A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects

Background The Colombian population, as well as those in other Latin American regions, arose from a recent tri-continental admixture among Native Americans, Spanish invaders, and enslaved Africans, all of whom passed through a population bottleneck due to widespread infectious diseases that left small isolated local settlements. As a result, the current population reflects multiple founder effects derived from diverse ancestries. Methods We characterized the role of admixture and founder effects on the origination of the mutational landscape that led to neurodegenerative disorders under these historical circumstances. Genomes from 900 Colombian individuals with Alzheimer’s disease (AD) [n = 376], frontotemporal lobar degeneration-motor neuron disease continuum (FTLD-MND) [n = 197], early-onset dementia not otherwise specified (EOD) [n = 73], and healthy participants [n = 254] were analyzed. We examined their global and local ancestry proportions and screened this cohort for deleterious variants in disease-causing and risk-conferring genes. Results We identified 21 pathogenic variants in AD-FTLD related genes, and PSEN1 harbored the majority (11 pathogenic variants). Variants were identified from all three continental ancestries. TREM2 heterozygous and homozygous variants were the most common among AD risk genes (102 carriers), a point of interest because the disease risk conferred by these variants differed according to ancestry. Several gene variants that have a known association with MND in European populations had FTLD phenotypes on a Native American haplotype. Consistent with founder effects, identity by descent among carriers of the same variant was frequent. Conclusions Colombian demography with multiple mini-bottlenecks probably enhanced the detection of founder events and left a proportionally higher frequency of rare variants derived from the ancestral populations. These findings demonstrate the role of genomically defined ancestry in phenotypic disease expression, a phenotypic range of different rare mutations in the same gene, and further emphasize the importance of inclusiveness in genetic studies.Q2Q2Antecedentes La población colombiana, así como la de otras regiones latinoamericanas, surgió de una mezcla tricontinental reciente entre los nativos americanos, los invasores españoles y los africanos esclavizados, todos los cuales pasaron por un cuello de botella poblacional debido a enfermedades infecciosas generalizadas que dejaron a pequeños aislados. asentamientos locales. Como resultado, la población actual refleja múltiples efectos fundadores derivados de diversas ascendencias. Métodos Caracterizamos el papel de la mezcla y los efectos fundadores en el origen del paisaje mutacional que condujo a trastornos neurodegenerativos en estas circunstancias históricas. Genomas de 900 individuos colombianos con enfermedad de Alzheimer (EA) [n = 376], continuo degeneración lobar frontotemporal-enfermedad de la motoneurona (FTLD-MND) [n = 197], demencia de inicio temprano no especificada (EOD) [n = 73 ], y participantes sanos [n = 254] fueron analizados. Examinamos sus proporciones de ascendencia global y local y examinamos esta cohorte en busca de variantes nocivas en los genes que causan enfermedades y confieren riesgos. Resultados Identificamos 21 variantes patogénicas en genes relacionados con AD-FTLD, y PSEN1 albergaba la mayoría (11 variantes patogénicas). Se identificaron variantes de las tres ascendencias continentales. Las variantes heterocigotas y homocigotas de TREM2 fueron las más comunes entre los genes de riesgo de EA (102 portadores), un punto de interés porque el riesgo de enfermedad conferido por estas variantes difería según la ascendencia. Varias variantes genéticas que tienen una asociación conocida con MND en poblaciones europeas tenían fenotipos FTLD en un haplotipo nativo americano. De acuerdo con los efectos del fundador, la identidad por descendencia entre portadores de la misma variante fue frecuente. Conclusiones La demografía colombiana con múltiples mini-cuellos de botella probablemente mejoró la detección de eventos fundadores y dejó una frecuencia proporcionalmente más alta de variantes raras derivadas de las poblaciones ancestrales. Estos hallazgos demuestran el papel de la ascendencia definida genómicamente en la expresión fenotípica de la enfermedad, un rango fenotípico de diferentes mutaciones raras en el mismo gen, y enfatizan aún más la importancia de la inclusión en los estudios genéticos.https://orcid.org/0000-0001-6529-7077https://scholar.google.com/citations?hl=es&user=kaGongoAAAAJ&view_op=list_works&sortby=pubdatehttps://scienti.minciencias.gov.co/cvlac/visualizador/generarCurriculoCv.do?cod_rh=0000055000&lang=esRevista Internacional - Indexad

A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects.

