologías, su causa más común es la enfermedad de Alzheimer (EA). Las marcas neuropatológicas distintivas de esta patología son la acumulación de placas de proteína β-amiloide y la de proteína tau hiperfosforilada que forma, entre otros, ovillos neurofibrilares. El primer lugar en el que se han detectado cambios en el proceso de formación de estas acumulaciones es el locus coeruleus (LC). Este es un núcleo situado en el tegmento pontino y es la mayor fuente de noradrenalina del sistema nervioso central. La integridad estructural del LC se ha investigado tanto en EA como en población en riesgo de desarrollar EA, sin embargo la preservación funcional de este núcleo a lo largo del continuum del TNC restaba sin estudiar. En esta tesis se presentan dos estudios centrados en la evaluación de la conectividad funcional entre el LC y diferentes regiones corticales y subcorticales, en grupos en riesgo de EA: hijos de pacientes con EA de inicio tardío (H-EAIT), individuos con deterioro cognitivo leve (DCL) y pacientes con trastorno depresivo mayor en edad avanzada (TDM); con el fin de comprobar si la medición de la funcionalidad del LC puede constituir un marcador precoz del comienzo del proceso neurodegenerativo en estas etapas tempranas del TNC. El primer estudio se centra en analizar la conectividad del LC en un grupo de H- EAIT, en comparación con sujetos sanos, durante una secuencia de resonancia magnética funcional en estado de reposo. En el segundo estudio se incluyó un grupo de DCL, de TDM y un grupo control; y se estudió la conectividad del LC durante la realización de una tarea oddball o de detección de estímulos, que permite estudiar la actividad neuronal del LC. En ambos casos correlacionamos los resultados de los análisis de neuroimagen con medidas clínicas, neuropsicológicas y conductuales, con el fin de caracterizar los patrones de alteración funcional y su asociación con posibles variables clínicas o cognitivas. Nuestros resultados apuntan a la disminución de la conectividad global del LC en el grupo de H-EAIT durante el estado de reposo y en TDM ante la detección de estímulos salientes (oddball). En ambos grupos observamos una disminución de la conectividad entre el LC y regiones del cerebelo posterior, implicadas en la modulación de la actividad de la red por defecto, de control ejecutivo y de saliencia. Igualmente, el grupo de TDM se caracteriza por presentar una disminución de la conectividad entre el LC y el giro fusiforme y la corteza cingulada anterior (CCA) ante los estímulos oddball. En los H-EAIT encontramos una correlación positiva entre la conectividad del LC-cerebelo posterior y medidas de recuerdo diferido que señala la implicación de este patrón en la función mnésica. Además, encontramos una asociación negativa entre la severidad de síntomas depresivos y la conectividad LC-cerebelo posterior. En los TDM, la conectividad LC-CCA se asocia negativamente con medidas de severidad y carga del trastorno depresivo, reflejo de la diferenciación entre dos subgrupos de pacientes depresivos: en episodio activo de depresión y en remisión. Los resultados de este estudio confirman que existen alteraciones en la conectividad del LC en estadios iniciales del TNC y en población con un riesgo incrementado de desarrollo de EA. Además, apoyan la modulación del LC de regiones corticales y subcorticales implicadas en función mnésica, atencional y regulación del arousal. Esta tesis supone un punto de base para la investigación más profunda del LC a lo largo del continuo del TNC, con el fin de poder desarrollar herramientas diagnósticas no invasivas que permitan detectar precozmente procesos neurodegenerativos y el desarrollo de tratamientos más personalizados., [eng] Neurocognitive disorders (NCD) are a heterogeneous group of clinical entities that share as a principal hallmark the impairment in all or some of the previously acquired cognitive and functional capacities. Among this group, Alzheimer’s disease (AD) is the most prevalent cause of NCD. The two biological hallmarks of AD are the β-amyloid plaques and hyperphosphorylated tau neurofibrillary tangles. The locus coeruleus (LC) nucleus, the major source of noradrenaline to the central nervous system, is the region where pathological changes start in the continuum of AD. Structural integrity of this nucleus has been investigated in AD and AD at-risk population, but its functional preservation remained unstudied. In this thesis, we present two studies focused in the LC functional connectivity. The first study included a group of offspring of late onset AD (O-LOAD) and we used a resting-state functional magnetic resonance (rs-fMRI). For the second study a group of mild cognitive impairment (MCI) and late-life major depressive disorder (MDD) were recruited and they performed an oddball task during the acquisition of functional magnetic resonance imaging (fMRI). In both works, neuroimaging results were correlated with clinical, neuropsychological and behavioral data. Firstly, we found that both O-LOAD and MDD groups showed a diminished LC global connectivity, and these groups also presented a lower connectivity between LC and posterior cerebellum regions, during rs-fMRI and the oddball task, respectively. Moreover, MDD showed a lower connectivity between LC and fusiform gyrus and anterior cingulate cortex (ACC) in front of oddball stimuli. In O-LOAD we observed a negative association between LC-posterior cerebellum and depression symptoms and memory measures; and MDD showed an inverse correlation between LC-CCA connectivity and depression severity and the number of episodes measures. Our results point to the presence of connectivity alterations of LC in early stages of NCD and in AD at- risk population. A deeper investigation of functional activity and connectivity of the LC through the NCD continuum would be useful for the development of non-invasive diagnostic tools and the development of personalized treatments.

