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INTRODUCTION: This study involved a parallel comparison of the diagnostic and longitudinal monitoring potential of plasma glial fibrillary acidic protein (GFAP), total tau (t-tau), phosphorylated tau (p-tau181 and p-tau231), and neurofilament light (NFL) in preclinical Alzheimer's disease (AD). METHODS: Plasma proteins were measured using Simoa assays in cognitively unimpaired older adults (CU), with either absence (Aß-) or presence (Aß+) of brain amyloidosis. RESULTS: Plasma GFAP, t-tau, p-tau181, and p-tau231 concentrations were higher in Aß+ CU compared with Aß- CU cross-sectionally. GFAP had the highest effect size and area under the curve (AUC) in differentiating between Aß+ and Aß- CU; however, no statistically significant differences were observed between the AUCs of GFAP, p-tau181, and p-tau231, but all were significantly higher than the AUC of NFL, and the AUC of GFAP was higher than the AUC of t-tau. The combination of a base model (BM), comprising the AD risk factors, age, sex, and apolipoprotein E gene (APOE) ε4 status with GFAP was observed to have a higher AUC (>90%) compared with the combination of BM with any of the other proteins investigated in the current study. Longitudinal analyses showed increased GFAP and p-tau181 in Aß+ CU and increased NFL in Aß- CU, over a 12-month duration. GFAP, p-tau181, p-tau231, and NFL showed significant correlations with cognition, whereas no significant correlations were observed with hippocampal volume. DISCUSSION: These findings highlight the diagnostic and longitudinal monitoring potential of GFAP and p-tau for preclinical AD.
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Enfermedad de Alzheimer , Amiloidosis , Anciano , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides , Biomarcadores , Humanos , Pronóstico , Proteínas tauRESUMEN
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that currently has no cure. Identifying biochemical changes associated with neurodegeneration prior to symptom onset, will provide insight into the biological mechanisms associated with neurodegenerative processes, that may also aid in identifying potential drug targets. The current study therefore investigated associations between plasma neurofilament light chain (NF-L), a marker of neurodegeneration, with plasma metabolites that are products of various cellular processes. Plasma NF-L, measured by ultrasensitive Single molecule array (Simoa) technology (Quanterix) and plasma metabolites, measured by mass-spectrometry (AbsoluteIDQ® p400HR kit, BIOCRATES), were assessed in the Kerr Anglican Retirement Village Initiative in Ageing Health (KARVIAH) cohort comprising 100 cognitively normal older adults. Metabolites belonging to biogenic amine (creatinine, symmetric dimethylarginine, asymmetric dimethylarginine; ADMA, kynurenine, trans-4-hydroxyproline), amino acid (citrulline, proline, arginine, asparagine, phenylalanine, threonine) and acylcarnitine classes were observed to have positive correlations with plasma NF-L, suggesting a link between neurodegeneration and biological pathways associated with neurotransmitter regulation, nitric oxide homoeostasis, inflammation and mitochondrial function. Additionally, after stratifying participants based on low/high brain amyloid-ß load (Aß ±) assessed by positron emission tomography, while creatinine, SDMA and citrulline correlated with NF-L in both Aß- and Aß+ groups, ADMA, proline, arginine, asparagine, phenylalanine and acylcarnitine species correlated with NF-L only in the Aß+ group after adjusting for confounding variables, suggesting that the association of these metabolites with neurodegeneration may be relevant to AD-related neuropathology. Metabolites identified to be associated with plasma NF-L may have the potential to serve as prognostic markers for neurodegenerative diseases, however, further studies are required to validate the current findings in an independent cohort, both cross-sectionally and longitudinally.
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Enfermedades Neurodegenerativas/sangre , Anciano , Anciano de 80 o más Años , Péptidos beta-Amiloides/análisis , Aminas Biogénicas/metabolismo , Biomarcadores/análisis , Cognición , Estudios de Cohortes , Encefalitis/metabolismo , Femenino , Humanos , Masculino , Espectrometría de Masas/métodos , Mitocondrias/metabolismo , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/psicología , Proteínas de Neurofilamentos/análisis , Neurotransmisores/metabolismo , Óxido Nítrico/metabolismo , Tomografía de Emisión de Positrones , PronósticoRESUMEN
Plasma amyloid-beta (Aß) has long been investigated as a blood biomarker candidate for Cerebral Amyloid Angiopathy (CAA), however previous findings have been inconsistent which could be attributed to the use of less sensitive assays. This study investigates plasma Aß alterations between pre-symptomatic Dutch-type hereditary CAA (D-CAA) mutation-carriers (MC) and non-carriers (NC) using two Aß measurement platforms. Seventeen pre-symptomatic members of a D-CAA pedigree were assembled and followed up 3-4 years later (NC = 8; MC = 9). Plasma Aß1-40 and Aß1-42 were cross-sectionally and longitudinally analysed at baseline (T1) and follow-up (T2) and were found to be lower in MCs compared to NCs, cross-sectionally after adjusting for covariates, at both T1(Aß1-40: p = 0.001; Aß1-42: p = 0.0004) and T2 (Aß1-40: p = 0.001; Aß1-42: p = 0.016) employing the Single Molecule Array (Simoa) platform, however no significant differences were observed using the xMAP platform. Further, pairwise longitudinal analyses of plasma Aß1-40 revealed decreased levels in MCs using data from the Simoa platform (p = 0.041) and pairwise longitudinal analyses of plasma Aß1-42 revealed decreased levels in MCs using data from the xMAP platform (p = 0.041). Findings from the Simoa platform suggest that plasma Aß may add value to a panel of biomarkers for the diagnosis of pre-symptomatic CAA, however, further validation studies in larger sample sets are required.
