Nanoparticulated Bimodal Contrast Agent for Ultra-High-Field Magnetic Resonance Imaging and Spectral X-ray Computed Tomography.

Bimodal medical imaging based on magnetic resonance imaging (MRI) and computed tomography (CT) is a well-known strategy to increase the diagnostic accuracy. The most recent advances in MRI and CT instrumentation are related to the use of ultra-high magnetic fields (UHF-MRI) and different working voltages (spectral CT), respectively. Such advances require the parallel development of bimodal contrast agents (CAs) that are efficient under new instrumental conditions. In this work, we have synthesized, through a precipitation reaction from a glycerol solution of the precursors, uniform barium dysprosium fluoride nanospheres with a cubic fluorite structure, whose size was found to depend on the Ba/(Ba + Dy) ratio of the starting solution. Moreover, irrespective of the starting Ba/(Ba + Dy) ratio, the experimental Ba/(Ba + Dy) values were always lower than those used in the starting solutions. This result was assigned to lower precipitation kinetics of barium fluoride compared to dysprosium fluoride, as inferred from the detailed analysis of the effect of reaction time on the chemical composition of the precipitates. A sample composed of 34 nm nanospheres with a Ba0.51Dy0.49F2.49 stoichiometry showed a transversal relaxivity (r2) value of 147.11 mM-1·s-1 at 9.4 T and gave a high negative contrast in the phantom image. Likewise, it produced high X-ray attenuation in a large range of working voltages (from 80 to 140 kVp), which can be attributed to the presence of different K-edge values and high Z elements (Ba and Dy) in the nanospheres. Finally, these nanospheres showed negligible cytotoxicity for different biocompatibility tests. Taken together, these results show that the reported nanoparticles are excellent candidates for UHF-MRI/spectral CT bimodal imaging CAs.

Lanthanide vanadate-based trimodal probes for near-infrared luminescent bioimaging, high-field magnetic resonance imaging, and X-ray computed tomography.

We have developed a trimodal bioimaging probe for near-infrared luminescent imaging, high-field magnetic resonance imaging, and X-ray computed tomography using Dy3+ as the paramagnetic component and Nd3+ as the luminescent cation, both of them incorporated in a vanadate matrix. Among different essayed architectures (single phase and core-shell nanoparticles) the one showing the best luminescent properties is that consisting of uniform DyVO4 nanoparticles coated with a first uniform layer of LaVO4 and a second layer of Nd3+-doped LaVO4. The magnetic relaxivity (r2) at high field (9.4 T) of these nanoparticles was among the highest values ever reported for this kind of probes and their X-ray attenuation properties, due to the presence of lanthanide cations, were also better than those of a commercial contrast agent (iohexol) commonly used for X-ray computed tomography. In addition, they were chemically stable in a physiological medium in which they could be easily dispersed owing to their one-pot functionalization with polyacrylic acid, and, finally, they were non-toxic for human fibroblast cells. Such a probe is, therefore, an excellent multimodal contrast agent for near-infrared luminescent imaging, high-field magnetic resonance imaging, and X-ray computed tomography.

Carboxylate functionalized NaDy(MoO4)2 nanoparticles with tunable size and shape as high magnetic field MRI contrast agents.

Uniform sodium-dysprosium double molybdate (NaDy(MoO4)2) nanoparticles having different morphologies (spheres and ellipsoids) and tunable size have been synthesized for the first time in literature. The procedure is based on a homogeneous precipitation process at moderated temperatures (≤220 °C) from solutions containing appropriated precursors dissolved in ethylene glycol-water mixtures, in the absence (spheres) or the presence (ellipsoids) of tartrate anions. The effects of the morphological characteristics (size and shape) of the nanoparticles on the magnetic relaxivity at high field (9.4 T) have been evaluated finding that the latter magnitude was higher for the spheres than for the ellipsoids, indicating their better suitability as contrast agents for high-field magnetic resonance imaging. Such nanoparticles have been successfully coated with polymers bearing carboxylate functional groups through a layer-by-layer process, which improves the colloidal stability of the nanoparticles in physiological media. It has been also found that the coating layer had no significant effects on the nanoparticles relaxivity and that such coated nanoparticles exhibited a high biocompatibility and a high chemical stability. In summary, we have developed NaDy(MoO4)2 based bioprobes which meet the required criteria for their use as contrast agents for high-field magnetic resonance imaging.

