Defective hippocampal neurogenesis underlies cognitive impairment by carotid stenosis-induced cerebral hypoperfusion in mice.

Chronic cerebral hypoperfusion due to carotid artery stenosis is a major cause of vascular cognitive impairment and dementia (VCID). Bilateral carotid artery stenosis (BCAS) in rodents is a well-established model of VCID where most studies have focused on white matter pathology and subsequent cognitive deficit. Therefore, our aim was to study the implication of adult hippocampal neurogenesis in hypoperfusion-induced VCID in mice, and its relationship with cognitive hippocampal deficits. Mice were subjected to BCAS; 1 and 3 months later, hippocampal memory and neurogenesis/cell death were assessed, respectively, by the novel object location (NOL) and spontaneous alternation performance (SAP) tests and by immunohistology. Hypoperfusion was assessed by arterial spin labeling-magnetic resonance imaging (ASL-MRI). Hypoperfused mice displayed spatial memory deficits with decreased NOL recognition index. Along with the cognitive deficit, a reduced number of newborn neurons and their aberrant morphology indicated a remarkable impairment of the hippocampal neurogenesis. Both increased cell death in the subgranular zone (SGZ) and reduced neuroblast proliferation rate may account for newborn neurons number reduction. Our data demonstrate quantitative and qualitative impairment of adult hippocampal neurogenesis disturbances associated with cerebral hypoperfusion-cognitive deficits in mice. These findings pave the way for novel diagnostic and therapeutic targets for VCID.

Comparison of 2 medium cutoff dialyzers versus on-line hemodiafiltration regarding depurative ability and albumin loss: An uncontrolled clinical research.

BACKGROUND: Hemodialysis (HD) techniques that best remove molecules in the middle to high molecular weight range are on-line hemodiafiltration (OL-HDF) and HD with medium cut-off (MCO) membranes. The aim of this study was to compare efficacy and safety of OL-HDF with FxCordiax HDF 800™, with HD with 2 MCO dialyzers: Theranova 500® and the new Elisio 21HX™ dialyzer. METHODS: Fourteen patients following treatment with OL-HDF using FxCordiax HDF 800™ were randomized to receive a consecutive 1-week HD treatment with Theranova 500® and Elisio 21HX™.The reduction rate (RR) of differently sized molecules was compared, as well as the variation rate in molecules smaller than 1000, detected by nuclear magnetic resonance based chemometrics (metabolomics). Albumin loss in dialysate was quantified. RESULTS: Lower RRs were found for molecules around 20 000 with Elisio 21HX™ compared to OL- HDF (RR prolactin 58.5% versus 66.7%, p = 0.034; RR Kappa light chain 63.1% versus 71.8%, p = 0.010). Albumin loss per session was higher with Theranova 500® than with OL-HDF and with Elisio 21HX™ (2249.9 ± 714.1 mg, 815.2 ± 474.0 mg, 442.9 ± 135.9 mg, p < 0.001, respectively). Metabolomic studies suggested, by semi-quantitative analysis, a greater depurative capacity of OL-HDF, followed by Elisio 21HX™, and then Theranova 500®. CONCLUSIONS: In this study, HD with Theranova 500® has proven to be very similar in efficacy to OL-HDF, although with a significantly higher albumin loss. HD with Elisio 21HX™ resulted in lower removal of molecules around 20 000 compared to OL-HDF, with no significant difference compared to Theranova 500®, and with less albumin loss than Theranova 500®.

Analysis of urinary exosomal metabolites identifies cardiovascular risk signatures with added value to urine analysis.

