Tau Oligomer–Containing Synapse Elimination by Microglia and Astrocytes in Alzheimer Disease

Importance: Factors associated with synapse loss beyond amyloid-β plaques and neurofibrillary tangles may more closely correlate with the emergence of cognitive deficits in Alzheimer disease (AD) and be relevant for early therapeutic intervention. // Objective: To investigate whether accumulation of tau oligomers in synapses is associated with excessive synapse elimination by microglia or astrocytes and with cognitive outcomes (dementia vs no dementia [hereinafter termed resilient]) of individuals with equal burdens of AD neuropathologic changes at autopsy. // Design, Setting, and Participants: This cross-sectional postmortem study included 40 human brains from the Massachusetts Alzheimer Disease Research Center Brain Bank with Braak III to IV stages of tau pathology but divergent antemortem cognition (dementia vs resilient) and cognitively normal controls with negligible AD neuropathologic changes. The visual cortex, a region without tau tangle deposition at Braak III to IV stages, was assessed after expansion microscopy to analyze spatial relationships of synapses with microglia and astrocytes. Participants were matched for age, sex, and apolipoprotein E status. Evidence of Lewy bodies, TDP-43 aggregates, or other lesions different from AD neuropathology were exclusion criteria. Tissue was collected from July 1998 to November 2020, and analyses were conducted from February 1, 2022, through May 31, 2023. // Main Outcomes and Measures: Amyloid-β plaques, tau neuropil thread burden, synapse density, tau oligomers in synapses, and internalization of tau oligomer–tagged synapses by microglia and astrocytes were quantitated. Analyses were performed using 1-way analysis of variance for parametric variables and the Kruskal-Wallis test for nonparametric variables; between-group differences were evaluated with Holm-Šídák tests. // Results: Of 40 included participants (mean [SD] age at death, 88 [8] years; 21 [52%] male), 19 had early-stage dementia with Braak stages III to IV, 13 had resilient brains with similar Braak stages III to IV, and 8 had no dementia (Braak stages 0-II). Brains with dementia but not resilient brains had substantial loss of presynaptic (43%), postsynaptic (33%), and colocalized mature synaptic elements (38%) compared with controls and significantly higher percentages of mature synapses internalized by IBA1-positive microglia (mean [SD], 13.3% [3.9%] in dementia vs 2.6% [1.9%] in resilient vs 0.9% [0.5%] in control; P < .001) and by GFAP-positive astrocytes (mean [SD], 17.2% [10.9%] in dementia vs 3.7% [4.0%] in resilient vs 2.7% [1.8%] in control; P = .001). In brains with dementia but not in resilient brains, tau oligomers more often colocalized with synapses, and the proportions of tau oligomer–containing synapses inside microglia (mean [SD] for presynapses, mean [SD], 7.4% [1.8%] in dementia vs 5.1% [1.9%] resilient vs 3.7% [0.8%] control; P = .006; and for postsynapses 11.6% [3.6%] dementia vs 6.8% [1.3%] resilient vs 7.4% [2.5%] control; P = .001) and astrocytes (mean [SD] for presynapses, 7.0% [2.1%] dementia vs 4.3% [2.2%] resilient vs 4.0% [0.7%] control; P = .001; and for postsynapses, 7.9% [2.2%] dementia vs 5.3% [1.8%] resilient vs 3.0% [1.5%] control; P < .001) were significantly increased compared with controls. Those changes in brains with dementia occurred in the absence of tau tangle deposition in visual cortex. // Conclusion and Relevance: The findings from this cross-sectional study suggest that microglia and astrocytes may excessively engulf synapses in brains of individuals with dementia and that the abnormal presence of tau oligomers in synapses may serve as signals for increased glial-mediated synapse elimination and early loss of brain function in AD

The Neural Basis of Decision-Making and Reward Processing in Adults with Euthymic Bipolar Disorder or Attention-Deficit/Hyperactivity Disorder (ADHD)

Attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BD) share DSM-IV criteria in adults and cause problems in decision-making. Nevertheless, no previous report has assessed a decision-making task that includes the examination of the neural correlates of reward and gambling in adults with ADHD and those with BD

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Genetic Drivers of Heterogeneity in Type 2 Diabetes Pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P \u3c 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P &lt; 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.</p

O movimento psicanalítico no Rio de Janeiro (1937-1959): um processo de institucionalização