Delayed care in carotid-cavernous fistula due to the Covid-19 pandemic / Atraso no atendimento de casos de fístula carótido-cavernosa devido à pandemia de Covid-19

ABSTRACT Direct carotid-cavernous fistula is a high-flow communication between the internal carotid artery and the cavernous sinus that requires early transarterial embolization for its resolution. We report a case of a patient with a direct carotid-cavernous fistula who subsequently developed a central retinal vein thrombosis due to a delay in treatment related to the health collapse experienced in the first months of the Covid-19 pandemic in Spain.

RESUMO A fístula carótido-cavernosa direta é uma comunicação de alto fluxo entre a artéria carótida interna e o seio cavernoso que requer embolização trans-arterial precoce para sua resolução. É relatado aqui o caso de um paciente com fístula carótido-cavernosa direta que posteriormente desenvolveu uma trombose da veia central da retina devido a um atraso no tratamento relacionado ao colapso de saúde experimentado nos primeiros meses da pandemia de Covid-19 na Espanha.

Outstanding MRI contrast with dysprosium phosphate nanoparticles of tuneable size.

The use of high-field magnets for magnetic resonance imaging (MRI) is expected to experience the fastest growth rate during the present decade. Although several CAs for MRI scanners using high magnetic fields have been reported, they are mostly based on fluoride matrices, which are known for their low chemical stability in aqueous suspensions. Chemically stable MRI CAs for high-field magnets are therefore needed to enable the advances in MRI technique. Herein, we synthesized uniform DyPO4 nanoparticles (NPs) with tuneable sizes between 23 and 57 nm using homogeneous precipitation in butanol. The NPs were successfully functionalized with polyacrylic acid (PAA) and showed good colloidal stability in aqueous suspensions. Chemical stability was also assessed in PBS, showing negligible solubility. The effect of particle size on the transversal relaxivity value (r2) was further explored at 9.4 T, finding a clear increase in r2 with particle size. The r2 value found for the largest NPs was 516 mM-1 s-1, which is, to the best of our knowledge, the highest r2 value ever reported at 9.4 T for any Dy-based nanometric particles in the literature. Finally, the latter NPs were submitted to biosafety studies after polyethylene glycol (PEG) functionalization. Cell morphology, induction of necrotic/late apoptotic cells, and mitochondrial activity were thoroughly analyzed. The results clearly indicated negligible toxicity effects under the assayed conditions. Short- and long-term in vivo pharmacokinetics of the intravenously injected NPs were assessed by dynamic T2-weighted MRI and quantitative T2 mapping, revealing faster liver than spleen uptake, while no accumulation was observed in the kidneys. Finally, no histopathological changes were observed in any of the studied organs, including the liver, kidney, spleen, and lung, which provide further evidence of the biocompatibility of DyPO4 NPs and, therefore, their suitability as bioimaging probes.

Accuracy in optical diagnosis for polyps between 5 and 15 mm and its implications on surveillance. A prospective, multicenter study. (POPS study).