BACKGROUND: Subclinical atherosclerosis may result in fatal cardiovascular (CV) events, but the underlying mechanisms and molecular players leading to disease are not entirely understood. Thus, novel approaches capable of identifying the factors involved in pathological progression and providing a better understanding of the subjacent mechanisms are needed. Extracellular vesicles (EVs) have been shown to have numerous biological functions, and their metabolome has recently generated interest as a source of novel biomarkers. The metabolic content of the exosomes has been so far unexplored in cardiovascular disease (CVD), and here, we developed an analytical strategy aimed at probing urinary exosomal metabolite content and its association to CV risk. RESULTS: Direct analysis of the exosomes without metabolite extraction was evaluated by high-resolution magic angle spinning (1H HR-MAS). Other two methodologies for the analysis of exosomal metabolites by 1H NMR were set up, based on methanol or organic solvents sequential extraction. The three methods were compared in terms of the number of detected signals and signal to noise ratio (S/N). The methanol method was applied to identify altered metabolites in the urinary exosomes of subjects with programmed coronary artery by-pass grafting (CABG) versus a control group. Target mass spectrometry (MS) was also performed for differential analysis. The clinical performance of exosomal metabolites of interest in CVD was investigated, and the added value of the exosomes compared to urine analysis was evaluated. Based on S/N ratio, simplicity, reproducibility, and quality of the spectrum, the methanol method was chosen for the study in CVD. A cardiometabolic signature composed by 4-aminohippuric acid, N-1-methylnicotinamide, and citric acid was identified in urinary exosomes. Directly in urine, 4-aminohippuric acid and citric acid do not show variation between groups and changes in N-1-methylnicotinamide are less pronounced, proving the added value of exosomes. CONCLUSIONS: We set up a novel methodology to analyze metabolic alterations in urinary exosomes and identified a cardiometabolic signature in these microvesicles. This study constitutes the first evidence of a role for the exosomal metabolism in CVD and demonstrates the possibility to evaluate the urinary exosomal metabolic content by NMR and MS.

Urinary metabolic signatures reflect cardiovascular risk in the young, middle-aged, and elderly populations.

The predictive value of traditional cardiovascular risk estimators is limited, and young and elderly populations are particularly underrepresented. We aimed to investigate the urine metabolome and its association with cardiovascular risk to identify novel markers that might complement current estimators based on age. Urine samples were collected from 234 subjects categorized into three age-grouped cohorts: 30-50 years (cohort I, young), 50-70 years (cohort II, middle-aged), and > 70 years (cohort III, elderly). Each cohort was further classified into three groups: (a) control, (b) individuals with cardiovascular risk factors, and (c) those who had a previous cardiovascular event. Novel urinary metabolites linked to cardiovascular risk were identified by nuclear magnetic resonance in cohort I and then evaluated by target mass spectrometry quantification in all cohorts. A previously identified metabolic fingerprint associated with atherosclerosis was also analyzed and its potential risk estimation investigated in the three aged cohorts. Three different metabolic signatures were identified according to age: 2-hydroxybutyrate, gamma-aminobutyric acid, hypoxanthine, guanidoacetate, oxaloacetate, and serine in young adults; citrate, cyclohexanol, glutamine, lysine, pantothenate, pipecolate, threonine, and tyramine shared by middle-aged and elderly adults; and trimethylamine N-oxide and glucuronate associated with cardiovascular risk in all three cohorts. The urinary metabolome contains a metabolic signature of cardiovascular risk that differs across age groups. These signatures might serve to complement existing algorithms and improve the accuracy of cardiovascular risk prediction for personalized prevention. KEY MESSAGES: • Cardiovascular risk in the young and elderly is underestimated. • The urinary metabolome reflects cardiovascular risk across all age groups. • Six metabolites constitute a metabolic signature of cardiovascular risk in young adults. • Middle-aged and elderly adults share a cardiovascular risk metabolic signature. • TMAO and glucuronate levels reflect cardiovascular risk across all age groups.

Abolition of aberrant neurogenesis ameliorates cognitive impairment after stroke in mice.

Poststroke cognitive impairment is considered one of the main complications during the chronic phase of ischemic stroke. In the adult brain, the hippocampus regulates both encoding and retrieval of new information through adult neurogenesis. Nevertheless, the lack of predictive models and studies based on the forgetting processes hinders the understanding of memory alterations after stroke. Our aim was to explore whether poststroke neurogenesis participates in the development of long-term memory impairment. Here, we show a hippocampal neurogenesis burst that persisted 1 month after stroke and that correlated with an impaired contextual and spatial memory performance. Furthermore, we demonstrate that the enhancement of hippocampal neurogenesis after stroke by physical activity or memantine treatment weakened existing memories. More importantly, stroke-induced newborn neurons promoted an aberrant hippocampal circuitry remodeling with differential features at ipsi- and contralesional levels. Strikingly, inhibition of stroke-induced hippocampal neurogenesis by temozolomide treatment or using a genetic approach (Nestin-CreERT2/NSE-DTA mice) impeded the forgetting of old memories. These results suggest that hippocampal neurogenesis modulation could be considered as a potential approach for treatment of poststroke cognitive impairment.