Background: The Colombian population, as well as those in other Latin American regions, arose from a recent tri-continental admixture among Native Americans, Spanish invaders, and enslaved Africans, all of whom passed through a population bottleneck due to widespread infectious diseases that left small isolated local settlements. As a result, the current population reflects multiple founder effects derived from diverse ancestries. Methods: We characterized the role of admixture and founder effects on the origination of the mutational landscape that led to neurodegenerative disorders under these historical circumstances. Genomes from 900 Colombian individuals with Alzheimer's disease (AD) [n = 376], frontotemporal lobar degeneration-motor neuron disease continuum (FTLD-MND) [n = 197], early-onset dementia not otherwise specified (EOD) [n = 73], and healthy participants [n = 254] were analyzed. We examined their global and local ancestry proportions and screened this cohort for deleterious variants in disease-causing and risk-conferring genes. Results: We identified 21 pathogenic variants in AD-FTLD related genes, and PSEN1 harbored the majority (11 pathogenic variants). Variants were identified from all three continental ancestries. TREM2 heterozygous and homozygous variants were the most common among AD risk genes (102 carriers), a point of interest because the disease risk conferred by these variants differed according to ancestry. Several gene variants that have a known association with MND in European populations had FTLD phenotypes on a Native American haplotype. Consistent with founder effects, identity by descent among carriers of the same variant was frequent. Conclusions: Colombian demography with multiple mini-bottlenecks probably enhanced the detection of founder events and left a proportionally higher frequency of rare variants derived from the ancestral populations. These findings demonstrate the role of genomically defined ancestry in phenotypic disease expression, a phenotypic range of different rare mutations in the same gene, and further emphasize the importance of inclusiveness in genetic studies

The impact of SARS-CoV-2 in dementia across Latin America : A call for an urgent regional plan and coordinated response

The SARS-CoV-2 global pandemic will disproportionately impact countries with weak economies and vulnerable populations including people with dementia. Latin American and Caribbean countries (LACs) are burdened with unstable economic development, fragile health systems, massive economic disparities, and a high prevalence of dementia. Here, we underscore the selective impact of SARS-CoV-2 on dementia among LACs, the specific strain on health systems devoted to dementia, and the subsequent effect of increasing inequalities among those with dementia in the region. Implementation of best practices for mitigation and containment faces particularly steep challenges in LACs. Based upon our consideration of these issues, we urgently call for a coordinated action plan, including the development of inexpensive mass testing and multilevel regional coordination for dementia care and related actions. Brain health diplomacy should lead to a shared and escalated response across the region, coordinating leadership, and triangulation between governments and international multilateral networks

Advancements in dementia research, diagnostics and care in Latin America : highlights from the 2023 Alzheimer's association international conference satellite symposium in Mexico City

While Latin America (LatAm) is facing an increasing burden of dementia due to the rapid aging of the population, it remains underrepresented in dementia research, diagnostics and care. In 2023, the Alzheimer’s Association hosted its eighth Satellite Symposium in Mexico, highlighting emerging dementia research, priorities, and challenges within LatAm. A wide range of topics were covered, including epidemiology, social determinants, dementia national plans, risk reduction, genetics, biomarkers, biobanks, and advancements in treatments. Large initiatives in the region including intra-country support showcased their efforts in fostering national and international collaborations; genetic studies unveiled the unique genetic admixture in LatAm; emerging clinical trials discussed ongoing culturally specific interventions; and the urgent need to harmonize practices and studies, improve diagnosis and care and implement affordable biomarkers in the region was highlighted

Dementia in Latin America : paving the way towards a regional action plan

Regional challenges faced by Latin American and Caribbean countries (LACs) to fight dementia, such as heterogeneity, diversity, political instabilities, and socioeconomic disparities, can be addressed more effectively grounded in a collaborative setting based on the open exchange of knowledge. In this work, the Latin American and Caribbean Consortium on Dementia (LAC-CD) proposes an agenda for integration to deliver a Knowledge to Action Framework (KtAF). First, we summarize evidence-based strategies (epidemiology, genetics, biomarkers, clinical trials, nonpharmacological interventions, networking and translational research) and align them to current global strategies to translate regional knowledge into actions with transformative power. Then, by characterizing genetic isolates, admixture in populations, environmental factors, and barriers to effective interventions and mapping these to the above challenges, we provide the basic mosaics of knowledge that will pave the way towards a KtAF. We describe strategies supporting the knowledge creation stage that underpins the translational impact of KtAF