BACKGROUND AND AIMS: Polyps histology and diameter up to 1 cm determine whether a patient needs a colonoscopy after 3 years or less, or far ahead. Endoscopists' and pathologists' size estimations can be imprecise. Our aim was to assess endoscopist ability to correctly recommend surveillance colonoscopies for patients with polyps around the 10 mm threshold, based on its endoscopic sizing and optical diagnosis by NBI. METHODS: NBI-assisted diagnosis and endoscopist estimation of polyp size were compared with reference standard, considering this as the post resection polyp measurements by the nurse assistant and the pathologic results, in a prospective, multicenter, real life study, that recruited adults undergoing colonoscopy in five hospitals. By comparing the endoscopic and pathologist size estimation, with polyps' measurement after resection, and optical and histological diagnoses in patients with polyps between 5 and 15 mm, sensitivity was assessed at the patient level by means of two characteristics: the presence of adenoma, and the surveillance interval. Surveillance intervals were established by the endoscopist, based on optical diagnosis, and by another gastroenterologist, grounded on the pathologic report. Determinants of accuracy were explored at the polyp level. RESULTS: 532 polyps were resected in 451 patients. Size estimation was more precise for the endoscopist. Endoscopist sensitivity for the presence of adenoma or carcinoma was 98.7%. Considering the presence of high-grade dysplasia or cancer, sensitivity was 82.6% for the endoscopic optical diagnosis. Sensitivity for a correct 3-year surveillance interval was 91.5%, specificity 82.3%, with a PPV of 93.2% and NPV of 78.5% for the endoscopist. 6.51% of patients would have had their follow-up colonoscopy delayed, whereas 22 (4.8%) would have it been performed earlier, had endoscopist recommendations been followed. CONCLUSION: Our study observes that NBI optical diagnosis can be recommended in routine practice to establish surveillance intervals for polyps between 5 and 15 mm. CLINICAL TRIALS REGISTRATION NUMBER: NCT04232176.

Delayed care in carotid-cavernous fistula due to the Covid-19 pandemic.

Direct carotid-cavernous fistula is a high-flow communication between the internal carotid artery and the cavernous sinus that requires early transarterial embolization for its resolution. We report a case of a patient with a direct carotid-cavernous fistula who subsequently developed a central retinal vein thrombosis due to a delay in treatment related to the health collapse experienced in the first months of the Covid-19 pandemic in Spain.

NaY(MoO4)2-based nanoparticles: synthesis, luminescence and photocatalytic properties.

We report on a novel synthesis method, which produces NaY(MoO4)2 nanoparticles having an almost spherical shape and hydrophilic character. The procedure is also suitable for the preparation of NaY(MoO4)2-based nanophosphors by doping this host with lanthanide cations (Eu3+, Tb3+ and Dy3+), which, under UV illumination, exhibit intense luminescence whose color is determined by the selected doping cation (red for Eu3+, green for Tb3+ and yellow for Dy3+). The effects of the cations doping level on the luminescent properties are analyzed in terms of emission intensities and luminescent lifetime, to find the optimum phosphors. Finally, the performance of these nanophosphors and that of the undoped system for the photocatalytic degradation of rhodamine B, used as a model compound, is also analyzed.

Holmium phosphate nanoparticles as negative contrast agents for high-field magnetic resonance imaging: Synthesis, magnetic relaxivity study and in vivo evaluation.

The increasing use of high magnetic fields in magnetic resonance imaging (MRI) scanners demands new contrast agents, since those used in low field instruments are not effective at high fields. In this paper, we report the synthesis of a negative MRI contrast agent consisting of HoPO4 nanoparticles (NPs). Three different sizes (27 nm, 48 nm and 80 nm) of cube-shaped NPs were obtained by homogeneous precipitation in polyol medium and then coated with poly(acrylic) acid (PAA) to obtain stable colloidal suspensions of HoPO4@PAA NPs in physiological medium (PBS). The transverse relaxivity (r2) of aqueous suspensions of the resulting NPs was evaluated at both 1.44 T and 9.4 T. A positive correlation between r2 values and field strength as well as between r2 values and particle size at both magnetic field strengths was found although this correlation failed for the biggest NPs at 9.4 T, likely due to certain particles aggregation inside the magnet. The highest r2 value (489.91 mM-1s-1) was found for the 48 nm NPs at 9.4 T. Toxicity studies demonstrated that the latter NPs exhibited low toxicity to living systems. Finally, in vivo studies demonstrated that HoPO4@PAA NPs could be a great platform for next-generation T2-weighted MRI contrast agents at high magnetic field.

Dysprosium and Holmium Vanadate Nanoprobes as High-Performance Contrast Agents for High-Field Magnetic Resonance and Computed Tomography Imaging.