As epilepsias afetam aproximadamente 1% da população mundial, sendo que 80% dos pacientes habitam países subdesenvolvidos ou em desenvolvimento e de 20 a 30% ou não tem acesso ou não respondem aos tratamentos disponíveis. As epilepsias causam grande prejuízo à qualidade de vida dos pacientes pelos sintomas associados e os problemas acometem também familiares e cuidadores visto que essas doenças ainda são muito estigmatizadas. Embora as etiologias das epilepsias sejam conhecidas em sua maioria, algumas causas desconhecidas desencadeiam episódios de crises epilépticas. O metabolismo encefálico de forma geral é investigado para esclarecimento da fisiopatologia de várias doenças neurodegenerativas, mais especificamente a função e/ou disfunção mitocondrial vem tendo muito mais atenção da comunidade científica. A disfunção mitocondrial é apontada como um fator de risco em alguns tipos de epilepsias genéticas, mas em casos de epilepsias adquiridas o seu papel permanece elusivo. Técnicas sofisticadas como a respirometria de alta resolução são empregadas e aprimoradas constantemente para a avaliação da função mitocondrial. Nesse contexto, avaliamos por meio de diferentes estratégias investigativas o efeito de indutores de crises epilépticas em modelos animais (peixe-zebra e camundongos) sobre a função mitocondrial. As questões deste estudo são: i) Os indutores de crises promovem danos mitocôndrias durante e após as crises epilépticas? ii) O pentilenotetrazol possui algum outro efeito sobre mitocôndrias além do estresse oxidativo já demonstrado? Os resultados observados mostram que o efeito agudo de pentilenotetrazol in vitro quando adicionado ao meio contendo células intactas e dissociadas de tecido encefálico de peixe-zebra aumenta a eficiência de acoplamento (p/O2), o que pode indicar uma hidrólise aumentada de ATP neuronal. Também observamos aumento na capacidade de reserva no grupo status epilepticus induzido por ácido caínico in vivo, o que pode estar relacionado à capacidade mitocondrial de responder a um aumento na demanda de energia, especialmente em neurônios. Além disso, buscamos entender o papel das variações da concentração Ca2+ empregando concentrações de 500nm (repouso) e 5μM (ativação) em homogeneizado de tecido encefálico de peixe-zebra adulto. Nós observamos que a bioenergética mitocondrial é prejudicada de forma concentração-dependente, o estado 3, estado 4 e o desacoplamento são diminuídos pela presença de ambas concentrações de Ca2+, corroborando com a diminuição do controle respiratório, indicativo de integridade mitocondrial. No entanto, o entendimento do papel do Ca2+ no metabolismo encefálico e na bioenergética permanece como perspectiva deste trabalho. Após, realizamos o isolamento de mitocôndrias a partir de fígado e encéfalo de camundongos e observamos que as mesmas mitocôndrias são afetadas quando expostas diretamente ao pentilenotetrazol, especificamente o complexo I é inibido, independente de desidrogenases e transporte e por mecanismo diferente a inibição causada por rotenona. Inferimos que as mitocôndrias encefálicas são mais sensíveis ao pentilenotetrazol porque concentrações mais baixas foram capazes de diminuir a atividade do complexo I em comparação com as mitocôndrias hepáticas. Por fim, o presente trabalho traz evidências que sustentam o conceito de que crises epilépticas estão relacionadas com comprometimento de funções mitocondriais, o que de forma translacional pode indicar contribuição da disfunção mitocondrial para a condição clínica de pacientes diagnosticados com epilepsias adquiridas. Isto é, indica-se considerar o dano mitocondrial como parte da fisiopatologia de epilepsias adquiridas. Dessa forma, a prevenção e/ou o reparo do dano mitocondrial podem ser estratégias de prevenção e tratamento adicionados às diretrizes clínicas. Epilepsies affect approximately 1% of the world population, 80% of the patients live in underdeveloped or developing countries and 20% to 30% either do not have access to or do not respond to available treatments. Epilepsies impair the quality of life of patients due to associated symptoms; the problems also affect family members and caregivers as these diseases are still highly stigmatized. Although the etiologies of epilepsies are mostly known, some unknown causes trigger seizure episodes. Brain metabolism, in general, is investigated to clarify the pathophysiology of several neurodegenerative diseases. More specifically, mitochondrial function and/or dysfunction has been receiving much more attention from the scientific community. Mitochondrial dysfunction is identified as a risk factor in some types of genetic epilepsies, but its role remains elusive in cases of acquired epilepsies. Sophisticated techniques such as high-resolution respirometry are constantly applied and improved to assess mitochondrial function. In this context, we evaluated through different investigative strategies the effect of SE inducers in animal models (zebrafish and mice) on mitochondrial function. The questions of this study are: i) Do seizure inducers promote mitochondrial damage during and after epileptic seizures? ii) Does pentylenetetrazole have any other effects on mitochondria besides the oxidative stress already reported? We observed that the acute exposure to PTZ in vitro in the medium containing intact and dissociated cells from zebrafish brain tissue increases the coupling efficiency (p/O2), which may indicate an increased hydrolysis of neuronal ATP. We also observed an increase in reserve capacity in the SE group induced by kainic acid in vivo, which may be related to the mitochondrial ability to respond to an increase in energy demand, especially neurons. We also sought to understand the role of variations in Ca2+ concentration using concentrations of 500nm (resting) and 5μM (activation) in adult zebrafish brain tissue homogenate. We observed that mitochondrial bioenergetics is concentration-dependently impaired, state 3, state 4 and uncoupled are impaired by the presence of both concentrations of Ca2+, corroborating to the decrease in respiratory control, indicative of mitochondrial integrity. However, the understanding of the role of Ca2+ in brain metabolism and bioenergetics remains a perspective of this work. Afterwards, we performed the isolation of mitochondria from the liver and brain of mice and observed that the same mitochondria are affected when directly exposed to PTZ, specifically complex I is inhibited, independent of dehydrogenases and transport and by a different mechanism of the inhibition caused by rotenone. We imply that brain mitochondria are more sensitive to pentylenetetrazole because lower concentrations were able to impair complex I activity compared to liver mitochondria. Finally, the present work provides evidence that supports the concept that epileptic seizures are related to impairment of mitochondrial functions, which in a translational way may indicate the contribution of mitochondrial dysfunction to the clinical condition of patients diagnosed with acquired epilepsies. In other words, we should consider mitochondrial damage as part of the pathophysiology of acquired epilepsies. Thus, the prevention and/or repair of mitochondrial damage can be prevention and treatment strategies added to clinical guidelines.

