In Alzheimer’s disease (AD), tau phosphorylation in the brain and its subsequent release into cerebrospinal fluid (CSF) and blood is a dynamic process that changes during disease evolution. The main ...aim of our study was to characterize the pattern of changes in phosphorylated tau (p‐tau) in the preclinical stage of the Alzheimer’s continuum. We measured three novel CSF p‐tau biomarkers, phosphorylated at threonine‐181 and threonine‐217 with an N‐terminal partner antibody and at threonine‐231 with a mid‐region partner antibody. These were compared with an automated mid‐region p‐tau181 assay (Elecsys) as the gold standard p‐tau measure. We demonstrate that these novel p‐tau biomarkers increase more prominently in preclinical Alzheimer, when only subtle changes of amyloid‐β (Aβ) pathology are detected, and can accurately differentiate Aβ‐positive from Aβ‐negative cognitively unimpaired individuals. Moreover, we show that the novel plasma N‐terminal p‐tau181 biomarker is mildly but significantly increased in the preclinical stage. Our results support the idea that early changes in neuronal tau metabolism in preclinical Alzheimer, likely in response to Aβ exposure, can be detected with these novel p‐tau assays.
SYNOPSIS
This study investigated novel CSF and plasma p‐tau biomarkers in the preclinical stage of the Alzheimer’s continuum and compared them with the widely used CSF Mid‐ptau181.
Novel p‐tau biomarkers CSF N‐p‐tau181, N‐p‐tau217 and Mid‐p‐tau231 increase early in the Alzheimer’s continuum, when only subtle changes in Aβ pathology are detected.
CSF N‐p‐tau181, N‐p‐tau217 and Mid‐p‐tau231 can accurately differentiate Aβ‐positive, cognitively unimpaired individuals from those that are Aβ‐negative.
Plasma N‐p‐tau181 biomarker is significantly increased in the preclinical stage of the Alzheimer’s continuum.
These results suggest that there are early changes in tau metabolism in preclinical Alzheimer, probably in response to emerging Aβ pathology.
This study investigated novel CSF and plasma p‐tau biomarkers in the preclinical stage of the Alzheimer’s continuum and compared them with the widely used CSF Mid‐ptau181.
IMPORTANCE: Oxidative stress and vascular impairment are believed to partly mediate age-related cognitive decline, a strong risk factor for development of dementia. Epidemiologic studies suggest that ...a Mediterranean diet, an antioxidant-rich cardioprotective dietary pattern, delays cognitive decline, but clinical trial evidence is lacking. OBJECTIVE: To investigate whether a Mediterranean diet supplemented with antioxidant-rich foods influences cognitive function compared with a control diet. DESIGN, SETTING, AND PARTICIPANTS: Parallel-group randomized clinical trial of 447 cognitively healthy volunteers from Barcelona, Spain (233 women 52.1%; mean age, 66.9 years), at high cardiovascular risk were enrolled into the Prevención con Dieta Mediterránea nutrition intervention trial from October 1, 2003, through December 31, 2009. All patients underwent neuropsychological assessment at inclusion and were offered retesting at the end of the study. INTERVENTIONS: Participants were randomly assigned to a Mediterranean diet supplemented with extravirgin olive oil (1 L/wk), a Mediterranean diet supplemented with mixed nuts (30 g/d), or a control diet (advice to reduce dietary fat). MAIN OUTCOMES AND MEASURES: Rates of cognitive change over time based on a neuropsychological test battery: Mini-Mental State Examination, Rey Auditory Verbal Learning Test (RAVLT), Animals Semantic Fluency, Digit Span subtest from the Wechsler Adult Intelligence Scale, Verbal Paired Associates from the Wechsler Memory Scale, and the Color Trail Test. We used mean z scores of change in each test to construct 3 cognitive composites: memory, frontal (attention and executive function), and global. RESULTS: Follow-up cognitive tests were available in 334 participants after intervention (median, 4.1 years). In multivariate analyses adjusted for confounders, no between-group differences were observed for cognitive tests. Similarly adjusted cognitive composites (mean z scores with 95% CIs) for changes above baseline of the memory composite were 0.04 (−0.10 to 0.17) for the Mediterranean diet plus olive oil, 0.10 (−0.04 to 0.24; P = .04 vs controls) for the Mediterranean diet plus nuts, and −0.16 (−0.32 to −0.01) for the control diet. Respective changes from baseline of the frontal cognition composite were 0.23 (0.02 to 0.43; P = .004 vs controls), 0.03 (−0.26 to 0.32), and −0.33 (−0.57 to −0.09). Changes from baseline of the global cognition composite were 0.04 (−0.12 to 0.20; P = .008 vs controls) for the Mediterranean diet plus olive oil, −0.04 (−0.27 to 0.19) for the Mediterranean diet plus nuts, and −0.37 (−0.56 to −0.17) for the control diet. All cognitive composites significantly (P < .05) decreased from baseline in controls. CONCLUSIONS AND RELEVANCE: In an older population, a Mediterranean diet supplemented with olive oil or nuts was associated with improved composite measures of cognitive function. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN35739639
Introduction
The biological pathways involved in the preclinical stage of the Alzheimer's continuum are not well understood.