We describe a wet chemical method for the synthesis of uniform and well-dispersed dysprosium vanadate (DyVO4) and holmium vanadate (HoVO4) nanoparticles with an almost spherical shape and a mean size of ∼60 nm and their functionalization with poly(acrylic acid). The transverse magnetic relaxivity of both systems at 9.4 T is analyzed on the basis of magnetic susceptibility and magnetization measurements in order to evaluate their potential for application as high-field MRI contrast agents. In addition, the X-ray attenuation properties of these systems are also studied to determine their capabilities as computed tomography contrast agent. Finally, the colloidal stability under physiological pH conditions and the cytotoxicity of the functionalized NPs are also addressed to assess their suitability for bioimaging applications.

Carotid stent occlusion after emergent stenting in acute ischemic stroke: Incidence, predictors and clinical relevance.

BACKGROUND AND AIMS: Emergent stent placement may be required during neurothrombectomy. Our aim was to investigate the incidence, predictors and clinical relevance of early extracranial carotid stent occlusion following neurothrombectomy. METHODS: We retrospectively analyzed a cohort of 761 consecutive neurothrombectomies performed at our center between May 2010 and August 2018, from whom a total of 106 patients had acute internal carotid artery occlusions. Early stent occlusion was defined as complete vessel occlusion within 24 h of neurothrombectomy. Clinical outcome was evaluated at day 90 with the modified Rankin Score scale (mRS). Pretreatment, procedural and outcome variables were recorded and analyzed using logistic regression. RESULTS: Carotid stenting was performed in 99 (13%) patients. Of those, 22 (22%) had early stent occlusion at follow-up. Stent occlusion was associated with a lower use of post-stenting angioplasty [adjusted OR (aOR) = 11.2, 95%CI = 2.49-50.78, p = 0.002)], increased residual intrastent stenosis (aOR = 2.1, 95%CI = 1.38-3.06, p < 0.001) and unsuccesful intracranial recanalization (modified TICI score 0-2a) (aOR = 13.5, 95%CI = 1.97-92.24, p = 0.008). Stent occlusion was associated with poor clinical outcome at day 90 (poorer mRS shift, aOR = 3.9, 95%CI = 1.3-11.3, p = 0.014; mRS>2, aOR = 6.3, 95%CI = 1.8-22.7, p = 0.005), and with an increased rate of symptomatic intracranial hemorrhage at 24 h (14% versus 1%, p = 0.033). CONCLUSIONS: Early carotid stent occlusion occurred in one out of five neurothrombectomies and was associated with periprocedural factors that included increased residual intrastent stenosis, a lower use of post-stenting angioplasty and unsuccessful intracranial recanalization. Further investigation is warranted for the evaluation of strategies aimed to prevent carotid stent occlusion.

Temporal trends and geographical variability of the prevalence and incidence of attention deficit/hyperactivity disorder diagnoses among children in Catalonia, Spain.

Attention deficit/hyperactivity disorder (ADHD) is one of the most common behavioral disorders in childhood. According to a recent systematic review, the worldwide estimate of ADHD prevalence is 7.2% in children. This study aims to assess the prevalence of ADHD diagnoses in 2017 and the incidence of ADHD diagnoses in 2009-2017 in children living in Catalonia, Spain, as well as their temporal and geographical variability, and stratifying by sex and age. We used administrative data for all children aged 4 to 17 years who were insured in the public Catalan Health System in 2009-2017. We identified all ADHD cases diagnosed in 2009-2017 (ICD-9 code 314). We estimated the prevalence of ADHD diagnoses in 2017 and the overall annual incidence of ADHD diagnoses in 2009-2017. We used Poisson regression models to assess temporal trends in the incidence. We estimated a prevalence of ADHD diagnoses of 4.06% (95%CI 4.03, 4.10) in 2017, being 5.81% (95%CI 5.75, 5.87) for boys and 2.20% (95%CI 2.16, 2.24) for girls, the highest prevalence being in 13-to-17-year-olds (7.28% (95%CI 7.20, 7.36)). We did not observe a statistically significant increase of the incidence of ADHD diagnoses during the study period. Geographical differences were found across the healthcare areas in both prevalence and annual incidence and constant during the study period. In conclusion, the prevalence of ADHD diagnoses observed in this study was 4.06%, which was lower than the estimates reported in previous systematic reviews, but in line with the prevalence estimates from other recent European studies. The prevalence was higher in boys than girls, with a sex ratio consistent with previous studies. We did not observe an increase in the temporal trend of incidence of ADHD diagnoses in recent years, but we found geographical differences.