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The human Alzheimer’s disease (AD) brain accumulates angiogenic markers but paradoxically, the cerebral microvasculature is reduced around Aß plaques. Here we demonstrate that angiogenesis is started near Aß plaques in both AD mouse models and human AD samples. However, endothelial cells express the molecular signature of non-productive angiogenesis (NPA) and accumulate, around Aß plaques, a tip cell marker and IB4 reactive vascular anomalies with reduced NOTCH activity. Notably, NPA induction by endothelial loss of presenilin, whose mutations cause familial AD and which activity has been shown to decrease with age, produced a similar vascular phenotype in the absence of Aß pathology. We also show that Aß plaque-associated NPA locally disassembles blood vessels, leaving behind vascular scars, and that microglial phagocytosis contributes to the local loss of endothelial cells. These results define the role of NPA and microglia in local blood vessel disassembly and highlight the vascular component of presenilin loss of function in AD., A.E.R.-N. was the recipient of a JdlC-F fellowship from the Spanish Ministry of Economy, Industry, and Competitiveness (MINEICO) (FJCI-2015-23708), M.I.A.-V., N.L.-U., and C.O.-d.S.L. were the recipient of an FPU fellowship from Spanish Ministry of Education, Culture, and Sport (respectively, FPU15/02898, FPU14-02115, and AP2010‐1598), and R.M.-D. was the recipient of a “Sara Borrell” fellowship from ISCIII (CD09/0007). Work was supported by grants to A.P. by the Spanish MINEICO, ISCIII, and FEDER (SAF2012‐33816, SAF2015‐64111‐R, RTI2018-096629-B-100, SAF2017-90794-REDT, and PIE13/0004), by the regional Government of Andalusia (“Proyectos de Excelencia”, P12‐CTS‐2138 and P12‐CTS‐2232) co-funded by CEC and FEDER funds, and by the “Ayuda de Biomedicina 2018”, Fundación Domingo Martínez; J.Vitorica: Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union (PI18/01556) by La Marató-TV3 Foundation grant 20141431; by CIBERNED (CB06/05/0094); and by Junta de Andalucia Consejería de Economía y Conocimiento through grant US-1262734; A.G.: Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union, through grant PI18/01557; and by Junta de Andalucia Consejería de Economía y Conocimiento through grants UMA18-FEDERJA-211 and P18-RT-2233 co-financed by Programa Operativo FEDER 2014-2020.

Introduction Although the aetiology and pathophysiology of depression are multifactorial, to date most studies have examined either biological or environmental mechanisms without looking at the integration of both; with most studies conducted in high-income countries (HICs). Therefore, we conducted a systematic review of worldwide studies investigating the relationship between biological and environmental stress risk factors for major depressive disorder (MDD) in adolescence. Methods We searched MEDLINE (via Ovid), PsycINFO, Cochrane Database of Systematic Reviews, Web of Science (Core Collection), Lilacs, African Journals Online and Global Health for prospective and cross-sectional studies that examined the association between biological markers and environmental stress risk factors in MDD during adolescence. Findings Of 11,089 articles identified, 21 were included, with only two from middle-income countries. Increased inflammation, telomere length and brain abnormalities, including blunted reward-related activity, white matter disruptions, and altered volume of limbic brain regions, were associated with increased risk for MDD mainly in the context of early life adversity. There is little evidence suggesting that the neurobiological changes investigated were associated with MDD in the context of recent life stress. Interpretation The developmental trajectory of depression appears to start with early life adversities and occurs in the context of immune and brain abnormalities. Understanding these biopsychosocial processes will help to improve our ability to detect individuals at risk of developing depression in adolescence. However, generalizability is limited by few studies examining both biological and environmental stress risk factors and a lack of studies on adolescents and young adults in low-and-middle-income countries (LMICs).

Over the past years, brain development has been investigated in rodent models, which were particularly relevant to establish the role of specific genes in this process. However, the cytoarchitectonic features, which determine neuronal network formation complexity, are unique to humans. This implies that the developmental program of the human brain and neurological disorders can only partly be reproduced in rodents. Advancement in the study of the human brain surged with cultures of human brain tissue in the lab, generated from induced pluripotent cells reprogrammed from human somatic tissue. These cultures, termed brain organoids, offer an invaluable model for the study of the human brain. Brain organoids reproduce the cytoarchitecture of the cortex and can develop multiple brain regions and cell types. Integration of functional activity of neural cells within brain organoids with genetic, cellular, and morphological data in a comprehensive model for human development and disease is key to advance in the field. Because the functional activity of neural cells within brain organoids relies on cell repertoire and time in culture, here, we review data supporting the gradual formation of complex neural networks in light of cell maturity within brain organoids. In this context, we discuss how the technology behind brain organoids brought advances in understanding neurodevelopmental, pathogen-induced, and neurodegenerative diseases.

