Systematic Review: microRNAs as Potential Biomarkers in Mild Cognitive Impairment Diagnosis

The rate of progression from Mild Cognitive Impairment (MCI) to Alzheimer's disease (AD) is estimated at >10% per year, reaching up to 80–90% after 6 years. MCI is considered an indicator of early-stage AD. In this context, the diagnostic screening of MCI is crucial for detecting individuals at high risk of AD before they progress and manifest further severe symptoms. Typically, MCI has been determined using neuropsychological assessment tools such as the Montreal Cognitive Assessment (MoCA) or Mini-Mental Status Examination (MMSE). Unfortunately, other diagnostic methods are not available or are unable to identify MCI in its early stages. Therefore, identifying new biomarkers for MCI diagnosis and prognosis is a significant challenge. In this framework, miRNAs in serum, plasma, and other body fluids have emerged as a promising source of biomarkers for MCI and AD-related cognitive impairments. Interestingly, miRNAs can regulate several signaling pathways via multiple and diverse targets in response to pathophysiological stimuli. This systematic review aims to describe the current state of the art regarding AD-related target genes modulated by differentially expressed miRNAs in peripheral fluids samples in MCI subjects to identify potential miRNA biomarkers in the early stages of AD. We found 30 articles that described five miRNA expression profiles from peripheral fluid in MCI subjects, showing possible candidates for miRNA biomarkers that may be followed up as fluid biomarkers or therapeutic targets of early-stage AD. However, additional research is needed to validate these miRNAs and characterize the precise neuropathological mechanisms.Fil: Ogonowski, Natalia Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentina. Universidad Adolfo Ibañez; ChileFil: Salcidua, Stefanny. Universidad Adolfo Ibañez; ChileFil: Leon, Tomas. Universidad de Chile; Chile. Trinity College; IrlandaFil: Chamorro Veloso, Nayaret. Neurognos Spa; ChileFil: Valls, Cristian. Neurognos Spa; ChileFil: Avalos, Constanza. Universidad Adolfo Ibañez; ChileFil: Bisquertt, Alejandro. Neurognos Spa; ChileFil: Rentería, Miguel E.. Berghofer Medical Research Institute; AustraliaFil: Orellana, Paulina. Universidad Adolfo Ibañez; ChileFil: Duran Aniotz, Claudia. Universidad Adolfo Ibañez; Chil

Lem2 is essential for cardiac development by maintaining nuclear integrity

Aims: Nuclear envelope integrity is essential for the compartmentalization of the nucleus and cytoplasm. Importantly, mutations in genes encoding nuclear envelope (NE) and associated proteins are the second highest cause of familial dilated cardiomyopathy. One such NE protein that causes cardiomyopathy in humans and affects mouse heart development is Lem2. However, its role in the heart remains poorly understood. Methods and results: We generated mice in which Lem2 was specifically ablated either in embryonic cardiomyocytes (Lem2 cKO) or in adult cardiomyocytes (Lem2 iCKO) and carried out detailed physiological, tissue, and cellular analyses. High-resolution episcopic microscopy was used for three-dimensional reconstructions and detailed morphological analyses. RNA-sequencing and immunofluorescence identified altered pathways and cellular phenotypes, and cardiomyocytes were isolated to interrogate nuclear integrity in more detail. In addition, echocardiography provided a physiological assessment of Lem2 iCKO adult mice. We found that Lem2 was essential for cardiac development, and hearts from Lem2 cKO mice were morphologically and transcriptionally underdeveloped. Lem2 cKO hearts displayed high levels of DNA damage, nuclear rupture, and apoptosis. Crucially, we found that these defects were driven by muscle contraction as they were ameliorated by inhibiting myosin contraction and L-type calcium channels. Conversely, reducing Lem2 levels to ∼45% in adult cardiomyocytes did not lead to overt cardiac dysfunction up to 18 months of age. Conclusions: Our data suggest that Lem2 is critical for integrity at the nascent NE in foetal hearts, and protects the nucleus from the mechanical forces of muscle contraction. In contrast, the adult heart is not detectably affected by partial Lem2 depletion, perhaps owing to a more established NE and increased adaptation to mechanical stress. Taken together, these data provide insights into mechanisms underlying cardiomyopathy in patients with mutations in Lem2 and cardio-laminopathies in general