Association between Early Life Exposure to Air Pollution and Working Memory and Attention.

BACKGROUND: Although previous studies have reported negative associations between exposure to air pollution and cognition, studies of the effects of prenatal and postnatal exposures in early childhood have been limited. OBJECTIVES: We sought to assess the role exposure to fine particulate matter ([Formula: see text]) during different prenatal and postnatal windows may play in children's cognitive development at school age. METHODS: Within the Brain Development and Air Pollution Ultrafine Particles in School Children (BREATHE) Project, we estimated residential [Formula: see text] exposures by land use regression for the prenatal period and first seven postnatal years of 2,221 children from Barcelona, Spain. The participants ([Formula: see text]) completed computerized tests assessing working memory, attentiveness, and conflict network during four visits in 2012­2013. We used linear mixed effects and distributed lag models to assess the period of exposure to [Formula: see text] in association with cognitive development. RESULTS: Inverse associations were identified between [Formula: see text] exposure during the fifth and sixth postnatal years and working memory, with boys showing much higher vulnerability. Regarding attention functions, exposure to higher [Formula: see text] levels during the prenatal period and from the fourth postnatal year were associated with a reduction in conflict network performance, though we found no association with attentiveness. The overall estimated cumulative effect of a [Formula: see text] increase in [Formula: see text] resulted in a reduction in the working memory [Formula: see text] score of [Formula: see text] [95% confidence interval (CI): [Formula: see text], [Formula: see text]] points and an increase in the conflict attentional network of 11.31 (95% CI: 6.05, 16.57) milliseconds, indicating a poorer performance. CONCLUSIONS: Early life exposure to [Formula: see text] was associated with a reduction in fundamental cognitive abilities, including working memory and conflict attentional network. https://doi.org/10.1289/EHP3169.

Mediastinal node staging by positron emission tomography-computed tomography and selective endoscopic ultrasound with fine needle aspiration for patients with upper gastrointestinal cancer: Results from a regional centre.

AIM: To investigate the impact of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and positron emission tomography-computed tomography (PET-CT) in the nodal staging of upper gastrointestinal (GI) cancer in a tertiary referral centre. METHODS: We performed a retrospective review of prospectively recorded data held on all patients with a diagnosis of upper GI cancer made between January 2009 and December 2015. Only those patients who had both a PET-CT and EUS with FNA sampling of a mediastinal node distant from the primary tumour were included. Using a positive EUS-FNA result as the gold standard for lymph node involvement, the sensitivity, specificity, positive and negative predictive values (PPV and NPV) and accuracy of PET-CT in the staging of mediastinal lymph nodes were calculated. The impact on therapeutic strategy of adding EUS-FNA to PET-CT was assessed. RESULTS: One hundred and twenty one patients were included. Sixty nine patients had a diagnosis of oesophageal adenocarcinoma (Thirty one of whom were junctional), forty eight had oesophageal squamous cell carcinoma and four had gastric adenocarcinoma. The FNA results were inadequate in eleven cases and the PET-CT findings were indeterminate in two cases, therefore thirteen patients (10.7%) were excluded from further analysis. There was concordance between PET-CT and EUS-FNA findings in seventy one of the remaining one hundred and eight patients (65.7%). The sensitivity, specificity, PPV and NPV values of PET-CT were 92.5%, 50%, 52.1% and 91.9% respectively. There was discordance between PET-CT and EUS-FNA findings in thirty seven out of one hundred and eight patients (34.3%). MDT discussion led to a radical treatment pathway in twenty seven of these cases, after the final tumour stage was altered as a direct consequence of the EUS-FNA findings. Of these patients, fourteen (51.9%) experienced clinical remission of a median of nine months (range three to forty two months). CONCLUSION: EUS-FNA leads to altered staging of upper GI cancer, resulting in more patients receiving radical treatment that would have been the case using PET-CT staging alone.

Impact of commuting exposure to traffic-related air pollution on cognitive development in children walking to school.