Submitted by Marcos Mota Borges Pereira (marcos.borges-pereira@unesp.br) on 2021-02-25T13:34:44Z No. of bitstreams: 1 tese pronta dez20.pdf: 684072 bytes, checksum: cef1ccc91a384dcc026778091bba33b9 (MD5) Approved for entry into archive by ROSANGELA APARECIDA LOBO null (rosangelalobo@btu.unesp.br) on 2021-02-25T21:05:44Z (GMT) No. of bitstreams: 1 pereira_mmb_dr_bot_par.pdf: 432964 bytes, checksum: 4657baaaf3dbdc58cc4959d907545ecf (MD5) Made available in DSpace on 2021-02-25T21:05:44Z (GMT). No. of bitstreams: 1 pereira_mmb_dr_bot_par.pdf: 432964 bytes, checksum: 4657baaaf3dbdc58cc4959d907545ecf (MD5) Previous issue date: 2020-10-01 As características dos tumores gliais na imagem de ressonância magnética em cães são extremamente similares às encontradas em humanos. Mudanças sutis na imagem podem revelar uma classificação de menor ou maior grau, indicando caráter agressivo e um prognóstico sombrio ao paciente. O total de 18 cães foram submetidos ao exame de ressonância magnética (RM) do encéfalo com a utilização de contraste paramagnético e o critério de inclusão adotado para o presente estudo foi a detecção de lesões solitárias intra-axiais na imagem de RM. A partir da sugestão diagnóstica de tumor intra-axial por imagem de ressonância magnética os animais foram submetidos ao tratamento com o uso da lomustina, quimioterápico utilizado para tratamento de tumores intracranianos, associado ao tratamento de suporte convencional. Cada paciente foi monitorado clinicamente durante o período de tratamento compilando-se os sinais clínicos apresentados. Os resultados obtidos na imagem de RM demostraram que os tumores primários intra-axias sotitários apresentaram localização predominante no telencéfalo (75%) e intensificação de contraste moderada. No monitoramento clínico dos animais, referente ao protocolo terapêutico instituído, observou-se maior acometimento da raça Boxer, idade média de 8,5 anos e o sinal clínico mais relevante foi alteração de estado mental. Na análise de sobrevida identificou-se a média de 85 dias para os tumores de localização supratentoriais e 26 dias para os tumores infratentoriais. O presente estudo possibilitou obter informações específicas e maior compreensão das características dos tumores intra-axiais em cães, assim como informações dos principais sinais clínicos e da sobrevida dos animais sob monitoramento do protocolo terapêutico. The characteristics of glial tumors in the MRI image in dogs are extremely similar to those found in humans. Subtle changes in the image can reveal a lower or higher degree of classification, thus indicating an aggressive character and a dismal prognosis for the patient. A total of 18 dogs underwent brain magnetic resonance examination using paramagnetic contrast and the inclusion criterion adopted for the present study was the detection of primary intra-axial lesions. Based on the diagnostic suggestion of an intra-axial tumor by magnetic resonance imaging, the animals were subjected to treatment using of lomustine, chemotherapy used to treat intracranial tumors, associated with conventional supportive treatment. Each patient was monitored clinically during the treatment period by compiling the clinical signs presented. The results obtained in the magnetic resonance image showed that the primary tumors of the solitary intra-axia showed a predominant location in the telencephalon (75%) and a moderate increase in contrast. In the clinical monitoring of the animals, referring to the established therapeutic protocol, a greater involvement of the Boxer breed was observed, with an average age of 8.5 years and the change in mental status was the most evident clinical sign. In the survival analysis, the average of 85 days for tumors of supratentorial location and 26 days for infratentorial tumors was identified. The present study made it possible to obtain specific information and a better understanding of the characteristics of intra axial tumors in dogs, as well as clinical information and animal survival under therapeutic protocol and clinical monitoring.

In Alzheimer’s disease (AD), and other tauopathies, microtubule destabilization compromises axonal and synaptic integrity contributing to neurodegeneration. These diseases are characterized by the intracellular accumulation of hyperphosphorylated tau leading to neurofibrillary pathology. AD brains also accumulate amyloid-beta (Aβ) deposits. However, the effect of microtubule stabilizing agents on Aβ pathology has not been assessed so far. Here we have evaluated the impact of the brain-penetrant microtubule-stabilizing agent Epothilone D (EpoD) in an amyloidogenic model of AD. Three-month-old APP/PS1 mice, before the pathology onset, were weekly injected with EpoD for 3 months. Treated mice showed significant decrease in the phospho-tau levels and, more interesting, in the intracellular and extracellular hippocampal Aβ accumulation, including the soluble oligomeric forms. Moreover, a significant cognitive improvement and amelioration of the synaptic and neuritic pathology was found. Remarkably, EpoD exerted a neuroprotective effect on SOM-interneurons, a highly AD-vulnerable GABAergic subpopulation. Therefore, our results suggested that EpoD improved microtubule dynamics and axonal transport in an AD-like context, reducing tau and Aβ levels and promoting neuronal and cognitive protection. These results underline the existence of a crosstalk between cytoskeleton pathology and the two major AD protein lesions. Therefore, microtubule stabilizers could be considered therapeutic agents to slow the progression of both tau and Aβ pathology., This study was supported by Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union, through grants PI15/00796 and PI18/01557 (both to AG), PI15/00957 and PI18/01556 (both to JV), and CIBERNED (CB06/05/1116 to AG and CB06/05/0094 to JV); by Malaga University grant PPIT.UMA.B1.2017/26 (to RSV). JJFV and CMC were supported by FPU PhD fellowships (Spanish Ministry of Science, Innovation and Universities). RSV held a postdoctoral contract from Malaga University. IMG is recipient of a senior postdoctoral contract from Ramon y Cajal Program (Spain Government).