Urine metabolomics insight into acute kidney injury point to oxidative stress disruptions in energy generation and H2S availability.

Acute kidney injury (AKI) is one of the main complications in acute care medicine and a risk factor for chronic kidney disease (CKD). AKI incidence has increased; however, its diagnosis has limitations and physiopathological mechanisms are underexplored. We investigated urine samples, aiming to identify major metabolite changes during human AKI evolution. Metabolic signatures found were further explored for a potential link to severity of injury. Twenty-four control subjects and 38 hospitalized patients with AKI were recruited and urine samples were collected at the time of diagnosis, during follow-up and at discharge. Nuclear magnetic resonance (NMR) was used in a first discovery phase for identifying potential metabolic differences. Target metabolites of interest were confirmed by liquid chromatography-mass spectrometry (LC-MS/MS) in an independent group. Underlying metabolic defects were further explored by kidney transcriptomics of murine toxic AKI. Urinary 2-hydroxybutyric acid, pantothenic acid, and hippuric acid were significantly downregulated and urinary N-acetylneuraminic acid, phosphoethanolamine, and serine were upregulated during AKI. Hippuric acid, phosphoethanolamine, and serine showed further downregulation/upregulation depending on the metabolite in acute tubular necrosis (ATN) AKI compared to prerenal AKI. Kidney transcriptomics disclosed decreased expression of cystathionase, cystathionine-ß-synthase, and ethanolamine-phosphate cytidylyltransferase, and increased N-acetylneuraminate synthase as the potentially underlying cause of changes in urinary metabolites. A urinary metabolite panel identified AKI patients and provided insight into intrarenal events. A urine fingerprint made up of six metabolites may be related to pathophysiological changes in oxidative stress, energy generation, and H2S availability associated with AKI. KEY MESSAGES: The urinary metabolome reflects AKI evolution and severity of injury. Kidney transcriptomics revealed enzymatic expression changes. Enzymatic expression changes may be the potentially underlying cause of changes in urine metabolites. Identified metabolite changes link oxidative stress, energy generation, and H2S availability to AKI.

Metabolomics of meat exudate: Its potential to evaluate beef meat conservation and aging.

In this study we analyzed the exudate of beef to evaluate its potential as non invasive sampling for nuclear magnetic resonance (NMR) based metabolomic analysis of meat samples. Exudate, as the natural juice from raw meat, is an easy to obtain matrix that it is usually collected in small amounts in commercial meat packages. Although meat exudate could provide complete and homogeneous metabolic information about the whole meat piece, this sample has been poorly studied. Exudates from 48 beef samples of different breeds, cattle and storage times have been studied by (1)H NMR spectroscopy. The liquid exudate spectra were compared with those obtained by High Resolution Magic Angle Spinning (HRMAS) of the original meat pieces. The close correlation found between both spectra (>95% of coincident peaks in both registers; Spearman correlation coefficient = 0.945) lead us to propose the exudate as an excellent alternative analytical matrix with a view to apply meat metabolomics. 60 metabolites could be identified through the analysis of mono and bidimensional exudate spectra, 23 of them for the first time in NMR meat studies. The application of chemometric tools to analyze exudate dataset has revealed significant metabolite variations associated with meat aging. Hence, NMR based metabolomics have made it possible both to classify meat samples according to their storage time through Principal Component Analysis (PCA), and to predict that storage time through Partial Least Squares (PLS) regression.

Cortical thickness in fetal alcohol syndrome and attention deficit disorder.

Fetal alcohol syndrome represents the classic and most severe manifestation of epigenetic changes induced by exposure to alcohol during pregnancy. Often these patients develop attention deficit hyperactivity disorder. We analyzed cortical thickness in 20 children and adolescents with fetal alcohol syndrome and attention deficit hyperactivity disorder (group 1), in 20 patients without fetal alcohol syndrome (group 2), and in 20 control cases. The first group revealed total cortical thickness significantly superior to those of the other two groups. In per-lobe analyses of cortical thickness, group 1 demonstrated greater cortical thickness in the frontal, occipital, and right temporal and left frontal lobes compared with the second group, and in both temporal lobes and the right frontal lobe compared with the control group. This study demonstrated greater cortical thickness in patients with attention deficit hyperactivity disorder and heavy prenatal exposure to alcohol, probably as an expression of immature or abnormal brain development.