The Skin of Conflict: Voices of Vista Hermosa

Este texto es la voz de la piel de la guerra. Cada diálogo de entrevistador y entrevistado llega hasta la herida y se mete en ella. Muestra los guerreros, embravecidos en el combate, concentrados en conseguir la muerte del enemigo; los instantes humanos, de cuidado del otro, de amor de pareja en las noches que amanece en batalla; el fragor de balas que pegan sin dolor como golpes brutales; el sufrimiento y silencio y aislamiento cuando paran las explosiones; el campo de muertos; el quedar inconscientes y despertar en hospitales de cambuche, en enfermerías enemigas; el encontrarse perplejos ante el futuro, con la marca en la piel, con el órgano destruido o desaparecido para siempre. Así, surge la pregunta de si vale la pena seguir viviendo cuando los compañeros pasaron al otro lado, con el interrogante ¿para qué sirvió esto? Francisco de Roux, S. J.Bogot

Current diagnostic challenges from an analysis of social-demographic characteristics of 2453 patients in a memory and cognition hospital

INTRODUCCIÓN Y OBJETIVO: al programa de la Clínica de Memoria del Hospital Universitario San Ignacio (CM PUJ-HUSI) en Colombia, consultan, cada vez más pacientes con estadíos más tempranos de demencia. Estos plantean un reto para distinguir no solo entre los tipos de demencia, sino también entre las condiciones que pueden compartir algunas características con las enfermedades demenciales. A partir de un estudio descriptivo se analizan las variables sociodemográficas, resultados de la valoración y diagnóstico por consenso de los pacientes que asistieron por primera vez al programa y se proponen los retos diagnósticos actuales. MATERIALES Y MÉTODOS: se realiza un estudio descriptivo de corte transversal de los pacientes que asisten por primera vez a la CM PUJ-HUSI desde septiembre de 1996 hasta mayo del 2014. RESULTADOS: aunque el diagnóstico más frecuente sigue siendo la demencia tipo Alzheimer (43,45%), el diagnóstico de la demencia frontotemporal ha ido en aumento (de 5,49 a 11,5%), con una disminución de los diagnósticos psiquiátricos (de 14,31 a 7,7%). Las escalas aplicadas para la evaluación de los pacientes se encuentran, en diferentes proporciones, alteradas en todos los grupos de pacientes, incluyendo aquellos considerados normales. CONCLUSIONES: hubo evidencia de cambios significativos en el tipo de pacientes remitidos a la CMPUJ-HUSI que generan dificultad en establecer un diagnóstico definitivo, principalmente en enfermedades neurodegenerativas (EN) o demencia de inicio temprano (DIT). Se establece la necesidad de utilizar herramientas diagnósticas más precisas como las entrevistas e instrumentos que den cuenta de variables de conducta, comportamiento o cognición social.INTRODUCTION AND OBJECTIVES: The number of patients in earlier stages of the disease who consult to the memory clinic has increased. This poses a challenge to differentiate, not only between types of dementia, but also between conditions which may share characteristics with dementia-related illnesses. Starting from a descriptive study the current diagnostic challenges are proposed in order to then analyze sociodemographic characteristics, the results of assessment and diagnosis made by consensus of the patients who were attended for the first time in the memory clinic program at the Hospital Universitario San Ignacio in Bogotá, Colombia (CM PUJ-HUSI). MATERIALS AND METHODS: A descriptive cross-sectional study was performed on the group of patients who were attended for the first time in the CM PUJ-HUSI, from September 1996 to May 2014. RESULTS: Alzheimer’s dementia is the most frequent diagnosis (43,45%), but frontotemporal dementia has been increasing over the years, with less psychiatric diagnoses. The scales applied for the evaluation of the patients are, in different proportions, altered in all groups of patients, including those who were considered normal. CONCLUSIONS: The changes in the type of patients referred to the CMPUJ-HUSI, generate important insights related to a greater need to clarify neurodegenerative diseases (EN) or early onset dementia (DIT), with more precise diagnostic tools, such as the interview and instruments to evaluate the conduct, behavior or social cognition.Revista Internacional - Indexad

Exploring Signatures of Neurodegeneration in Early-Onset Older-Age Bipolar Disorder and Behavioral Variant Frontotemporal Dementia

