Serum TCA cycle metabolites in Lewy bodies dementia and Alzheimer's disease: Network analysis and cognitive prognosis

Se han documentado anomalías en el ciclo del ácido tricarboxílico (TCA) en la demencia. A través del análisis de redes, los metabolitos del ciclo TCA podrían reflejar indirectamente anomalías conocidas relacionadas con la demencia en las vías bioquímicas, y los metabolitos clave podrían estar asociados con el pronóstico. Este estudio analizó los metabolitos del ciclo de TCA como predictores del deterioro cognitivo en una cohorte de demencia leve y exploró las posibles interacciones con el diagnóstico de demencia con cuerpos de Lewy (LBD) o enfermedad de Alzheimer (EA) y el genotipo APOE-ε4. Se incluyeron 145 pacientes con demencia leve (LBD = 59; AD = 86). Los metabolitos del ciclo de TCA en suero se analizaron al inicio del estudio y se realizaron redes de correlación parcial. El rendimiento cognitivo se midió anualmente durante 5 años con el Mini-examen del estado mental. Los modelos Tobit de efectos mixtos longitudinales evaluaron cada metabolito de referencia como predictor del deterioro cognitivo a los 5 años. Se exploraron las interacciones APOE-ε4 y de diagnóstico. Los resultados mostraron concentraciones de metabolitos comparables en LBD y AD. Las redes corregidas de pruebas múltiples mostraron coeficientes más grandes para una correlación negativa entre piruvato-succinato y correlaciones positivas entre fumarato-malato y citrato-isocitrato tanto en LBD como en AD. En la muestra total, los modelos mixtos ajustados mostraron asociaciones significativas entre la concentración inicial de citrato y las puntuaciones longitudinales del MMSE. En los portadores de APOE-ε4, el isocitrato inicial predijo las puntuaciones del MMSE. Concluimos que, en la demencia leve, las concentraciones de citrato sérico podrían estar asociadas con el deterioro cognitivo posterior, así como las concentraciones de isocitrato en los portadores de APOE-ε4. La regulación a la baja de la actividad enzimática en la primera mitad del ciclo TCA (deshidrogenasas descarboxiladoras), con regulación al alza en la segunda mitad (solo deshidrogenasas), podría reflejarse indirectamente en las redes de metabolitos del ciclo TCA sérico.Q2Abnormalities in the Tri-Carboxylic-Acid (TCA) cycle have been documented in dementia. Through network analysis, TCA cycle metabolites could indirectly reflect known dementia-related abnormalities in biochemical pathways, and key metabolites might be associated with prognosis. This study analyzed TCA cycle metabolites as predictors of cognitive decline in a mild dementia cohort and explored potential interactions with the diagnosis of Lewy Body Dementia (LBD) or Alzheimer's Disease (AD) and APOE-ε4 genotype. We included 145 mild dementia patients (LBD = 59; AD = 86). Serum TCA cycle metabolites were analyzed at baseline, and partial correlation networks were conducted. Cognitive performance was measured annually over 5-years with the Mini-mental State Examination. Longitudinal mixed-effects Tobit models evaluated each baseline metabolite as a predictor of 5-year cognitive decline. APOE-ε4 and diagnostic interactions were explored. Results showed comparable metabolite concentrations in LBD and AD. Multiple testing corrected networks showed larger coefficients for a negative correlation between pyruvate – succinate and positive correlations between fumarate – malate and citrate – Isocitrate in both LBD and AD. In the total sample, adjusted mixed models showed significant associations between baseline citrate concentration and longitudinal MMSE scores. In APOE-ε4 carriers, baseline isocitrate predicted MMSE scores. We conclude that, in mild dementia, serum citrate concentrations could be associated with subsequent cognitive decline, as well as isocitrate concentrations in APOE-ε4 carriers. Downregulation of enzymatic activity in the first half of the TCA cycle (decarboxylating dehydrogenases), with upregulation in the latter half (dehydrogenases only), might be indirectly reflected in serum TCA cycle metabolites' networks.https://orcid.org/0000-0001-5832-0603https://scholar.google.com/citations?user=MrICwaMAAAAJ&hl=enhttps://scienti.minciencias.gov.co/cvlac/visualizador/generarCurriculoCv.do?cod_rh=0001429659Revista Internacional - IndexadaS