Neuroimagen en el trastorno por déficit de atención/hiperactividad / Neuroimaging in attention deficit hyperactivity disorder

Introducción. Los avances en neuroimagen en la última década han aportado numerosos hallazgos en el trastorno por déficit de atención/hiperactividad (TDAH). El rápido desarrollo tecnológico, junto con el de la genética y la investigación neuroquímica, sugiere una disfunción del circuito frontoestriatal que involucra a la corteza prefrontal y a su relación con los núcleos de la base, tálamo y cerebelo como base fisiopatológica de este trastorno. Por otro lado, es posible que, en un futuro, la neuroimagen pueda ser complementaria a la evaluación clínica, favoreciendo diagnósticos más precisos, identificando los subtipos e incluso la modalidad de tratamiento y su monitorización. Objetivo y desarrollo. Realizar un examen de la bibliografía más significativa acerca de la neuroimagen y el TDAH y exponer la utilidad y los inconvenientes de las diferentes modalidades de técnicas de neuroimagen aplicables de cara a un mejor y más profundo conocimiento del TDAH en el futuro. Conclusiones. Aunque el desarrollo de la neuroimagen en el TDAH es prometedor, actualmente su utilidad diagnóstica es muy limitada. Una de las mayores dificultades al respecto se basa en la heterogeneidad clínica, genética y fisiopatológica del trastorno, por lo que, ante la inexistencia de un marcador específico, se hace imperativa, de cara a los próximos estudios, la búsqueda varios marcadores que tengan un adecuado valor en el diagnóstico, pronóstico y/o tratamiento de los diferentes subtipos de TDAH (AU)

Introduction. Advances in neuroimaging in the last decade have allowed a number of new findings about attention deficit hyperactivity disorder (ADHD) to be obtained. Quickly developing technology, together with the progress being made in genetics and neurochemical research, suggests a dysfunction of the fronto striatal circuit that involves the prefrontal cortex and its relationship with the basal, thalamic and cerebellar nuclei as the pathophysiological foundation of this disorder. On the other hand, neuroimaging in the future may complement clinical evaluation, which will favour more accurate diagnoses and allow the subtypes and even the mode of treatment and its monitoring to be identified. Aims and development. The aim of this study was to review the more significant literature on neuroimaging and ADHD and to discuss the usefulness and drawbacks of the different modes of neuroimaging techniques that can be applied with a view to gaining an improved and deeper knowledge of ADHD in the future. Conclusions. Although the development of neuroimaging in ADHD is a promising area, at the present time its diagnostic value is very restricted. One of the greatest difficulties in this respect concerns the clinical, genetic and pathophysiological heterogeneity of the disorder. Hence, given the inexistence of a specific marker, future studies will have to search for several markers that have a suitable value in the diagnosis, prognosis and/or treatment of the different subtypes of ADHD (AU)

Proton magnetic resonance spectroscopy and magnetoencephalographic estimation of delta dipole density: a combination of techniques that may contribute to the diagnosis of Alzheimer's disease.

Whole-head magnetoencephalographic recordings were obtained from 10 patients with Alzheimer's disease (AD) and 10 healthy controls in a resting position. Spectroscopic examinations were performed by means of a 1.5-tesla whole-body scanner in the temporoparietal regions of both hemispheres. The relationship between (1)H-MRS-based and magnetoencephalography (MEG)-based measures and their conjoined capability to improve the diagnosis of AD were investigated in this study. Logistic regression analyses were performed. Three separated logistic models were calculated for (1)H-MRS-based metabolites, low-frequency magnetic activity, and the combination of both measures. A combined myoinositol/N-acetyl aspartate (mI/NAA)-delta dipole density (DD) model predicted the diagnosis with 90% sensitivity and 100% specificity. Additionally, the combination of temporoparietal mI/NAA and delta DD values explained the variability of individuals' cognitive status. The results support the notion that a multidisciplinary approach may improve the understanding and diagnosis of AD.