RESUMO
While Alzheimer's disease (AD) diagnosis, management, and care have become priorities for healthcare providers and researcher's worldwide due to rapid population aging, epidemiologic surveillance efforts are currently limited by costly, invasive diagnostic procedures, particularly in low to middle income countries (LMIC). In recent years, wastewater-based epidemiology (WBE) has emerged as a promising tool for public health assessment through detection and quantification of specific biomarkers in wastewater, but applications for non-infectious diseases such as AD remain limited. This early review seeks to summarize AD-related biomarkers and urine and other peripheral biofluids and discuss their potential integration to WBE platforms to guide the first prospective efforts in the field. Promising results have been reported in clinical settings, indicating the potential of amyloid ß, tau, neural thread protein, long non-coding RNAs, oxidative stress markers and other dysregulated metabolites for AD diagnosis, but questions regarding their concentration and stability in wastewater and the correlation between clinical levels and sewage circulation must be addressed in future studies before comprehensive WBE systems can be developed.
Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/epidemiologia , Peptídeos beta-Amiloides , Vigilância Epidemiológica Baseada em Águas Residuárias , Águas Residuárias , Estudos Prospectivos , BiomarcadoresRESUMO
Alzheimer's disease (AD) represents a substantial burden to patients, their caregivers, health systems, and society in Latin America and the Caribbean (LAC). This impact is exacerbated by limited access to diagnosis, specialized care, and therapies for AD within and among nations. The region has varied geographic, ethnic, cultural, and economic conditions, which create unique challenges to AD diagnosis and management. To address these issues, the Americas Health Foundation convened a panel of eight neurologists, geriatricians, and psychiatrists from Argentina, Brazil, Colombia, Ecuador, Guatemala, Mexico, and Peru who are experts in AD for a three-day virtual meeting to discuss best practices for AD diagnosis and treatment in LAC and create a manuscript offering recommendations to address identified barriers. In LAC, several barriers hamper diagnosing and treating people with dementia. These barriers include access to healthcare, fragmented healthcare systems, limited research funding, unstandardized diagnosis and treatment, genetic heterogeneity, and varying social determinants of health. Additional training for physicians and other healthcare workers at the primary care level, region-specific or adequately adapted cognitive tests, increased public healthcare insurance coverage of testing and treatment, and dedicated search strategies to detect populations with gene variants associated with AD are among the recommendations to improve the landscape of AD.
RESUMO
Low concentrations of biomarkers as well as the complexity of biological samples make the clinical diagnoses of several diseases a challenging task. Sample preparation protocols remain a fundamental piece in the puzzle of analytical processes, and smart sorbents including molecularly imprinted polymers (MIPs) have been successfully used in this case. In this review, we depict the state of art for the rational design of MIPs to be used in solid phase extraction of disease biomarkers from biological samples. The topics are divided into (1) strategies for MIP syntheses, (2) setups for sample preparation protocols with MIPs, (3) the applications of these combined principles in the analyses of different classes of disease biomarkers, and (4) remaining challenges and future trends for the application of Molecular Imprinting Technology in sample preparation for clinical diagnosis.
Assuntos
Impressão Molecular , Polímeros , Biomarcadores , Impressão Molecular/métodos , Polímeros Molecularmente Impressos , Extração em Fase Sólida/métodosRESUMO
Multiple sclerosis is an autoimmune neurodegenerative disease of the central nervous system characterized by pronounced inflammatory infiltrates entering the brain, spinal cord and optic nerve leading to demyelination. Focal demyelination is associated with relapsing-remitting multiple sclerosis, while progressive forms of the disease show axonal degeneration and neuronal loss. The tests currently used in the clinical diagnosis and management of multiple sclerosis have limitations due to specificity and sensitivity. MicroRNAs (miRNAs) are dysregulated in many diseases and disorders including demyelinating and neuroinflammatory diseases. A review of recent studies with the experimental autoimmune encephalomyelitis animal model (mostly female mice 6-12 weeks of age) has confirmed miRNAs as biomarkers of experimental autoimmune encephalomyelitis disease and importantly at the pre-onset (asymptomatic) stage when assessed in blood plasma and urine exosomes, and spinal cord tissue. The expression of certain miRNAs was also dysregulated at the onset and peak of disease in blood plasma and urine exosomes, brain and spinal cord tissue, and at the post-peak (chronic) stage of experimental autoimmune encephalomyelitis disease in spinal cord tissue. Therapies using miRNA mimics or inhibitors were found to delay the induction and alleviate the severity of experimental autoimmune encephalomyelitis disease. Interestingly, experimental autoimmune encephalomyelitis disease severity was reduced by overexpression of miR-146a, miR-23b, miR-497, miR-26a, and miR-20b, or by suppression of miR-182, miR-181c, miR-223, miR-155, and miR-873. Further studies are warranted on determining more fully miRNA profiles in blood plasma and urine exosomes of experimental autoimmune encephalomyelitis animals since they could serve as biomarkers of asymptomatic multiple sclerosis and disease course. Additionally, studies should be performed with male mice of a similar age, and with aged male and female mice.