Lem2 is essential for cardiac development by maintaining nuclear integrity

Aims: Nuclear envelope integrity is essential for the compartmentalization of the nucleus and cytoplasm. Importantly, mutations in genes encoding nuclear envelope (NE) and associated proteins are the second highest cause of familial dilated cardiomyopathy. One such NE protein that causes cardiomyopathy in humans and affects mouse heart development is Lem2. However, its role in the heart remains poorly understood. Methods and results: We generated mice in which Lem2 was specifically ablated either in embryonic cardiomyocytes (Lem2 cKO) or in adult cardiomyocytes (Lem2 iCKO) and carried out detailed physiological, tissue, and cellular analyses. High-resolution episcopic microscopy was used for three-dimensional reconstructions and detailed morphological analyses. RNA-sequencing and immunofluorescence identified altered pathways and cellular phenotypes, and cardiomyocytes were isolated to interrogate nuclear integrity in more detail. In addition, echocardiography provided a physiological assessment of Lem2 iCKO adult mice. We found that Lem2 was essential for cardiac development, and hearts from Lem2 cKO mice were morphologically and transcriptionally underdeveloped. Lem2 cKO hearts displayed high levels of DNA damage, nuclear rupture, and apoptosis. Crucially, we found that these defects were driven by muscle contraction as they were ameliorated by inhibiting myosin contraction and L-type calcium channels. Conversely, reducing Lem2 levels to ∼45% in adult cardiomyocytes did not lead to overt cardiac dysfunction up to 18 months of age. Conclusions: Our data suggest that Lem2 is critical for integrity at the nascent NE in foetal hearts, and protects the nucleus from the mechanical forces of muscle contraction. In contrast, the adult heart is not detectably affected by partial Lem2 depletion, perhaps owing to a more established NE and increased adaptation to mechanical stress. Taken together, these data provide insights into mechanisms underlying cardiomyopathy in patients with mutations in Lem2 and cardio-laminopathies in general

Biomarkers for dementia in Latin American countries: Gaps and opportunities

Limited knowledge on dementia biomarkers in Latin American and Caribbean (LAC) countries remains a serious barrier. Here, we reported a survey to explore the ongoing work, needs, interests, potential barriers, and opportunities for future studies related to biomarkers. The results show that neuroimaging is the most used biomarker (73%), followed by genetic studies (40%), peripheral fluids biomarkers (31%), and cerebrospinal fluid biomarkers (29%). Regarding barriers in LAC, lack of funding appears to undermine the implementation of biomarkers in clinical or research settings, followed by insufficient infrastructure and training. The survey revealed that despite the above barriers, the region holds a great potential to advance dementia biomarkers research. Considering the unique contributions that LAC could make to this growing field, we highlight the urgent need to expand biomarker research. These insights allowed us to propose an action plan that addresses the recommendations for a biomarker framework recently proposed by regional experts.Fil: Parra, Mario A.. University of Strathclyde; Reino UnidoFil: Orellana, Paulina. Universidad Adolfo Ibañez; ChileFil: Leon, Tomas. Trinity College Dublin; Reino Unido. Universidad de Chile; ChileFil: Victoria, Cabello G.. Universidad de Chile; Chile. Universidad Adolfo Ibañez; ChileFil: Henriquez, Fernando. Pontificia Universidad Católica de Chile; Chile. Universidad de Chile; Chile. Geroscience Center For Brain Health And Metabolism; Chile. Universidad Católica de Chile; ChileFil: Gomez, Rodrigo. Universidad de Chile; Chile. Universidad Mayor; ChileFil: Avalos, Constanza. Universidad Adolfo Ibañez; ChileFil: Damian, Andres. Universidad de la Republica; UruguayFil: Slachevsky, Andrea. Universidad del Desarrollo; Chile. Geroscience Center For Brain Health And Metabolism; Chile. Universidad de Chile; ChileFil: Ibanez Barassi, Agustin Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de San Andrés; Argentina. Trinity College Dublin; Reino Unido. Universidad Adolfo Ibañez; Chile. University of California; Estados UnidosFil: Zetterberg, Henrik. University of Gothenburg; Suecia. Clear Water Bay; Hong Kong. Colegio Universitario de Londres; Reino Unido. Sahlgrenska University Hospital; SueciaFil: Tijms, Betty M.. Alzheimercentrum Amsterdam; Países BajosFil: Yokoyama, Jennifer S.. University of California; Estados UnidosFil: Piña Escudero, Stefanie D.. University of California; Estados UnidosFil: Cochran, J. Nicholas. Hudsonalpha Institute For Biotechnology; Estados UnidosFil: Matallana, Diana L.. Pontificia Universidad Javeriana; Colombia. Hospital Universitario San Ignacio; Colombia. Hospital Universitario Santa Fe de Bogotá; ColombiaFil: Acosta, Daisy. Universidad Nacional Pedro Henríquez Ureña; República DominicanaFil: Allegri, Ricardo Francisco. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Universidad de la Costa; Colombia. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Arias Suárez, Bianca P.. Universidad Nacional Mayor de San Marcos; PerúFil: Barra, Bernardo. Universidad Andrés Bello; Chile. Universidad de Los Andes; ChileFil: Behrens, Maria Isabel. Universidad del Desarrollo; Chile. Universidad de Chile; ChileFil: Brucki, Sonia M. D.. Universidade de Sao Paulo; BrasilFil: Busatto, Geraldo. Universidade de Sao Paulo; BrasilFil: Caramelli, Paulo. Universidade Federal de Minas Gerais; BrasilFil: Castro-Suarez, Sheila. Instituto Nacional de Ciencias Neurologicas; Perú. University of California; Estados UnidosFil: Contreras, María Valeria. Hospital Central de Las Fuerzas Armadas; UruguayFil: Custodio, Nilton. Instituto Peruano de Neurociencias; PerúFil: Dansilio, Sergio. Universidad de la República; UruguayFil: la Cruz Puebla, Myriam De. Universitat Autònoma de Barcelona; España. Technical University Of Ambato; Ecuador. Institut D'investigació Biomedica de Bellvitge; España. University of California; Estados UnidosFil: de Souza, Leonardo Cruz. Universidade de Sao Paulo; Brasil. Pontificia Universidade Católica do Rio Grande do Sul; Brasi