Methods
We used NeuroToolKit and Elecsys® immunoassays to measure ...cerebrospinal fluid (CSF) amyloid‐β (Aβ)42, Aβ40, phosphorylated tau (p‐tau), total tau (t‐tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100, and α‐synuclein in cognitively unimpaired participants of the ALFA+ study, many within the Alzheimer's continuum.
Results
CSF t‐tau, p‐tau, and neurogranin increase throughout aging only in Aβ‐positive individuals, whereas NfL and glial biomarkers increase with aging regardless of Aβ status. We modelled biomarker changes as a function of CSF Aβ42/40, p‐tau and p‐tau/Aβ42 as proxies of disease progression. The first change observed in the Alzheimer's continuum was a decrease in the CSF Aβ42/40 ratio. This is followed by a steep increase in CSF p‐tau; t‐tau; neurogranin; and, to a lesser extent, in NfL and glial biomarkers.
Discussion
Multiple biological pathways are altered and could be targeted very early in the Alzheimer's continuum.
Aims
To assess the effects of walnuts on cardiometabolic outcomes in obese people and to explore the underlying mechanisms using novel methods including metabolomic, lipidomic, glycomic and ...microbiome analysis, integrated with lipid particle fractionation, appetite‐regulating hormones and haemodynamic measurements.
Materials and Methods
A total of 10 obese individuals were enrolled in this cross‐over, randomized, double‐blind, placebo‐controlled clinical trial. The participants had two 5‐day inpatient stays, during which they consumed a smoothie containing 48 g walnuts or a macronutrient‐matched placebo smoothie without nuts, with a 1‐month washout period between the two visits.
Results
Walnut consumption improved aspects of the lipid profile; it reduced fasting small and dense LDL particles (P < 0.02) and increased postprandial large HDL particles (P < 0.01). Lipoprotein insulin resistance score, glucose and the insulin area under the curve (AUC) decreased significantly after walnut consumption (P < 0.01, P < 0.02 and P < 0.04, respectively). Consuming walnuts significantly increased 10 N‐glycans, with eight of them carrying a fucose core. Lipidomic analysis showed a robust reduction in harmful ceramides, hexosylceramides and sphingomyelins, which have been shown to mediate effects on cardiometabolic risk. The peptide YY AUC significantly increased after walnut consumption (P < 0.03). No major significant changes in haemodynamic or metabolomic analysis or in microbiome host health‐promoting bacteria such as Faecalibacterium were found.
Conclusions
These data provide a more comprehensive mechanistic perspective of the effect of dietary walnut consumption on cardiometabolic variables. Lipidomic and lipid nuclear magnetic resonance spectroscopy analysis showed an early but significant reduction in ceramides and other atherogenic lipids with walnut consumption, which may explain the longer‐term benefits of walnuts or other nuts on insulin resistance, cardiovascular risk and mortality.