We studied the arterial circle in the brain of five specimens of the Alouatta belzebul primate. The material had the arterial system perfused (water at 40°C), injected with stained latex (Neoprene 650), fixed in aqueous formaldehyde solution (10%) and dissected for vessel verification. The arterial circle of this primate is composed of two vascular systems: the vertebra-basilar and the carotid ones, which anastomose to close the arterial circuit. In the caudal portion of the arterial circle, there are the vertebral arteries and their branches: the rostral spinal artery and the caudal inferior cerebellar artery. The anastomosis of the vertebral arteries gives rise to the basilar artery. It presented an anatomical variation at the beginning of its path, forming a double basilar artery, called arterial island. In its course, it emitted branches giving rise to the rostral inferior cerebellar artery, the pontine arteries, the rostral cerebellar arteries, the satellite rostral cerebellar arteries and its terminal branch, the caudal cerebral artery, which presented itself in two segments: the pre-communicating one and post-communicating, joining the internal carotid artery and originating the caudal communicating artery. This group of arteries and anastomoses enclose the caudal portion of the arterial circle. From the right and left internal carotid arteries begins the rostral portion of the arterial circle, which consists of the right and left rostral cerebral arteries and the right and left middle cerebral arteries. The rostral cerebral arteries anastomose into a single trunk, giving rise to the interhemispheric artery, and in A. belzebul and Sapajus libidinosus, the rostral communicating artery is absent. The interhemispheric artery goes to the midbrain region and the corpus callosum knee divides into pericalous artery and callosarginal artery, which will supply the pre and post-central regions of the cerebral hemispheres of this species, as well as other non-human and human primates. It is noted that in the first part of the left rostral cerebral artery, there is a direct inosculation between the recurrent branch of the rostral cerebral artery and left middle cerebral artery to supply the entorhinal region. This fact also occurs in Pongo spp. The middle cerebral artery travels along the lateral sulcus where it emits several superficial branches to irrigate the superior and inferior lateral cortical regions of the frontal, parietal and temporal lobes. It is not part of the arterial circle but is the terminal branch of the internal carotid artery. A. belzebul can be considered to depend on two sources of supply to the brain: the vertebra-basilar and carotid systems, contributing to the intervention of veterinarians during clinical and surgical procedures in other primates, as well as the preservation of wild animals. RESUMO: Estudamos o círculo arterial no encéfalo de cinco espécimes do primata Alouatta belzebul. O material teve o sistema arterial perfundido (água a 40°C), injetado com látex corado (Neoprene 650), fixado em solução aquosa de formaldeído (10%) e dissecado para verificação dos vasos. O círculo arterial deste primata é composto por dois sistemas vasculares: vértebro-basilar e o sistema carotídeo, que se anastomosam para fechar o circuito arterial. Na porção caudal do círculo arterial encontra-se as artérias vertebrais e seus ramos: artéria espinal rostral e a cerebelar inferior caudal. A anastomose das artérias vertebrais dá origem a artéria basilar. Esta apresentou uma variação anatômica no início do seu trajeto, formando uma dupla artéria basilar, denominada ilha arterial. Em seu trajeto emitiu ramos dando origem a artéria cerebelar inferior rostral, as artérias pontinas, as artérias cerebelares rostrais, as artérias cerebelares rostrais satélites e o seu ramo terminal, a artéria cerebral caudal, que apresentou-se em dois segmentos: o pré-comunicante e pós-comunicante, unindo-se a artéria carótida interna e originando a artéria comunicante caudal. Este grupo de artérias e anastomoses encerram a porção caudal do círculo arterial. Das artérias carótidas internas direita e esquerda, inicia-se a porção rostral do círculo arterial, ao qual é constituído pelas artérias cerebrais rostrais direita e esquerda e as artérias cerebrais médias direita e esquerda. As artérias cerebrais rostrais se anastomosam em um tronco único dando origem a artéria inter-hemisférica e em A. belzebul e Sapajus libidinosus, a artéria comunicante rostral se encontra ausente. A artéria inter-hemisférica segue para região média do encéfalo e no joelho do corpo caloso se divide em artéria pericalosa e artéria calosomarginal, que vão suprir as regiões pré e pós-central dos hemisférios cerebrais desta espécie, assim como outros primatas não humanos e humano. Nota-se que na primeira parte da artéria cerebral rostral esquerda, ocorre uma inosculação direta entre o ramo recorrente da artéria cerebral rostral e artéria cerebral média esquerda para suprir a região entorrinal, esse fato também ocorre em Pongo spp. A artéria cerebral média segue seu trajeto pelo sulco lateral onde emite vários ramos superficiais para irrigar as regiões corticais supero e ínfero lateral do lobo frontal, parietal e temporal, esta não faz parte do círculo arterial mas é o ramo terminal da artéria carótida interna. Pode-se considerar que A. belzebul depende de duas fontes de suprimento para o encéfalo: os sistemas vértebro-basilar e carotídeo, contribuindo na intervenção de médicos veterinários durante os procedimentos clínicos e cirúrgicos em outros primatas, assim como na preservação de animais silvestres.