Introduction: Older-age bipolar disorder (OABD) may involve neurocognitive decline and behavioral disturbances that could share features with the behavioral variant of frontotemporal dementia (bvFTD), making the differential diagnosis difficult in cases of suspected dementia. Objective: To compare the neuropsychological profile, brain morphometry, and structural connectivity patterns between patients diagnosed with bvFTD, patients classified as OABD with an early onset of the disease (EO-OABD), and healthy controls (HC). Methods: bvFTD patients (n = 25, age: 66 ± 7, female: 64%, disease duration: 6 ± 4 years), EO-OABD patients (n = 17, age: 65 ± 9, female: 71%, disease duration: 38 ± 8 years), and HC (n = 28, age: 62 ± 7, female: 64%) were evaluated through neuropsychological tests concerning attention, memory, executive function, praxis, and language. Brain morphometry was analyzed through surface-based morphometry (SBM), while structural brain connectivity was assessed through diffusion tensor imaging (DTI). Results: Both bvFTD and EO-OABD patients showed lower performance in neuropsychological tests of attention, verbal fluency, working memory, verbal memory, and praxis than HC. Comparisons between EO-OABD and bvFTD showed differences limited to cognitive flexibility delayed recall and intrusion errors in the memory test. SBM analysis demonstrated that several frontal, temporal, and parietal regions were altered in both bvFTD and EO-OABD compared to HC. In contrast, comparisons between bvFTD and EO-OABD evidenced differences exclusively in the right temporal pole and the left entorhinal cortex. DTI analysis showed alterations in association and projection fibers in both EO-OABD and bvFTD patients compared to HC. Commissural fibers were found to be particularly affected in EO-OABD. The middle cerebellar peduncle and the pontine crossing tract were exclusively altered in bvFTD. There were no significant differences in DTI analysis between EO-OABD and bvFTD. Discussion: EO-OABD and bvFTD may share an overlap in cognitive, brain morphometry, and structural connectivity profiles that could reflect common underlying mechanisms, even though the etiology of each disease can be different and multifactorial

Empathy for others’ sufering and its mediators in mental health professionals

Q1Q1Profesionales de la saludEmpathy is a complex cognitive and afective process that allows humans to experience concern for others, comprehend their emotions, and eventually help them. In addition to studies with healthy subjects and various neuropsychiatric populations, a few reports have examined this domain focusing on mental health workers, whose daily work requires the development of a saliently empathic character. Building on this research line, the present population-based study aimed to (a) assess diferent dimensions of empathy for pain in mental health workers relative to general-physicians and non-medical workers; and (b) evaluate their relationship with relevant factors, such as moral profle, age, gender, years of experience, and workplace type. Relative to both control groups, mental health workers exhibited higher empathic concern and discomfort for others’ sufering, and they favored harsher punishment to harmful actions. Furthermore, this was the only group in which empathy variability was explained by moral judgments, years of experience, and workplace type. Taken together, these results indicate that empathy is continuously at stake in mental health care scenarios, as it can be afected by contextual factors and social contingencies. More generally, they highlight the importance of studying this domain in populations characterized by extreme empathic demandsRevista Internacional - Indexad

The role of social cognition skills and social determinants of health in predicting symptoms of mental illnes

Q1Q1Social factors, such as social cognition skills (SCS) and social determinants of health (SDH), may be vital for mental health, even when compared with classical psycho-physical predictors (demographic, physical, psychiatric, and cognitive factors). Although major risk factors for psychiatric disorders have been previously assessed, the relative weight of SCS and SDH in relation to classical psycho-physical predictors in predicting symptoms of mental disorders remains largely unknown. In this study, we implemented multiple structural equation models (SEM) from a randomized sample assessed in the Colombian National Mental Health Survey of 2015 (CNMHS, n = 2947, females: 1348) to evaluate the role of SCS, SDH, and psycho-physical factors (totaling 17 variables) as predictors of mental illness symptoms (anxiety, depression, and other psychiatric symptoms). Specifically, we assessed the structural equation modeling of (a) SCS (emotion recognition and empathy skills); (b) SDH (including the experience of social adversities and social protective factors); (c) and classical psycho-physical factors, including psychiatric antecedents, physical–somatic factors (chronic diseases), and cognitive factors (executive functioning). Results revealed that the emotion recognition skills, social adverse factors, antecedents of psychiatric disorders and chronic diseases, and cognitive functioning were the best predictors of symptoms of mental illness. Moreover, SCS, particularly emotion recognition skills, and SDH (experiences of social adversities, familial, and social support networks) reached higher predictive values of symptoms than classical psycho-physical factors. Our study provides unprecedented evidence on the impact of social factors in predicting symptoms of mental illness and highlights the relevance of these factors to track early states of disease.Revista Internacional - Indexad