Scope
The aim of this study is to delineate the contribution of dietary saturated fatty acids (FA) versus liquid fructose to fatty liver and hypertriglyceridemia.
Methods and Results
Three groups of ...female rats are maintained for 3 months in standard chow (CT); High‐fat diet (46.9% of fat‐derived calories, rich in palmitic and stearic FA, HFD); and HFD with 10% w/v fructose in drinking water (HFHFr). Zoometric parameters, plasma biochemistry, and liver Oil‐Red O (ORO) staining, lipidomics, and expression of proteins involved in FA metabolism are analyzed. Both diets increase ingested calories without modifying body weight. Only the HFHFr diet increases liver triglycerides (x11.0), with hypertriglyceridemia (x1.7) and reduces FA β‐oxidation (x0.7), and increases liver FA markers of DNL (de novo lipogenesis). Whereas HFD livers show a high content of ceramides, HFHFr samples show unchanged ceramides, and an increase in diacylglycerols. Only the HFHFr diet leads to a marked increase in the expression of enzymes involved in DNL and triglyceride metabolism, such as carbohydrate response element binding protein β (ChREBPβ, x3.2), a transcription factor that regulates DNL, and patatin‐like phospholipase domain‐containing 3 (PNPLA3, x2.6), a lipase that mobilizes stored triglycerides for VLDL secretion.
Conclusion
The addition of liquid‐fructose to dietary FA is determinant in liver steatosis and hypertriglyceridemia production, through increased DNL and PNPLA3 expression, and reduced FA catabolism.
Rats receive a high fat diet with (HFHFr) and without liquid fructose (HFD). At the end of the experiment, body weight is unchanged, due to increased in thermogenesis. There are minor metabolic changes in livers from HFD‐fed rats, while HFHFr fed‐rats show liver steatosis and hypertriglyceridemia. HFHFr increases lipogenesis and reduces fatty acid catabolism without signs of liver inflammation.
Cognitive decline, and more specifically Alzheimer's disease, continues to increase in prevalence globally, with few, if any, adequate preventative approaches. Several tests of cognition are utilized ...in the diagnosis of cognitive decline that assess executive function, short- and long-term memory, cognitive flexibility, and speech and motor control. Recent studies have separately investigated the genetic component of both cognitive health, using these measures, and circulating fatty acids.
We aimed to examine the potential moderating effect of main species of ω-3 polyunsaturated fatty acids (PUFAs) on an individual's genetically conferred risk of cognitive decline.
The Offspring cohort from the Framingham Heart Study was cross-sectionally analyzed in this genome-wide interaction study (GWIS). Our sample included all individuals with red blood cell ω-3 PUFA, genetic, cognitive testing (via Trail Making Tests TMTs), and covariate data (N = 1620). We used linear mixed effects models to predict each of the 3 cognitive measures (TMT A, TMT B, and TMT D) by each ω-3 PUFA, single nucleotide polymorphism (SNP) (0, 1, or 2 minor alleles), ω-3 PUFA by SNP interaction term, and adjusting for sex, age, education, APOE ε4 genotype status, and kinship (relatedness).
Our analysis identified 31 unique SNPs from 24 genes reaching an exploratory significance threshold of 1×10
. Fourteen of the 24 genes have been previously associated with the brain/cognition, and 5 genes have been previously associated with circulating lipids. Importantly, 8 of the genes we identified, DAB1, SORCS2, SERINC5, OSBPL3, CPA6, DLG2, MUC19, and RGMA, have been associated with both cognition and circulating lipids. We identified 22 unique SNPs for which individuals with the minor alleles benefit substantially from increased ω-3 fatty acid concentrations and 9 unique SNPs for which the common homozygote benefits.
In this GWIS of ω-3 PUFA species on cognitive outcomes, we identified 8 unique genes with plausible biology suggesting individuals with specific polymorphisms may have greater potential to benefit from increased ω-3 PUFA intake. Additional replication in prospective settings with more diverse samples is needed.