In the 1980s and 1990s, the concept was introduced that molecular integration in the Central Nervous System could develop through allosteric receptor-receptor interactions in heteroreceptor complexes presents in neurons. A number of adenosine-dopamine heteroreceptor complexes were identified that lead to the A2A-D2 heteromer hypothesis of schizophrenia. The hypothesis is based on strong antagonistic A2A-D2 receptor-receptor interactions and their presence in the ventral striato-pallidal GABA anti-reward neurons leading to reduction of positive symptoms. Other types of adenosine A2A heteroreceptor complexes are also discussed in relation to this disease, such as A2A-D3 and A2A-D4 heteroreceptor complexes as well as higher order A2A-D2-mGluR5 and A2A-D2-Sigma1R heteroreceptor complexes. The A2A receptor protomer can likely modulate the function of the D4 receptors of relevance for understanding cognitive dysfunction in schizophrenia. A2A-D2-mGluR5 complex is of interest since upon A2A/mGluR5 coactivation they appear to synergize in producing strong inhibition of the D2 receptor protomer. For understanding the future of the schizophrenia treatment, the vulnerability of the current A2A-D2like receptor complexes will be tested in animal models of schizophrenia. A2A-D2-Simag1R complexes hold the highest promise through Sigma1R enhancement of inhibition of D2R function. In line with this work, Lara proposed a highly relevant role of adenosine for neurobiology of schizophrenia. Yes

Gliomas are the most common primary brain tumors in adults. They arise in the glial tissue and primarily occur in the brain. Low-grade tumors of World Health Organization (WHO) grade II tend to progress to high-grade gliomas of WHO grade III and, eventually, glioblastoma of WHO grade IV, which is the most common and deadly glioma, with a median survival of 12-15 months after final diagnosis. Knowledge of the molecular biology and genetics of glioblastoma has increased significantly in the past few years, giving rise to classification methods that can help in management and stratification of glioblastoma patients. However, glioblastoma remains an incurable disease. Glioblastoma cells have acquired genetic and metabolic adaptations in order to sustain tumor growth and progression, including changes in energetic metabolism, invasive capacity, migration, and angiogenesis, that make it very difficult to find suitable therapeutic targets and to develop effective drugs. The current standard of care for glioblastoma patients is surgery followed by radiotherapy plus concomitant and adjuvant chemotherapy with temozolomide. Although progress in glioblastoma therapies in recent years has been more limited than in other tumors, numerous drugs and targets are being proposed and many clinical trials are underway to develop effective subtype-specific treatments. Yes

RESUMEN Objetivo: describir las características sociodemográficas, aspectos clínicos y complicaciones de los niños de 0 a 10 años de edad que sufrieron traumatismo craneoencefálico, atendidos en el Hospital General de Medellín y en la Clínica Somer de Rionegro entre los años 2010 y 2017. Métodos: estudio descriptivo retrospectivo, toma como fuente de información las historias clínicas de los niños con diagnósticos relacionados con el traumatismo craneoencefálico entre 2010-2017. Se calcularon las proporciones de las variables sociodemográficas, circunstanciales, espacio-temporales y clínicas. Resultados: se encontraron 224 pacientes con traumatismo craneoencefálico, el 64,7 % de los casos fueron de sexo masculino, la edad promedio fue de 4,5 años. El trauma ocurrió con mayor frecuencia en el domicilio del paciente entre los días de la semana en las horas de la tarde. La causa principal del trauma fue caída (75 %), seguido por accidentes de tránsito (13,3 %). La gravedad del traumatismo se midió con la escala de coma de Glasgow, el 78 % fue leve, hubo un caso fatal y 7 (3 %) tuvieron complicaciones motoras durante la hospitalización. Conclusión: los hallazgos de este estudio coinciden con las principales características del traumatismo craneoencefálico de la población pediátrica en el mundo, amplía la información regional y local para el desarrollo de estrategias de prevención, diagnóstico y seguimiento a largo plazo de los pacientes. SUMMARY Objective: To describe the demography, clinical presentation and complications associated with traumatic brain injury (TBI) in a cohort of children, ages 0-10, treated at Hospital General de Medellín and Clínica Somer between 2010-2017. Methods: Cross sectional retrospective study chart review of all children with a diagnosis of TBI between 2010 and 2017. There were systematic review and recording of demographic information, mechanism of injury, clinical presentation, and associated complications. Results: A total of 224 patients with TBI were identified. Among them, 64.7% were males and mean age was 4.5 years. Injuries most frequently occurred at the patient’s home, during the afternoon hours and between Monday and Friday. The most common mechanisms of injury were falls (75%), followed by motor vehicle accidents (13.3%). Severity of injury, measured by Glasgow coma scale, found that 78% of cases were mild. Seven (3%) of cases had neuromuscular complications during hospitalization and one TBI related death was identified. Conclusion: Findings of this study are consistent with the known characteristics of pediatric TBI worldwide. This information may be used to improve prevention, diagnosis, and long term follow-up.

