Cerebrovascular Reactivity in Patients With Small Vessel Disease: A Cross-Sectional Study.

BACKGROUND: Cerebrovascular reactivity (CVR) is inversely related to white matter hyperintensity severity, a marker of cerebral small vessel disease (SVD). Less is known about the relationship between CVR and other SVD imaging features or cognition. We aimed to investigate these cross-sectional relationships. METHODS: Between 2018 and 2021 in Edinburgh, we recruited patients presenting with lacunar or cortical ischemic stroke, whom we characterized for SVD features. We measured CVR in subcortical gray matter, normal-appearing white matter, and white matter hyperintensity using 3T magnetic resonance imaging. We assessed cognition using Montreal Cognitive Assessment. Statistical analyses included linear regression models with CVR as outcome, adjusted for age, sex, and vascular risk factors. We reported regression coefficients with 95% CIs. RESULTS: Of 208 patients, 182 had processable CVR data sets (median age, 68.2 years; 68% men). Although the strength of association depended on tissue type, lower CVR in normal-appearing tissues and white matter hyperintensity was associated with larger white matter hyperintensity volume (BNAWM=-0.0073 [95% CI, -0.0133 to -0.0014] %/mm Hg per 10-fold increase in percentage intracranial volume), more lacunes (BNAWM=-0.00129 [95% CI, -0.00215 to -0.00043] %/mm Hg per lacune), more microbleeds (BNAWM=-0.00083 [95% CI, -0.00130 to -0.00036] %/mm Hg per microbleed), higher deep atrophy score (BNAWM=-0.00218 [95% CI, -0.00417 to -0.00020] %/mm Hg per score point increase), higher perivascular space score (BNAWM=-0.0034 [95% CI, -0.0066 to -0.0002] %/mm Hg per score point increase in basal ganglia), and higher SVD score (BNAWM=-0.0048 [95% CI, -0.0075 to -0.0021] %/mm Hg per score point increase). Lower CVR in normal-appearing tissues was related to lower Montreal Cognitive Assessment without reaching convention statistical significance (BNAWM=0.00065 [95% CI, -0.00007 to 0.00137] %/mm Hg per score point increase). CONCLUSIONS: Lower CVR in patients with SVD was related to more severe SVD burden and worse cognition in this cross-sectional analysis. Longitudinal analysis will help determine whether lower CVR predicts worsening SVD severity or vice versa. REGISTRATION: URL: https://www.isrctn.com; Unique identifier: ISRCTN12113543.

Effect of including a dietary supplement of raisins, a food rich in polyphenols, on cognitive function in healthy older adults; a study protocol for a randomized clinical trial.

BACKGROUND: Polyphenols have been shown to be effective against many chronic diseases, including neurodegenerative diseases. Specifically, the consumption of raisins, being a food rich in polyphenols, has been attributed with neuroprotective benefits. Therefore, our main objective is to evaluate the effect of including 50 g of raisins in the diet daily for 6 months, on the improvement of cognitive performance, cardiovascular risk factors and markers of inflammation in a population of older adults without cognitive impairment. METHODS: Design and intervention: This study will be a randomized controlled clinical trial of two parallel groups. Each subject included in the study will be randomly assigned to one of two study groups: control group (no supplement), intervention group (50 g of raisins daily during 6 months). STUDY POPULATION: The participants will be selected by consecutive sampling in the Primary Care consultations of urban health centers in Salamanca and Zamora (Spain), taking into account the selection criteria. STUDY VARIABLES: Two visits will be made, baseline and at 6 months. Cognitive performance will be evaluated (Mini-Mental State Examination test, Rey Auditory Verbal Learning Test, verbal fluency and montreal cognitive assessment (Moca)). It will also be analyzed the level of physical activity, quality of life, activities of daily living, energy and nutritional composition of the diet, body composition, blood pressure, heart rate, markers of inflammation and other laboratory tests of clinical relevance (glycaemia, total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides). In addition, sociodemographic data, personal and family history, medication use and alcohol and tobacco consumption will be collected. DISCUSSION: In this project, it is intended to contribute to minimize the problems derived from cognitive deterioration in older people. TRIAL REGISTRATION: ClincalTrials.gov Identifier: NCT04966455 Registration date: July 1, 2021.