Immunological signatures unveiled by integrative systems vaccinology characterization of dengue vaccination trials and natural infection

Introduction: Dengue virus infection is a global health problem lacking specific therapy, requiring an improved understanding of DENV immunity and vaccine responses. Considering the recent emerging of new dengue vaccines, here we performed an integrative systems vaccinology characterization of molecular signatures triggered by the natural DENV infection (NDI) and attenuated dengue virus infection models (DVTs). Methods and results: We analyzed 955 samples of transcriptomic datasets of patients with NDI and attenuated dengue virus infection trials (DVT1, DVT2, and DVT3) using a systems vaccinology approach. Differential expression analysis identified 237 common differentially expressed genes (DEGs) between DVTs and NDI. Among them, 28 and 60 DEGs were up or downregulated by dengue vaccination during DVT2 and DVT3, respectively, with 20 DEGs intersecting across all three DVTs. Enriched biological processes of these genes included type I/II interferon signaling, cytokine regulation, apoptosis, and T-cell differentiation. Principal component analysis based on 20 common DEGs (overlapping between DVTs and our NDI validation dataset) distinguished dengue patients by disease severity, particularly in the late acute phase. Machine learning analysis ranked the ten most critical predictors of disease severity in NDI, crucial for the anti-viral immune response. Conclusion: This work provides insights into the NDI and vaccine-induced overlapping immune response and suggests molecular markers (e.g., IFIT5, ISG15, and HERC5) for anti-dengue-specific therapies and effective vaccination development

Cross-sectional analysis of students and school workers reveals a high number of asymptomatic SARS-CoV-2 infections during school reopening in Brazilian cities

Brazil experienced one of the most prolonged periods of school closures, and reopening could have exposed students to high rates of SARS-CoV-2 infection. However, the infection status of students and school workers at the time of the reopening of schools located in Brazilian cities is unknown. Here we evaluated viral carriage by RT-PCR and seroprevalence of anti-SARS-CoV-2 antibodies (IgM and IgG) by immunochromatography in 2259 individuals (1139 students and 1120 school workers) from 28 schools in 28 Brazilian cities. We collected the samples within 30 days after public schools reopened and before the start of vaccination campaigns. Most students (n = 421) and school workers (n = 446) had active (qRT-PCR + IgM− IgG− or qRT-PCR + IgM + IgG−/+) SARS-CoV-2 infection. Regression analysis indicated a strong association between the infection status of students and school workers. Furthermore, while 45% (n = 515) of the students and 37% (n = 415) of the school workers were neither antigen nor antibody positive in laboratory tests, 16% of the participants (169 students and 193 school workers) were oligosymptomatic, including those reinfected. These individuals presented mild symptoms such as headache, sore throat, and cough. Notably, most of the individuals were asymptomatic (83.9%). These results indicate that many SARS-CoV-2 infections in Brazilian cities during school reopening were asymptomatic. Thus, our study highlights the need to promote a coordinated public health effort to guarantee a safe educational environment while avoiding exacerbating pre-existent social inequalities in Brazil, reducing social, mental, and economic losses for students, school workers, and their families

Neuropsychiatric symptoms and functional decline in alzheimerʼs disease and lewy body dementia