O Transtorno do Espectro Autista (TEA) é uma desordem do neurodesenvolvimento com prevalência atual estimada em 1:59 crianças de até 8 anos de idade nos Estados Unidos. Segundo o DSM-5, o TEA é caracterizado por uma díade comportamental, composta por prejuízos de comunicação e interação social, além da presença de comportamentos repetitivos ou estereotipados. A etiologia do TEA permanece pouco elucidada; porém, sabe-se que a exposição pré-natal a alguns fatores ambientais de risco durante a gestação, como o ácido valproico (VPA), podem contribuir para o desencadeamento desse transtorno. O modelo animal de autismo induzido pela exposição pré-natal ao VPA vem sendo usado para avaliar características comportamentais e moleculares comuns em pacientes com TEA. Além das avaliações comportamentais, existem evidências de que alterações nos níveis de microRNA específicos possam estar relacionados a distúrbios do neurodesenvolvimento. Sendo assim, a avaliação dessas moléculas no modelo VPA podem ajudar a entender a fisiopatologia da TEA. Dessa forma, o objetivo desse trabalho foi avaliar um conjunto de microRNA (miRNA) em cinco diferentes regiões encefálicas (córtex pré-frontal medial, área somatossensorial, região da amígdala, hipocampo e cerebelo) no modelo animal de autismo induzido pela exposição pré-natal ao VPA. Além disso, foi feita uma busca por genes alvos dos miRNA alterados visando estabelecer possíveis associações com a fisiopatologia do TEA. Ratas Wistar prenhes receberam no dia E12,5 uma dose intraperitoneal (i.p.) de VPA (600 mg/kg) ou solução salina (0,9%). No dia pósnatal 42 (P42) os animais foram eutanasiados por sobredose anestésica de cetamina (300 mg/kg) e xilazina (40mg/kg). Após a decapitação, as estruturas encefálicas foram isoladas e homogeneizadas em reagente Trizol® para posterior extração de RNA total e quantificação de miRNA por RT-qPCR. Os alvos encontrados para estes miRNA alterados estão envolvidos com as vias de sinalização da mTOR e de Wnt, ambas previamente relacionadas com o TEA. Como conclusão, o presente trabalho amplia a compreensão da fisiopatologia do TEA e denota importantes moléculas-alvo com potencial para a busca de novas estratégias farmacológicas. Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with a current prevalence estimated at 1:59 children under the age of 8 in the United States. According to DSM-5, ASD is characterized by a behavioral dyad, composed of impaired communication and social interaction, in addition to the presence of repetitive or stereotyped behaviors. The etiology of ASD remains unclear; however, it is known that prenatal exposure to some environmental risk factors during pregnancy, such as valproic acid (VPA), can contribute to the onset of this disorder. The animal model of autism induced by prenatal exposure to VPA has been used to assess common behavioral and molecular characteristics in patients with ASD. In addition to behavioral assessments, there is evidence that changes in specific microRNA levels may be related to neurodevelopmental disorders. Therefore, the evaluation of these molecules in the VPA model can help to understand the pathophysiology of ASD. Thus, the objective of this work was to evaluate a group of microRNA in five different brain regions (medial prefrontal cortex, somatosensory area, amygdala region, hippocampus and cerebellum) in the animal model of autism induced by prenatal exposure to VPA. In addition, a search was made for altered microRNA target genes, aiming to establish possible associations with the pathophysiology of ASD. Pregnant Wistar rats received an intraperitoneal (i.p.) dose of VPA (600 mg/kg) or saline solution (0.9%) on day E12.5. On postnatal day 42 (P42) the animals were euthanized by anesthetic overdose of ketamine (300 mg/kg) and xylazine (40 mg/kg). After decapitation, the brain structures were isolated and homogenized in Trizol® reagent for posterior RNA extraction and microRNA quantification by RT-qPCR. The targets found for altered miRNA are involved with the mTOR and Wnt signaling pathways, both previously related to TEA. In summary, the present work expands the understanding of ASD pathophysiology and highlights important target molecules with the potential to search for new pharmacological strategies.

Despite its prolific growth, neurolinguistic research on phonemic sequencing has largely neglected the study of individuals with highly developed skills in this domain. To bridge this gap, we report multidimensional signatures of two experts in backward speech, that is, the capacity to produce utterances by reversing the order of phonemes while retaining their identity. Our approach included behavioral assessments of backward and forward speech alongside neuroimaging measures of voxel-based morphometry, diffusion tensor imaging, and resting-state functional connectivity. Relative to controls, both backward speakers exhibited behavioral advantages for reversing words and sentences of varying complexity, irrespective of working memory skills. These patterns were accompanied by increased grey matter volume, higher mean diffusivity, and enhanced functional connectivity along dorsal and ventral stream regions mediating phonological and other linguistic operations, with complementary support of areas subserving associative-visual and domain-general processes. Still, the specific loci of these neural patterns differed between both subjects, suggesting individual variability in the correlates of expert backward speech. Taken together, our results offer new vistas on the domain of phonemic sequencing, while illuminating neuroplastic patterns underlying extraordinary language abilities. Fil: Torres Prioris, María José. Universidad de Málaga; España Fil: López Barroso, Diana. Universidad de Málaga; España Fil: Càmara, Estela. Universidad de Málaga; España Fil: Fittipaldi, María Sol. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt | Instituto de Neurología Cognitiva. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt | Fundación Favaloro. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt; Argentina Fil: Sedeño, Lucas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt | Instituto de Neurología Cognitiva. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt | Fundación Favaloro. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt; Argentina Fil: Ibañez, Agustin Mariano. Universidad de San Andrés; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Autónoma del Caribe; Colombia. University of California; Estados Unidos. Universidad Adolfo Ibañez; Chile Fil: Berthier, Marcelo L.. Universidad de Málaga; España Fil: García, Adolfo Martín. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Cuyo; Argentina. Universidad de San Andrés; Argentina. University of California; Estados Unidos. Universidad de Santiago de Chile; Chile

We investigated changes in oxidative biomarkers in brain regions such as brainstem, cerebellum, and cerebral cortex of 3-, 6-, 18-, 24-, and 30-month-old rats. We also assessed the effects of low-intensity exercise on these biomarkers in these regions of 6-, 18-, and 24-month-old rats that started exercise on a treadmill at 3, 15, and 21 months of age, respectively. Radiographic images of the femur were taken for all rats. A total of 25 rats (age: twelve 6-, ten 18-, ten 24-, and three 30-monthold rats) were used. Lipid hydroperoxide levels increased in cerebellum at 18 months. Total antioxidant activity exhibited lowest values in brainstem at 3 months. Superoxide dismutase activity did not exhibit significant changes during aging. Total thiol content exhibited lowest values in brain regions of 24- and 30-month-old rats. Exercise reduced total thiol content in brainstem at 6 months, but no change occurred in other regions and other ages. Femur increased its length and width and cortical thickness with advancing age. No change occurred in medullary width. Radiolucency increased and sclerosis was found in cortical and medullary bone with advancing age. Exercise reduced radiolucency and medullary sclerosis. Therefore, aging differentially changed oxidative biomarkers in different brain regions and radiographic measures of the femur. Low-intensity exercise only ameliorated some radiographic measurements of femur. Since the present study possessed limitations (small number of rats per group), a beneficial effect of regular low-intensity exercise on oxidative markers in brain cannot be ruled out.

