RESUMO
BACKGROUND: Inflammatory responses play key roles in the development and progression of many pathological conditions, including neurodegenerative diseases. Accurate quantification of inflammatory factors in saliva would be highly advantageous, given its convenience and non-invasive nature, especially in elderly populations. METHODS: In this study, we measured levels of 10 cytokines, and the pro-inflammatory factor, YKL-40, in plasma and saliva samples from a cohort of nondemented older adults (n = 71; 62% female; 70.3 ± 6.4 years) using sensitive electrochemiluminescence-based immunoassays. RESULTS: We found that the mean levels of all cytokines were higher in saliva compared to plasma and that strong sex differences were observed for both saliva and plasma cytokines in this population. Comparing each cytokine between the two biofluids, we found that levels of interferon-gamma (IFNγ), interleukin (IL)-6 and tumor necrosis factor-alpha (TNFα) in blood were significantly correlated with their respective levels in saliva. We further observed that levels of these cytokines in blood were significantly correlated with additional cytokines in saliva, including IL-1ß, IL-10, IL-8, IL12p70 and IL-13. CONCLUSIONS: These findings show that inflammatory markers in saliva are associated with those found in circulation, suggesting shared inflammatory mechanisms between these two fluids. The higher levels of cytokines measured in saliva suggest that it might represent a better peripheral fluid to gauge inflammatory processes. Finally, our findings of robust sex differences in several salivary cytokines could have important implications for their potential use as disease biomarkers in the elderly and might be related to sex differences in the prevalence of age-related conditions.
Assuntos
Citocinas , Saliva , Feminino , Humanos , Masculino , Idoso , Interleucina-6 , Fator de Necrose Tumoral alfa , BiomarcadoresRESUMO
The amyloid beta (Aß) 42/40 ratio has been widely studied as a biomarker in Alzheimer's disease (AD); however, other Aß peptides could also represent relevant biomarkers. We measured levels of Aß38/40/42 in plasma samples from cognitively-unimpaired older adults and determined the relationships between Aß levels and amyloid positron-emission-tomography (PET) and performance on a learning and memory task. We found that all Aß peptides individually and the Aß42/40 ratio, but not the Aß42/38 ratio, were significantly correlated with brain amyloid (Aß-PET). Multiple linear modeling, adjusting for age, sex, education, APOE4 and Aß-PET showed significant associations between the Aß42/38 ratio and memory. Further, associations between the Aß42/38 ratio and learning scores were stronger in males and in Aß-PET-negative individuals. In contrast, no significant associations were detected between the Aß42/40 ratio and any learning measure. These studies implicate the Aß42/38 ratio as a biomarker to assess early memory deficits and underscore the utility of the Aß38 fragment as an important biomarker in the AD field.
Assuntos
Peptídeos beta-Amiloides , Biomarcadores , Transtornos da Memória , Fragmentos de Peptídeos , Tomografia por Emissão de Pósitrons , Humanos , Peptídeos beta-Amiloides/sangue , Biomarcadores/sangue , Masculino , Feminino , Idoso , Transtornos da Memória/sangue , Transtornos da Memória/etiologia , Transtornos da Memória/diagnóstico , Fragmentos de Peptídeos/sangue , Idoso de 80 Anos ou mais , Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/diagnóstico por imagem , Cognição/fisiologia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Memória , Aprendizagem/fisiologiaRESUMO
Recent reports have suggested that the reactivation of otherwise transcriptionally silent transposable elements (TEs) might induce brain degeneration, either by dysregulating the expression of genes and pathways implicated in cognitive decline and dementia or through the induction of immune-mediated neuroinflammation resulting in the elimination of neural and glial cells. In the work we present here, we test the hypothesis that differentially expressed TEs in blood could be used as biomarkers of cognitive decline and development of AD. To this aim, we used a sample of aging subjects (age > 70) that developed late-onset Alzheimer's disease (LOAD) over a relatively short period of time (12-48 months), for which blood was available before and after their phenoconversion, and a group of cognitive stable subjects as controls. We applied our developed and validated customized pipeline that allows the identification, characterization, and quantification of the differentially expressed (DE) TEs before and after the onset of manifest LOAD, through analyses of RNA-Seq data. We compared the level of DE TEs within more than 600,000 TE-mapping RNA transcripts from 25 individuals, whose specimens we obtained before and after their phenotypic conversion (phenoconversion) to LOAD, and discovered that 1790 TE transcripts showed significant expression differences between these two timepoints (logFC ± 1.5, logCMP > 5.3, nominal p value < 0.01). These DE transcripts mapped both over- and under-expressed TE elements. Occurring before the clinical phenoconversion, this TE storm features significant increases in DE transcripts of LINEs, LTRs, and SVAs, while those for SINEs are significantly depleted. These dysregulations end with signs of manifest LOAD. This set of highly DE transcripts generates a TE transcriptional profile that accurately discriminates the before and after phenoconversion states of these subjects. Our findings suggest that a storm of DE TEs occurs before phenoconversion from normal cognition to manifest LOAD in risk individuals compared to controls, and may provide useful blood-based biomarkers for heralding such a clinical transition, also suggesting that TEs can indeed participate in the complex process of neurodegeneration.