RESUMO
Chagas cardiomyopathy is the most severe clinical manifestation of chronic Chagas disease. The disease affects most of the Latin American countries, being considered one of the leading causes of morbidity and death in the continent. The pathogenesis of Chagas cardiomyopathy is very complex, with mechanisms involving parasite-dependent cytopathy, immune-mediated myocardial damage and neurogenic disturbances. These pathological changes eventually result in cardiac myocyte hypertrophy, arrhythmias, congestive heart failure and stroke during chronic infection phase. Herein, we show that miR-208a, a microRNA that is a key factor in promoting cardiovascular dysfunction during cardiac hypertrophy processes of heart failure, has its circulating levels increased during chronic indeterminate phase when compared to cardiac (CARD) clinical forms in patients with Chagas disease. In contrast, we have not found altered serum levels of miR-34a, a microRNA known to promote pro-apoptotic role in myocardial infarction during degenerative process of cardiac injuries thus indicating intrinsic differences in the nature of the mechanisms underlying the heart failure triggered by Trypanosoma cruzi infection. Our findings support that the chronic indeterminate phase is a progressive phase involved in the genesis of chagasic cardiopathy and point out the use of plasma levels of miR-208a as candidate biomarker in risk-prediction score for the clinical prognosis of Chagas disease.
RESUMO
There is increasing evidence suggesting that one of the most relevant pathophysiological features of Alzheimer's disease (AD) is neuroinflammation, which plays an important role in the production and regulation of AD-related proteins (amyloid beta (Aß) and Tau) and exacerbates AD pathology. Neuroinflammation can also be induced by systemic influences (factors from outside the central nervous system). However, the role of systemic inflammation in AD pathophysiology is much less understood. Thus, our main objective in this study was to verify whether the presence of serum cytokines (IL-1ß, IL-6, IL-10, IL-12, and TNF-α) affects different AD biomarkers: Aß1-42 and Tau protein levels, hippocampal volumes (HV), and default mode network functional connectivity (DMN FC) in healthy elderly controls, amnestic mild cognitive impairment (aMCI) patients due to AD, and mild AD patients. To accomplish this, we acquired 3-T MRI, blood, and cerebrospinal fluid (CSF) samples from 42 healthy controls, 55 aMCI patients due to AD, and 33 mild AD patients. Comparing the groups, we found that the mild AD patients presented smaller HV, disrupted DMN FC, and proportionally less IL-1ß than the controls. The aMCI patients only differed from the controls in DMN FC. In intra-group comparison, aMCI and mild AD with detectable levels of cytokines (TNF-α, IL-1ß, IL-10, and IL-12) had decreased DMN FC. On the other hand, patients with detectable levels of IL-10 and IL-12 presented a more favorable AD biomarkers profile (larger HV, more CSF Aß1-42, and less p-Tau), indicating a possible protective role of these ILs. Our findings indicate a possible relationship between systemic inflammation with DMN FC disruption, hippocampal atrophy, and CSF protein levels in the subjects with mild AD and aMCI.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/complicações , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/complicações , Inflamação/líquido cefalorraquidiano , Inflamação/complicações , Idoso , Doença de Alzheimer/diagnóstico por imagem , Estudos de Casos e Controles , Disfunção Cognitiva/diagnóstico por imagem , Citocinas/líquido cefalorraquidiano , Feminino , Humanos , Inflamação/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes NeuropsicológicosRESUMO