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Péptidos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Angiopatía Amiloide Cerebral Familiar/genética , Fragmentos de Péptidos/genética , Adulto , Péptidos beta-Amiloides/sangre , Precursor de Proteína beta-Amiloide/sangre , Enfermedades Asintomáticas , Biomarcadores/sangre , Angiopatía Amiloide Cerebral Familiar/sangre , Angiopatía Amiloide Cerebral Familiar/diagnóstico , Angiopatía Amiloide Cerebral Familiar/patología , Progresión de la Enfermedad , Femenino , Expresión Génica , Genes Dominantes , Heterocigoto , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Mutación , Pruebas Neuropsicológicas , Linaje , Fragmentos de Péptidos/sangreRESUMEN
BACKGROUND: An increasing body of literature suggests a positive, neuroprotective effect for testosterone on cognition in older men. However, randomized clinical trials (RCTs) examining the effects of testosterone supplementation (TS) on cognitive function have been inconclusive. OBJECTIVE: To investigate the potential for TS to prevent cognitive decline in otherwise cognitively healthy older men, by examining the differential effects of TS on cognitively healthy older men in RCTs. METHODS: Comprehensive search of electronic databases, conference proceedings, and grey literature from 1990 to 2018 was performed to identify RCTs examining the effects of TS on cognition before and after supplementation, in cognitively healthy individuals. RESULTS: A final sample of 14 eligible RCTs met inclusion criteria. Using pooled random effects expressed as Hedge's g, comparison of placebo versus treatment groups pre- and postsupplementation showed improvements in the treatment group in executive function (g (11)â¯=â¯0.14, 95% confidence interval [CI]: 0.03-0.26, zâ¯=â¯0.56, pâ¯=â¯0.011). However, it was noted that two studies in our sample did not report a significant increase in mean serum total testosterone (TT) levels in the treatment group after supplementation. Following exclusion of these studies, analysis indicated improvement in the treatment group for the overall cognitive composite (g (11)â¯=â¯0.18, 95% CI: 0.02-0.33, zâ¯=â¯2.18), psychomotor speed (g (3)â¯=â¯0.22, 95% CI: 0.01-0.43, zâ¯=â¯2.07) and executive function (g (9)â¯=â¯0.15, 95% CI: 0.03-0.28, zâ¯=â¯2.35). No significant differences were noted for the global cognition, attention, verbal memory, visuospatial ability or visuospatial memory domains. CONCLUSION: Overall, our findings support the potential for TS as a preventative measure against cognitive decline, although the effect sizes were small. These findings warrant further observational studies and clinical trials of good methodological quality, to elucidate the effect of TS on cognition.
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Disfunción Cognitiva/prevención & control , Testosterona/sangre , Testosterona/farmacología , Anciano , Cognición/efectos de los fármacos , Suplementos Dietéticos , Humanos , Masculino , Memoria/efectos de los fármacos , Salud del Hombre , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Previous studies have indicated that physical activity may be beneficial in reducing the risk for Alzheimer's disease (AD), although the underlying mechanisms are not fully understood. The goal of this study was to evaluate the relationship between habitual physical activity levels and brain amyloid deposition and AD-related blood biomarkers (i.e., measured using a novel high-performance mass spectrometry-based assay), in apolipoprotein E (APOE) ε4 carriers and noncarriers. We evaluated 143 cognitively normal older adults, all of whom had brain amyloid deposition assessed using positron emission tomography and had their physical activity levels measured using the International Physical Activity Questionnaire (IPAQ). We observed an inverse correlation between brain amyloidosis and plasma beta-amyloid (Aß)1-42 but found no association between brain amyloid and plasma Aß1-40 and amyloid precursor protein (APP)669-711. Additionally, higher levels of physical activity were associated with lower plasma Aß1-40, Aß1-42, and APP669-711 levels in APOE ε4 noncarriers. The ratios of Aß1-40/Aß1-42 and APP669-711/Aß1-42, which have been associated with higher brain amyloidosis in previous studies, differed between APOE ε4 carriers and non-carriers. Taken together, these data indicate a complex relationship between physical activity and brain amyloid deposition and potential blood-based AD biomarkers in cognitively normal older adults. In addition, the role of APOE ε4 is still unclear, and more studies are necessary to bring further clarification.
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Evidence in support of links between type-2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) has increased considerably in recent years. AD pathological hallmarks include the accumulation of extracellular amyloid-ß (Aß) and intracellular hyperphosphorylated tau in the brain, which are hypothesized to promote inflammation, oxidative stress, and neuronal loss. T2DM exhibits many AD pathological features, including reduced brain insulin uptake, lipid dysregulation, inflammation, oxidative stress, and depression; T2DM has also been shown to increase AD risk, and with increasing age, the prevalence of both conditions increases. In addition, amylin deposition in the pancreas is more common in AD than in normal aging, and although there is no significant increase in cerebral Aß deposition in T2DM, the extent of Aß accumulation in AD correlates with T2DM duration. Given these similarities and correlations, there may be common underlying mechanism(s) that predispose to both T2DM and AD. In other studies, an age-related gradual loss of testosterone and an increase in testosterone resistance has been shown in men; low testosterone levels can also occur in women. In this review, we focus on the evidence for low testosterone levels contributing to an increased risk of T2DM and AD, and the potential of testosterone treatment in reducing this risk in both men and women. However, such testosterone treatment may need to be long-term, and would need regular monitoring to maintain testosterone at physiological levels. It is possible that a combination of testosterone therapy together with a healthy lifestyle approach, including improved diet and exercise, may significantly reduce AD risk.