Made available in DSpace on 2013-01-07T15:55:02Z (GMT). No. of bitstreams: 2 license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) 36.pdf: 10629328 bytes, checksum: 11b487ed94a0eb9bd720750200c38e46 (MD5) Previous issue date: 2009Fundação Oswaldo Cruz. Casa de Oswaldo Cruz. Programa de Pós-Graduação em História das Ciências e da Saúde. Rio de Janeiro, RJ, Brasil.O presente trabalho tem o objetivo de compreender a participação do processo de institucionalização da psicanálise na constituição do movimento psicanalítico: a prática da psicanálise e a formação de analistas. Apoiada pelo referencial teórico-metodológico apresentado por Rosenberg e Golden (1977), reunindo autores que nos auxiliaram a ler as fontes a partir de noções como enquadramento, negociação, legitimação e interesses nas relações entre os problemas da saúde, bem como as acomodações sociopolíticas da época, a dissertação divide-se em três eixos principais. O primeiro item descreve a situação política do país, as diretrizes de governo e as bases de negociação que definem a estruturação dos programas de saúde pública no período. Inicialmente focamos a situação do país desde a primeira metade do século XX, incluindo o primeiro governo Vargas (1930), as reestruturações político-administrativas do período do Estado Novo (1937-1945), que se seguiram de um novo panorama, fortemente marcado pelas exigências das alianças do período do pós-guerra (1945). Mostraremos como tais características refletiam-se nos programas das políticas de saúde pública e bem-estar, em face das novas demandas e exigências sociais e econômicas. O segundo item aborda o cenário descortinado pela Assistência ao Alienado, desde Juliano Moreira na direção (1903-1930), em meio às buscas da construção de um Brasil moderno, a fim de tratar, prevenir e controlar os desvios na direção do projeto de nação proposto. Apontamos a seguir para a influência das ideias científicas do período, suas representações e vínculos com os órgãos de governo. Nessa época merece destaque a proliferação de instituições públicas e privadas, entre elas a fundação e fechamento, em São Paulo, da primeira sociedade psicanalítica do Brasil e da América Latina (1928), a ação política da Liga Brasileira de Higiene Mental (LBHM-1932) e a criação do Serviço Nacional de Doenças Mentais (SNDM) em 1941, fonte de apoio e financiamento para a consolidação da psicanálise no Rio de Janeiro. Assim, no terceiro item discutimos como a psicanálise veio adentrar a Assistência aos Psicopatas, o modo pelo qual eram utilizados os conceitos freudianos a partir das necessidades e demandas da psiquiatria da época e os reflexos desse percurso no processo de institucionalização da psicanálise, quando da fundação das duas sociedades cariocas: a Sociedade Brasileira de Psicanálise do Rio de Janeiro – SBPRJ em 1955 e a Sociedade Psicanalítica do Rio de Janeiro – SPRJ em 1959, por delegação da International Psychoanalysis Association – IPA. O quarto e último item traz as discussões suscitadas e linhas de influência implicadas no encontro entre as ações de políticas públicas de saúde, a definição e consolidação da prática e do ensino da psiquiatria no período e a forma que a institucionalização da psicanálise tomou nesse cenário, bem como possíveis consequências para as formas de organização política dessas instituições.The objective of this present work is to understand the participation of the psychoanalysis institutionalization process in the building of the psychoanalytical movement, the practice and the “rendre psychanaliste1 . Based on a methodological theorist report presented by Rosenberg and Golden (1977), bringing together that helped us to read the sources starting from pattern negotiation, legitimating and interests in the relationship with health problems, as well as in the social-political accommodation period. This work is divided in three main parts. The first item describes the political situation in the country, the government directions and the negotiation bases that define the building of the public health programmes in the period. At first we focus the country situation since the first half of the XX century, including the first Vargas government (1930), the political administrative reorganization of the Estado Novo (1937-1945) that presented a new panorama, deeply registered by the post-war alliance demands period (1945). We will present how the influence of these characteristics reflected in the public health and welfare programs, facing the social-economic actions and demands. The second item is about the scenery designed by the “Assistência aos Alienados” at the time of Juliano Moreira’s command (1903-1930), searching for the construction of a modern Brazil to treat, prevent and control the divergent in the project direction of the nation. Then, we point at the influence of the scientific ideas of the time, its representation and links with the government departments. We highlight in this period the proliferation of the public and private institutions, specially the opening and closing in São Paulo of the first psychoanalytical Brazilian and South American society (1928), the political action of the Legião Brasileira de Higiene Mental – LBHM (1932), and the creation of the Serviço Nacional de Doenças Mentais – SNDM (1941), support and financial base for the psychoanalysis consolidation in Rio de Janeiro. In the third item we will discuss how the psychoanalysis penetrated the “Assistência aos Psicopatas”, how Freudian concepts were used from the psychiatric necessities and demands of the time and the results of these facts in the psychoanalysis institutional process, when the two “carioca’ societies were founded: the Sociedade Brasileira de Psicanálise do Rio de Janeiro – SBPRJ in 1955 and the Sociedade Psicanalítica do Rio de Janeiro – SPRJ in 1959, authorized by the International Psychoanalytical Association – IPA. The fourth and the last item brings out the discussions and the lines of influence involved in the crossing of the public health politicies, the definition and consolidation of the psychiatric practice and the teaching at the time and how the psychoanalysis process of the institutionalization occurred in this scenery as well as the probable consequences to the way of political organization in these institutions

Uncovering the expression of circPVT1 in the extracellular vesicles of acute myeloid leukemia patients

Extracellular vesicles (EVs) act as molecular mediators in the tumor microenvironment, by shuttling information contained within malignant cells and functioning as regulators of the immune system. Circular (circ)RNAs are characterized by a closed loop-like structure that makes them more stable in the extracellular milieu and suitable to be packaged inside EVs. circPVT1 (hsa_circ_0001821) showed an oncogenic role in several cancer types and immunosuppressive properties in myeloid and lymphoid cell subsets. In this study, we characterized EVs from acute myeloid leukemia (AML) patients in terms of size, concentrations, surface markers and circPVT1 cargo. We showed that circPVT1 is overexpressed by primary blast cells from newly-diagnosed AML patients compared with hematopoietic stem-progenitor cells and is released as cell-free RNA in the plasma. We isolated EVs from the plasma of AML patients and healthy subjects by size exclusion chromatography and characterized them by nanoparticle tracking analysis. EVs from patients’ plasma are larger compared with those from healthy subjects and their surface profile is characterized by higher levels of the leukemic cell markers CD133, CD105, CD49e and other immune-related epitopes, with differences according to AML molecular profile. Moreover, digital PCR analysis revealed that circPVT1 is more abundant inside EVs from the plasma of AML patients compared with healthy subjects. Our findings provide new insights on the features and content of AML EVs and suggest a role of circPVT1 in the crosstalk between AML cells and the tumor microenvironment