Mucopolysaccharidosis (MPS) is a group of lysosomal storage diseases (LSD), characterized by the deficiency of a lysosomal enzyme responsible for the degradation of glycosaminoglycans (GAG). This deficiency leads to the lysosomal accumulation of partially degraded GAG. Nevertheless, deficiency of a single lysosomal enzyme has been associated with impairment in other cell mechanism, such as apoptosis and redox balance. Although GAG analysis represents the main biomarker for MPS diagnosis, it has several limitations that can lead to a misdiagnosis, whereby the identification of new biomarkers represents an important issue for MPS. In this study, we used a system biology approach, through the use of a genome-scale human metabolic reconstruction to understand the effect of metabolism alterations in cell homeostasis and to identify potential new biomarkers in MPS. In-silico MPS models were generated by silencing of MPS-related enzymes, and were analyzed through a flux balance and variability analysis. We found that MPS models used approximately 2286 reactions to satisfy the objective function. Impaired reactions were mainly involved in cellular respiration, mitochondrial process, amino acid and lipid metabolism, and ion exchange. Metabolic changes were similar for MPS I and II, and MPS III A to C; while the remaining MPS showed unique metabolic profiles. Eight and thirteen potential high-confidence biomarkers were identified for MPS IVB and VII, respectively, which were associated with the secondary pathologic process of LSD. In vivo evaluation of predicted intermediate confidence biomarkers (ß-hexosaminidase and ß-glucoronidase) for MPS IVA and VI correlated with the in-silico prediction. These results show the potential of a computational human metabolic reconstruction to understand the molecular mechanisms this group of diseases, which can be used to identify new biomarkers for MPS.
Assuntos
Mucopolissacaridoses/metabolismo , Biomarcadores/metabolismo , Simulação por Computador , Células HEK293 , Humanos , Leucócitos Mononucleares/enzimologia , Análise do Fluxo Metabólico , Redes e Vias Metabólicas , Biologia de Sistemas , beta-N-Acetil-Hexosaminidases/metabolismoRESUMO
En 31 comensales regulares del Comedor Universitario de la Universidad Central de Venezuela (CUUCV), en Caracas. Se observó el efecto de la sustitución del aceite de girasol que se utiliza corrientemente en la preparación de las comidas en ese comedor, por un aceite obtenido de la mezcla de aceite de girasol y oleína de palma, en la proporción 70/30 (v/v) respectivamente. Después de 40 días continuos de la sustitución no hubo cambios significativos en las concentraciones de colesterol total (CT), ni del colesterol de las lipoproteínas de baja densidad (LDL) y muy baja densidad (VLDL). La concentración del colesterol de las lipoproteínas de alta densidad (HDL) aumentó significativamente (p<0,05). Los triglicéridos (TG) del plasma aumentaron en un 30%. La resistencia a la oxidación de las LDL aumentó considerablemente (p< 0,01). Hoy se considera a esta resistencia como un factor protector de gran importancia en la prevención del inicio del proceso aterogénico. Tomando en cuenta las modificaciones favorables como el aumento de colesterol de HDL sin modificación de la LDL y el claro aumento de la resistencia a la oxidación de la LDL, se considera que la oleína de palma es un aceite vegetal que puede ser utilizado sin mayores riesgos en mezcla con otros aceites que tengan una relación linoleico/palmítico más elevada como los aceites de girasol, maíz, soja y otros.
We analyzed in 31 subjects, regular guests of the University food service of the Central University of Venezuela (UCVFS), in Caracas, the effects of replacing sunflower oil, commonly used in the preparation of meals, by a mix of sunflower oil and palm olein 70/30 (v/v) respectively. Plasma concentrations of total cholesterol, low and very low density lipoproteins were not changed after 40 days of the substitution. On the contrary, concentrations of high density lipoprotein and total triglycerides increased. The resistance to the oxidation of low-density lipoproteins increased considerably (p<0, 01). Today this resistance is considered as a protective factor of great importance in the prevention of the initiation of the atherogenic process. Taking into account the favorable modifications of HDL cholesterol and the clear increased resistance to the oxidation of LDL, we think that palm olein, mixed with other oils with a high ratio linoleic/palmític (sunflower, corn, soya an the likes), can be used as a healthy alternative in human nutrition.