Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers

Amyloid-beta 42 (A beta 42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for A beta 42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple A beta 42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.Peer reviewe

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

DNA Vaccine Treatment in Dogs Experimentally Infected with Trypanosoma cruzi

Chagas disease is a chronic and potentially lethal disorder caused by the parasite Trypanosoma cruzi, and an effective treatment has not been developed for chronic Chagas disease. The objective of this study was to determine the effectiveness of a therapeutic DNA vaccine containing T. cruzi genes in dogs with experimentally induced Chagas disease through clinical, pathological, and immunological analyses. Infection of Beagle dogs with the H8 T. cruzi strain was performed intraperitoneally with 3500 metacyclic trypomastigotes/kg body weight. Two weeks after infection, plasmid DNA immunotherapy was administered thrice at 15-day intervals. The clinical (physical and cabinet studies), immunological (antibody and cytokine profiles and lymphoproliferation), and macro- and microscopic pathological findings were described. A significant increase in IgG and cell proliferation was recorded after immunotherapy, and the highest stimulation index (3.02) was observed in dogs treated with the pBCSSP4 plasmid. The second treatment with both plasmids induced an increase in IL-1, and the third treatment with the pBCSSP4 plasmid induced an increase in IL-6. The pBCSP plasmid had a good Th1 response regulated by high levels of IFN-gamma and TNF-alpha, whereas the combination of the two plasmids did not have a synergistic effect. Electrocardiographic studies registered lower abnormalities and the lowest number of individuals with abnormalities in each group treated with the therapeutic vaccine. Echocardiograms showed that the pBCSSP4 plasmid immunotherapy preserved cardiac structure and function to a greater extent and prevented cardiomegaly. The two plasmids alone controlled the infection moderately by a reduction in the inflammatory infiltrates in heart tissue. The immunotherapy was able to reduce the magnitude of cardiac lesions and modulate the cellular immune response; the pBCSP treatment showed a clear Th1 response; and pBCSSP4 induced a balanced Th1/Th2 immune response that prevented severe cardiac involvement. The pBCSSP4 plasmid had a better effect on most of the parameters evaluated in this study; therefore, this plasmid can be considered an optional treatment against Chagas disease in naturally infected dogs

The Brazilian standardization of the MATRICS consensus cognitive battery (MCCB): Psychometric study

Objective: Translate, adapt, and validate the MATRICS Consensus Cognitive Battery (MCCB) in Brazil. Method: The present study followed three steps: 1) translation to Portuguese, cultural adaptation, and back translation to English2) completion of a pilot study (N = 30) conducted with the purpose of assessing whether the general comprehension of the items was clear and all participants adequately responded to the battery3) completion of a Reliability and Validation Study of the Brazilian version of the MCCB with 99 individuals with schizophrenia and 99 healthy subjects. All participants were administered the Structured Clinical Interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders) and patients were also rated on the Global Assessment of Functioning (GAF) Scale and the Positive and Negative Symptoms Scale (PANSS). Results: The results showed adequate to high levels of baseline and 4-week retest reliability, except the MSCEIT-MEadequate internal consistency for the MSCEIT-ME for the total sample and patients group, and moderate Alpha for the health control sampleas well as evidence of convergent validity and sensitivity to differentiate performance between the groups. All the 10 MCCB measures showed the lowest learning effects. Conclusion: Overall the Brazilian version of the MCCB showed similar results to the original North American version. Our findings provides reassurance that the MCCB is a reliable and valid measure of cognition across different countries and cultures, which is especially important to the ongoing work in attempting to discover cognition enhancing drugs and the effects of cognitive interventions for the treatment of schizophrenia. (C) 2017 Elsevier B.V. All rights reserved.FAPESPUniv Fed Sao Paulo Unifesp, Dept Psychiat, Interdisciplinary Lab Clin Neurosci LiNC, Sao Paulo, BrazilUniv Fed Sao Paulo Unifesp, Dept Psychiat, Schizophrenia Program PROESQ, Sao Paulo, BrazilCtr Univ FIEO, Strict Sensu Educ Psychol Program, 300 UCLA Med Plaza,Room 2240, Los Angeles, CA 90095 USAUniv Calif Los Angeles, Dept Psychiat & Biobehav Sci, 300 UCLA Med Plaza,Room 2240, Los Angeles, CA 90095 USAUniv Calif Los Angeles, Dept Psychol, 300 UCLA Med Plaza,Room 2240, Los Angeles, CA 90095 USAUniv Fed Sao Paulo Unifesp, Dept Psychiat, Interdisciplinary Lab Clin Neurosci LiNC, Sao Paulo, BrazilUniv Fed Sao Paulo Unifesp, Dept Psychiat, Schizophrenia Program (PROESQ), BrazilFAPESPWeb of Scienc

Effects of socioeconomic status in cognition of people with schizophrenia:Results from a Latin American collaboration network with 1175 subjects