A few studies have found associations between the exposure to traffic-related air pollution at school and/or home and cognitive development. The impact on cognitive development of the exposure to air pollutants during commuting has not been explored. We aimed to assess the role of the exposure to traffic-related air pollutants during walking commute to school on cognitive development of children. We performed a longitudinal study of children (n = 1,234, aged 7-10 y) from 39 schools in Barcelona (Catalonia, Spain) who commuted by foot to school. Children were tested four times during a 12-month follow-up to characterize their developmental trajectories of working memory (d' of the three-back numbers test) and inattentiveness (hit reaction time standard error of the Attention Network Test). Average particulate matter ≤2.5 µm (PM2.5), Black Carbon (BC) and NO2 concentrations were estimated using Land Use Regression for the shortest walking route to school. Differences in cognitive growth were evaluated by linear mixed effects models with age-by-pollutant interaction terms. Exposure to PM2.5 and BC from the commutes by foot was associated with a reduction in the growth of working memory (an interquartile range increase in PM2.5 and BC concentrations decreased the annual growth of working memory by 5.4 (95% CI [-10.2, -0.6]) and 4.6 (95% CI [-9.0, -0.1]) points, respectively). The findings for NO2 were not conclusive and none of the pollutants were associated with inattentiveness. Efforts should be made to implement pedestrian school pathways through low traffic streets in order to increase security and minimize children's exposure to air pollutants.

A Longitudinal Study on Attention Development in Primary School Children with and without Teacher-Reported Symptoms of ADHD.

Background: Prospective longitudinal studies are essential in characterizing cognitive trajectories, yet few of them have been reported on the development of attention processes in children. We aimed to explore attention development in normal children and children with attention deficit and hyperactivity disorder (ADHD) symptoms in a repeated measures design using the attention network test (ANT). Methods: The population sample included 2,835 children (49.6% girls) aged 7-11 years from 39 schools in Barcelona (Catalonia, Spain) who performed the ANT four times from January 2012 to March 2013. According to teacher ratings, 10.5% of the children presented ADHD symptoms. We performed multilevel mixed-effects linear regression models, adjusting for school and individual, to test the effects of age-related growth on the ANT networks: alerting, orienting and executive attention, and three measurements related to attentiveness: median of hit reaction time (HRT), hit reaction time standard error (HRT-SE) and variability. Results: We observed age-related growth in all the outcomes, except orienting. The curves were steeper at the younger groups, although for alertness the improvement was further at the oldest ages. Gender and ADHD symptoms interacted with age in executive attention, HRT and variability. Girls performed better in executive attention at young ages although boys reached females at around 10 years of age. For HRT, males showed faster HRT. However, girls had a more pronounced improvement and reached the levels of boys at age 11. Children with ADHD symptoms had significant differences in executive attention, HRT and variability compared to children without ADHD symptoms. Conclusions: We detected an ongoing development of some aspects of attention in primary school children, differentiating patterns by gender and ADHD symptoms. Our findings support the ANT for assessing attention processes in children in large epidemiological studies.

Biologic Variation Approach to Daily Laboratory.

Biological variation gives valuable information about how the living organism regulates its constituents within and between subjects; this information on the behavior of body components allows us to derive consequences concerning reference populations and intervals. With a more pragmatic approach biological variation has three uses: setting the appropriate analytical performance specification for each analyte to limit the amount of error that laboratory could introduce in its measurements, to help distinguish health from disease, and to implement internal quality control with the automatic verification of results.

Traffic-related Air Pollution and Attention in Primary School Children: Short-term Association.