Nutritional strategies to maintain bone health in aging individuals are of great interest. Given the beneficial nutrient composition of walnuts, rich in alpha-linolenic (the vegetable n-3 fatty acid) ...and polyphenols, their regular consumption might be a dietary option to reduce age-related bone loss. We determined whether daily walnut consumption improves bone mineral density (BMD) and circulating biomarkers of bone turnover.
The Walnuts and Healthy Aging study (WAHA) is a two-center, parallel, randomized controlled trial evaluating the effect of a diet enriched with walnuts at ≈15% energy compared with a control diet for 2 years on age-related health outcomes in healthy men and women aged 63-79 years. Changes in BMD were a prespecified secondary outcome only at the Barcelona node of the trial, where 352 participants were randomized. Retention rate was 92.6%. Primary endpoints were 2-year changes in BMD at the spine and the nondominant femoral neck, determined by dual-energy X-ray absorptiometry (DXA). Secondary endpoints were 2-year changes in bone turnover biomarkers (adrenocorticotropic hormone, Dickkopf WNT signaling pathway inhibitor-1, osteoprotegerin, osteocalcin, osteopontin, sclerostin, parathyroid hormone, and fibroblast growth factor-23), which were quantified in 211 randomly selected participants.
The walnut diet versus the control diet had no effect on 2-year changes in BMD at the spine (0.15% vs. 0.35%, p = 0.632) and femoral neck (-0.90% vs. -0.70%, p = 0.653), or on bone turnover biomarkers. Results were similar in participants treated or not with bone resorption inhibitors or those with or without osteoporosis/osteopenia at inclusion.
Compared with the usual diet, a diet enriched with walnuts at 15% of energy for 2 years failed to improve BMD or circulating markers of bone metabolism in healthy older people.
Abstract
Based on studies in mice, leptin was expected to decrease body weight in obese individuals. However, the majority of the obese are hyperleptinemic and do not respond to leptin treatment, ...suggesting the presence of leptin tolerance and questioning the role of leptin as regulator of energy balance in humans. We thus performed detailed novel measurements and analyses of samples and data from our clinical trials biobank to investigate leptin effects on mechanisms of weight regulation in lean normo- and mildly hypo-leptinemic individuals without genetic disorders. We demonstrate that short-term leptin administration alters food intake during refeeding after fasting, whereas long-term leptin treatment reduces fat mass and body weight, and transiently alters circulating free fatty acids in lean mildly hypoleptinemic individuals. Leptin levels before treatment initiation and leptin dose do not predict the observed weight loss in lean individuals suggesting a saturable effect of leptin. In contrast to data from animal studies, leptin treatment does not affect energy expenditure, lipid utilization, SNS activity, heart rate, blood pressure or lean body mass.
Primary ventricular fibrillation (PVF) is a major driver of cardiac arrest in the acute phase of ST-segment elevation myocardial infarction (STEMI). Enrichment of cardiomyocyte plasma membranes with ...dietary polyunsaturated fatty acids (PUFA) reduces vulnerability to PVF experimentally, but clinical data are scarce. PUFA status in serum phospholipids is a valid surrogate biomarker of PUFA status in cardiomyocytes within a wide range of dietary PUFA. In this nested case-control study (n = 58 cases of STEMI-driven PVF, n = 116 control non-PVF STEMI patients matched for age, sex, smoking status, dyslipidemia, diabetes mellitus and hypertension) we determined fatty acids in serum phospholipids by gas-chromatography, and assessed differences between cases and controls, applying the Benjamini-Hochberg procedure on nominal P-values to control the false discovery rate (FDR). Significant differences between cases and controls were restricted to linoleic acid (LA), with PVF patients showing a lower level (nominal P = 0.002; FDR-corrected P = 0.027). In a conditional logistic regression model, each one standard deviation increase in the proportion of LA was related to a 42% lower prevalence of PVF (odds ratio = 0.58; 95% confidence interval, 0.37, 0.90; P = 0.02). The association lasted after the inclusion of confounders. Thus, regular consumption of LA-rich foods (nuts, oils from seeds) may protect against ischemia-driven malignant arrhythmias.
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