Background Cognition heavily relies on social determinants and genetic background. Latin America comprises approximately 8% of the global population and faces unique challenges, many derived from specific demographic and socioeconomic variables, such as violence and inequality. While such factors have been described to influence mental health outcomes, no large-scale studies with Latin American population have been carried out. Therefore, we aim to describe the cognitive performance of a representative sample of Latin American individuals with schizophrenia and its relationship to clinical factors. Additionally, we aim to investigate how socioeconomic status (SES) relates to cognitive performance in patients and controls. Methods We included 1175 participants from five Latin American countries (Argentina, Brazil, Chile, Colombia, and Mexico): 864 individuals with schizophrenia and 311 unaffected subjects. All participants were part of projects that included cognitive evaluation with MATRICS Consensus Cognitive Battery and clinical assessments. Results Patients showed worse cognitive performance than controls across all domains. Age and diagnosis were independent predictors, indicating similar trajectories of cognitive aging for both patients and controls. The SES factors of education, parental education, and income were more related to cognition in patients than in controls. Cognition was also influenced by symptomatology. Conclusions Patients did not show evidence of accelerated cognitive aging; however, they were most impacted by a lower SES suggestive of deprived environment than controls. These findings highlight the vulnerability of cognitive capacity in individuals with psychosis in face of demographic and socioeconomic factors in low-and middle-income countries.Fil: Sanguinetti Czepielewski, Letícia. Hospital de Clinicas de Porto Alegre; Brasil. Universidade Federal do Rio Grande do Sul; BrasilFil: Alliende, Luz Maria. Pontificia Universidad Católica de Chile; Chile. Instituto Psiquiátrico Dr. Horwitz Barak; ChileFil: Castañeda, Carmen Paz. Instituto Psiquiátrico Dr. Horwitz Barak; ChileFil: Castro, Mariana Nair. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Instituto de Neurociencias - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Neurociencias; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Salud Mental; ArgentinaFil: Guinjoan, Salvador Martín. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Instituto de Neurociencias - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Neurociencias; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Salud Mental; ArgentinaFil: Massuda, Raffael. Universidade Federal do Paraná; BrasilFil: Berberian, Arthur A.. Universidade Federal de Sao Paulo; BrasilFil: Fonseca, Ana Olivia. Universidade Federal de Sao Paulo; BrasilFil: Gadelha, Ary. Universidade Federal de Sao Paulo; BrasilFil: Bressan, Rodrigo. Universidade Federal de Sao Paulo; BrasilFil: Crivelaro, Marisa. Universidade de Sao Paulo; BrasilFil: Louzã, Mario. Universidade de Sao Paulo; BrasilFil: Undurraga, Juan. Universidad del Desarrollo; Chile. Instituto Psiquiátrico Dr. Horwitz Barak; ChileFil: González Valderrama, Alfonso. Instituto Psiquiátrico Dr. Horwitz Barak; Chile. Universidad Finis Terrae; ChileFil: Nachar, Rubén. Instituto Psiquiátrico Dr. Horwitz Barak; Chile. Universidad Finis Terrae; ChileFil: Nieto, Rodrigo. Universidad de Chile; ChileFil: Montes, Cristian. Universidad de Chile; ChileFil: Silva, Hernan. Universidad de Chile; ChileFil: Langer, Álvaro I.. Millennium Nucleus To Improve The Mental Health Of Adolescents And Youths; Chile. Millennium Institute For Research In Depression And Personality; Chile. Universidad Austral de Chile; ChileFil: Schmidt, Carlos. Universidad de Barcelona; España. Millennium Institute For Research In Depression And Personality; ChileFil: Mayol Troncoso, Rocío. Universidad de Chile. Facultad de Medicina; Chile. Millennium Nucleus To Improve The Mental Health Of Adolescents And Youths; ChileFil: Díaz Zuluaga, Ana M.. Universidad de Antioquia; ColombiaFil: Valencia Echeverry, Johanna. Universidad de Antioquia; ColombiaFil: López Jaramillo, Carlos. Universidad de Antioquia; ColombiaFil: Solís Vivanco, Rodolfo. Instituto Nacional de Neurología y Neurocirugía; MéxicoFil: Reyes Madrigal, Francisco. Instituto Nacional de Neurología y Neurocirugía; MéxicoFil: De La Fuente Sandoval, Camilo. Instituto Nacional de Neurología y Neurocirugía; MéxicoFil: Crossley, Nicolás A.. Universidad Católica de Chile; Chile. Pontificia Universidad Católica de Chile; Chile. King's College London; Reino UnidoFil: Gama, Clarissa S.. Universidade Federal do Rio Grande do Sul; Brasil. Hospital de Clinicas de Porto Alegre; Brasi

Dengue Fever Surveillance in Mato Grosso do Sul: Insights from Genomic Analysis and Implications for Public Health Strategies

Since its discovery in early 1916, dengue fever, a common vector-borne illness in Brazil, has resulted in extensive urban outbreaks and poses a serious threat to the public’s health. Understanding the dynamics of Dengue Virus (DENV) serotypes circulating in different regions of Brazil is essential for implementing effective disease control and prevention measures. In response to this urgent need, we conducted an on-site training program in genomic surveillance in collaboration with the Central Laboratory of Health and the Secretary of Health of the Mato Grosso do Sul state. This initiative resulted in the generation of 177 DENV genome sequences collected between May 2021 and May 2022, a period during which over 11,391 dengue fever cases were reported in the state. Through this approach, we were able to identify the co-circulation of two different dengue serotypes (DENV1 and DENV2) as well as the existence of diverse viral lineages within each genotype, suggesting that multiple introduction events of different viral strains occurred in the region. By integrating epidemiological data, our findings unveiled temporal fluctuations in the relative abundance of different serotypes throughout various epidemic seasons, highlighting the complex and changing dynamics of DENV transmission throughout time. These findings demonstrate the value of ongoing surveillance activities in tracking viral transmission patterns, monitoring viral evolution, and informing public health actions