Biomarkers for dementia in Latin American countries : gaps and opportunities

Limited knowledge on dementia biomarkers in Latin American and Caribbean (LAC) countries remains a serious barrier. Here, we report on the results from an online survey completed by dementia specialists from LAC. It aims to explore the ongoing work, needs, interests, potential barriers, and opportunities for future studies related to biomarkers. The survey was answered by 48 respondents from 10 LAC countries. The results show that neuroimaging is the most commonly used biomarker (73%), followed by genetic studies (40%), peripheral fluids biomarkers (31%) and cerebrospinal fluid biomarkers (29%). Regarding barriers in LAC, we identified that lack of funding appears to undermine the implementation of biomarkers in clinical or research settings, followed by insufficient infrastructure and training. The survey revealed that despite the above barriers, the region holds a great potential to advance dementia biomarkers research as the majority of respondents share an interest in the topic, would like to host studies, and confirmed access to unique populations. Considering the unique contributions that LAC could make to this growing field, we highlight the urgent need to introduce and expand biomarker research and suggest strategies to accelerate such developments. These insights allowed us to propose an action plan that addresses the recommendations towards a biomarker framework recently proposed by regional experts

Biomarkers for dementia in Latin American countries: Gaps and opportunities

Limited knowledge on dementia biomarkers in Latin American and Caribbean (LAC) countries remains a serious barrier. Here, we reported a survey to explore the ongoing work, needs, interests, potential barriers, and opportunities for future studies related to biomarkers. The results show that neuroimaging is the most used biomarker (73%), followed by genetic studies (40%), peripheral fluids biomarkers (31%), and cerebrospinal fluid biomarkers (29%). Regarding barriers in LAC, lack of funding appears to undermine the implementation of biomarkers in clinical or research settings, followed by insufficient infrastructure and training. The survey revealed that despite the above barriers, the region holds a great potential to advance dementia biomarkers research. Considering the unique contributions that LAC could make to this growing field, we highlight the urgent need to expand biomarker research. These insights allowed us to propose an action plan that addresses the recommendations for a biomarker framework recently proposed by regional experts