Background/objectives: Functional status is one of the most important markers of well-being in older adults, but the drivers of functional decline in dementia are not well known. The aim of our work was to study the association of neuropsychiatric symptoms (NPSs) with functional decline over 5 years in newly diagnosed people with Alzheimer´s disease (AD) and Lewy body dementia (LBD). Design: Secondary analysis of the Dementia Study of Western Norway longitudinal cohort study. Setting: Multicenter study conducted in memory clinics in western Norway. Participants: We included a total of 196 patients newly diagnosed with AD (n = 111) and LBD (n = 85), followed up annually for 5 years. Main Outcomes and Measures: The outcome was the rapid disability rating scale (items 1-13). Linear mixed-effects models were used for analysis with the total score of the Norwegian Neuropsychiatric Inventory (NPI) as a predictor measured either at baseline or longitudinally, adjusted for potential confounders, including cognition. Effect modification was checked by introducing interactions with NPI score and stratifying by diagnosis. Results: The total NPI score longitudinal course was associated with functional decline in both AD and LBD. At baseline, the total NPI score predicted functional decline in AD. Conclusion: NPSs were associated with the rate of functional decline in people with AD and LBD, independent of cognitive impairment. These results highlight the relevance of early detection and intervention of NPSs, which may also reduce functional decline

Neuroimmunology of rabies: New insights into an ancient disease

International audienceRabies is an ancient neuroinvasive viral (genus Lyssavirus, family Rhabdoviridae) disease affecting approximately 59,000 people worldwide. The central nervous system (CNS) is targeted, and rabies has a case fatality rate of almost 100% in humans and animals. Rabies is entirely preventable through proper vaccination, and thus, the highest incidence is typically observed in developing countries, mainly in Africa and Asia. However, there are still cases in European countries and the United States. Recently, demographic, increasing income levels, and the coronavirus disease 2019 (COVID‐19) pandemic have caused a massive raising in the animal population, enhancing the need for preventive measures (e.g., vaccination, surveillance, and animal control programs), postexposure prophylaxis, and a better understanding of rabies pathophysiology to identify therapeutic targets, since there is no effective treatment after the onset of clinical manifestations. Here, we review the neuroimmune biology and mechanisms of rabies. Its pathogenesis involves a complex and poorly understood modulation of immune and brain functions associated with metabolic, synaptic, and neuronal impairments, resulting in fatal outcomes without significant histopathological lesions in the CNS. In this context, the neuroimmunological and neurochemical aspects of excitatory/inhibitory signaling (e.g., GABA/glutamate crosstalk) are likely related to the clinical manifestations of rabies infection. Uncovering new links between immunopathological mechanisms and neurochemical imbalance will be essential to identify novel potential therapeutic targets to reduce rabies morbidity and mortality

Table_1_Immunological signatures unveiled by integrative systems vaccinology characterization of dengue vaccination trials and natural infection.xlsx

IntroductionDengue virus infection is a global health problem lacking specific therapy, requiring an improved understanding of DENV immunity and vaccine responses. Considering the recent emerging of new dengue vaccines, here we performed an integrative systems vaccinology characterization of molecular signatures triggered by the natural DENV infection (NDI) and attenuated dengue virus infection models (DVTs).Methods and resultsWe analyzed 955 samples of transcriptomic datasets of patients with NDI and attenuated dengue virus infection trials (DVT1, DVT2, and DVT3) using a systems vaccinology approach. Differential expression analysis identified 237 common differentially expressed genes (DEGs) between DVTs and NDI. Among them, 28 and 60 DEGs were up or downregulated by dengue vaccination during DVT2 and DVT3, respectively, with 20 DEGs intersecting across all three DVTs. Enriched biological processes of these genes included type I/II interferon signaling, cytokine regulation, apoptosis, and T-cell differentiation. Principal component analysis based on 20 common DEGs (overlapping between DVTs and our NDI validation dataset) distinguished dengue patients by disease severity, particularly in the late acute phase. Machine learning analysis ranked the ten most critical predictors of disease severity in NDI, crucial for the anti-viral immune response. ConclusionThis work provides insights into the NDI and vaccine-induced overlapping immune response and suggests molecular markers (e.g., IFIT5, ISG15, and HERC5) for anti-dengue-specific therapies and effective vaccination development. </p