Mitochondria contribute to shape intraneuronal Ca2+ signals. Excessive Ca2+ taken up by mitochondria could lead to cell death. Amyloid beta (A beta) causes cytosolic Ca2+ overload, but the effects of A beta on mitochondrial Ca2+ levels in Alzheimer's disease (AD) remain unclear. Using a ratiometric Ca2+ indicator targeted to neuronal mitochondria and intravital multiphoton microscopy, we find increased mitochondrial Ca2+ levels associated with plaque deposition and neuronal death in a transgenic mouse model of cerebral beta -amyloidosis. Naturally secreted soluble A beta applied onto the healthy brain increases Ca2+ concentration in mitochondria, which is prevented by blockage of the mitochondrial calcium uniporter. RNA-sequencing from post-mortem AD human brains shows downregulation in the expression of mitochondrial influx Ca2+ transporter genes, but upregulation in the genes related to mitochondrial Ca2+ efflux pathways, suggesting a counteracting effect to avoid Ca2+ overload. We propose lowering neuronal mitochondrial Ca2+ by inhibiting the mitochondrial Ca2+ uniporter as a novel potential therapeutic target against AD. Calvo-Rodriguez et al. show elevated calcium levels in neuronal mitochondria in a mouse model of cerebral beta -amyloidosis after plaque deposition, which precede rare neuron death events in this model. The mechanism involves toxic extracellular A beta oligomers and the mitochondrial calcium uniporter.

Introdução: Embora várias áreas do cérebro apresentem alterações na esquizofrenia, o papel do cerebelo não é claro. Apesar de algumas fMRI evidenciarem conectividade funcional cerebelar anormal em pacientes esquizofrênicos, o significado e o impacto desses achados não são claros, especialmente sobre a cognição social, um fator importante de comprometimento na esquizofrenia. Esses déficits, especialmente aqueles relacionados à "Teoria da mente (ToM)", são relevantes e sub-reconhecidos. Objetivo: Avaliar de dois déficits cognitivos diferentes ("working memory" e cognição social) com perfusão cerebelar em pacientes esquizofrênicos e controles por meio de fMRI ASL. Métodos: Vinte pacientes do sexo masculino com diagnóstico de esquizofrenia e vinte controles saudáveis foram incluídos no estudo. O “working memomry” foi avaliado pelo Teste Wisconsin de Classificação de Cartas, e a cognição social pelo teste " Read the Mind in the Eyes Test" e pelo ToM Stories. Trinta e seis sujeitos foram submetidos à ASL fMRI. Resultados: Comparados com controles saudáveis, os esquizofrênicos apresentaram escores significativamente mais baixos em todos os testes cognitivos. A análise ASL mostrou que pacientes esquizofrênicos apresentaram aumento da perfusão no putâmen esquerdo e no cerebelo direito e redução da perfusão em outras áreas do cérebro, quando comparados com controles saudáveis. A correlação negativa foi demonstrada entre o número de categorias completas nos testes WSCT e ToMS com aumento do fluxo no hemisfério cerebelar direito. Conclusão: Este estudo forneceu informações sobre as áreas e circuitos cerebrais envolvidos no comprometimento cognitivo na esquizofrenia, sugerindo que a disfunção na conectividade dos hemisférios cerebelares com outros circuitos corticais e subcorticais desempenha um papel importante no comprometimento cognitivo de pacientes esquizofrênicos, especialmente no que se refere a aspectos sociais do conhecimento. Estes resultados trazem novas perspectivas para o tratamento da doença através da estimulação de áreas específicas do cérebro por meio de estimulação magnética, elétrica ou fotônica (NIRS). Introduction: Although several brain areas present alterations in schizophrenia, the role of cerebellum is not clear. Though some fMRI evidences of abnormal cerebellar functional connectivity in schizophrenic patients, the meaning and impact of these findings are not clear, especially about social cognition, a major factor of impairment in schizophrenia. These deficits, especially those covered by the “Theory of Mind (ToM)” concept, are relevant and underrecognized. Objective: This study focused on the assessment of two different cognitive deficits ("working memory" and social cognition) with cerebellar perfusion in schizophrenic patients and controls through ASL fMRI. Methods: Twenty male patients with diagnosis of schizophrenia and 20 matched healthy controls were included in the study. Working memory was assessed by Wisconsin Card Sorting Test and social cognition by “Reading the Mind in the Eyes” test and ToM Stories. Thirty six patients underwent ASL fMRI. Results: Compared with healthy controls, schizophrenics showed significantly lower scores in all cognitive tests. ASL analysis showed that schizophrenic patients had increased perfusion in the left putamen and in the right cerebellum and reduced perfusion in other brain areas, when compared with healthy controls. Negative correlation was demonstrated between the number of complete categories in the WSCT and ToMS tests with increased hemispheric cerebellar flow. Conclusion: This study provided insights about brain areas and circuits involved in the cognitive impairment in schizophrenia, suggesting that the dysfunction in the connectivity of cerebellar hemispheres with other cortical and subcortical circuits plays an important role in the cognitive impairment of schizophrenic patients, especially regarding social cognition. These results bring new perspectives regarding the treatment of the disease through specific stimulation of these areas by means of magnetic, electrical or photonic stimulation (NIRS).