BACKGROUND: Although air pollution's short-term effects are well understood to be marked and preventable, its acute neuropsychological effects have, to our knowledge, not yet been studied. We aim to examine the association between daily variation in traffic-related air pollution and attention. METHODS: We conducted a follow-up study from January 2012 to March 2013 in 2,687 school children from 265 classrooms in 39 schools in Barcelona (Catalonia, Spain). We assessed four domains of children's attention processes every 3 months over four repeated visits providing a total of 10,002 computerized tests on 177 different days using the child Attention Network test (ANT). Ambient daily levels of nitrogen dioxide (NO2) and elemental carbon (EC) in particulate matter <2.5 µm (PM2.5) filters were measured at a fixed air quality background monitoring station and in schools. RESULTS: Daily ambient levels of both NO2 and EC were negatively associated with all attention processes (e.g., children in the bottom quartile of daily exposure to ambient NO2 levels had a 14.8 msecond [95% confidence interval, 11.2, 18.4] faster response time than those in the top quartile, which was equivalent to a 1.1-month [0.84, 1.37] retardation in the natural developmental improvement in response speed with age). Similar findings were observed after adjusting for the average indoor (classroom) levels of pollutants. Associations for EC were similar to those for NO2 and robust to several sensitivity analyses. CONCLUSIONS: The short-term association of traffic-related air pollutants with fluctuations in attention adds to the evidence that air pollution may have potential harmful effects on neurodevelopment. See video abstract at, http://links.lww.com/EDE/B158.

A Genome-Wide Association Study of Attention Function in a Population-Based Sample of Children.

BACKGROUND: Attention function filters and selects behaviorally relevant information. This capacity is impaired in some psychiatric disorders and has been proposed as an endophenotype for Attention-Deficit/Hyperactivity Disorder; however, its genetic basis remains largely unknown. This study aimed to identify single nucleotide polymorphism (SNPs) associated with attention function. MATERIALS AND METHODS: The discovery sample included 1655 children (7-12 years) and the replication sample included 546 children (5-8 years). Five attention outcomes were assessed using the computerized Attentional Network Test (ANT): alerting, orienting, executive attention, Hit Reaction time (HRT) and the standard error of HRT (HRTSE). A Genome-wide Association Study was conducted for each outcome. Gene set enrichment analyses were performed to detect biological pathways associated with attention outcomes. Additional neuroimaging analyses were conducted to test neural effects of detected SNPs of interest. RESULTS: Thirteen loci showed suggestive evidence of association with attention function (P<10-5) in the discovery sample. One of them, the rs4321351 located in the PID1 gene, was nominally significant in the replication sample although it did not survive multiple testing correction. Neuroimaging analysis revealed a significant association between this SNP and brain structure and function involving the frontal-basal ganglia circuits. The mTOR signaling and Alzheimer disease-amyloid secretase pathways were significantly enriched for alerting, orienting and HRT respectively (FDR<5%). CONCLUSION: These results suggest for the first time the involvement of the PID1 gene, mTOR signaling and Alzheimer disease-amyloid secretase pathways, in attention function during childhood. These genes and pathways have been proposed to play a role in neuronal plasticity, memory and neurodegenerative disease.

Developmental Trajectories in Primary Schoolchildren Using n-Back Task.

BACKGROUND: Neuropsychological instruments to assess cognitive trajectories during childhood in epidemiological studies are needed. This would improve neurodevelopment characterization in order to identify its potential determinants. We aimed to study whether repeated measures of n-back, a working memory task, detect developmental trajectories in schoolchildren during a 1-year follow-up. METHODS: We administered the n-back task to 2897 healthy children aged 7-11 years old from 39 schools in Barcelona (Spain). The task consisted of 2 levels of complexity or loads (2- and 3-back) and 2 different stimuli (numbers and words). Participants performed the task four times from January 2012 to March 2013. To study the trajectories during the follow-up, we performed linear mixed-effects models including school, individual and age as random effects. RESULTS: We observed improvements related to age in n-back outcomes d', HRT and accuracy, as well as reduced cognitive growth at older ages in d' and HRT. Greater improvements in performance were observed at younger ages, in 2-back, in verbal rather than numerical stimuli and in girls compared to boys. Boys responded faster at baseline, while girls showed increased growth in 2-back numbers. Children with ADHD (Attention Deficit and Hyperactivity Disorder) symptoms (15% of boys and 6% of girls) had a lower working memory at baseline, but they showed similar cognitive growth trajectories in numbers variants of the task, as compared to children without ADHD symptoms. However, the age-related improvement in response speed was not observed in children with ADHD symptoms. CONCLUSIONS: Changes in n-back outcomes reflected developmental trajectories in 1-year follow-up. The present results suggest that the repeated administration of this task can be used to study the factors that may alter the cognitive development during childhood.