Growth and shell hardness of the apple snail Pomacea flagellata Say, 1829, reared at three calcium concentrations.

The snail Pomacea flagellata inhabits aquatic systems with high calcium concentration and it is important to food webs; unfortunately, its natural populations are decreasing due to overfishing and habitat destruction. Here we tested the effect of three water calcium concentrations on the growth and hardness of snail shells in triplicate recirculation culture systems for 12 weeks. In each culture, 100 juvenile snails were seeded at constant density and fed with balanced tilapia feed. Thirty snails were randomly collected every 15 days and measured in length and total weight. The size, weight, and shell hardness of the snails for the 500 mg/L calcium treatment were significantly higher than the mean size of the snails in the other treatments (300 mg/L and 243.33 mg/L). The calcium supply in the culture promotes growth and allows the snails to produce healthier and stronger shells, in addition to improving their growth rate, which is important for the management of the species.

Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI.

Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at ∼450 000 cytosine-phosphate-guanine (CpG) sites in 9732 middle-aged to older adults from 14 community-based studies. Single CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10-8), was associated with F2 expression in blood (P = 6.4 × 10-5) and co-localized with FOLH1 expression in brain (posterior probability = 0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis and multi-omics co-localization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug-repositioning analysis indicated antihyperlipidaemic agents, more specifically peroxisome proliferator-activated receptor-alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood-brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidaemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood-brain barrier disruption.

Intestinal microbiota modulates pancreatic carcinogenesis through intratumoral natural killer cells.

Preclinical data demonstrate that the gut microbiota can promote pancreatic ductal adenocarcinoma (PDAC), but mechanisms remain unclear. We hypothesized that intestinal microbiota alters anti-tumor innate immunity response to facilitate PDAC progression. Human PDAC L3.6pl cells were heterotopically implanted into Rag1-/- mice after microbiota depletion with antibiotics, while syngeneic murine PDAC Pan02 cells were implanted intrapancreatic into germ-free (GF) C57BL/6 J mice. Natural killer (NK) cells and their IFNγ expression were quantitated by flow cytometry. NK cells were depleted in vivo using anti-Asialo GM1 antibody to confirm the role of NK cells. Bacteria-free supernatant from SPF and GF mice feces was used to test its effect on NK-92MI cell anti-tumor response in vitro. SPF and ex-GF mice (reconstituted with SPF microbiota) developed larger PDAC tumors with decreased NK cell tumor infiltration and IFNγ expression versus GF-Rag1-/-. Microbiota-induced PDAC tumorigenesis was attenuated by antibiotic exposure, a process reversed following NK cell depletion in both Rag1-/- and C57BL/6 J mice. Compared to GF, SPF-Rag1-/- abiotic stool culture supernatant inhibited NK-92MI cytotoxicity, migration, and anti-cancer related gene expression. Gut microbiota promotes PDAC tumor progression through modulation of the intratumoral infiltration and activity of NK cells.

Identification of Leukemia-Associated Immunophenotypes by Databaseguided Flow Cytometry Provides a Highly Sensitive and Reproducible Strategy for the Study of Measurable Residual Disease in Acute Myeloblastic Leukemia.

Background: Multiparametric Flow Cytometry (MFC) is an essential tool to study the involved cell lineages, the aberrant differentiation/maturation patterns and the expression of aberrant antigens in acute myeloid leukemia (AML). The characterization of leukemia-associated immunophenotypes (LAIPs) at the moment of diagnosis is critical to establish reproducible strategies for the study of measurable residual disease using MFC (MFC-MRD). Methods: In this study, we identify and characterize LAIPs by comparing the leukemic populations of 145 AML patients, using the EuroFlow AML/ MDS MFC panel, with six databases of normal myeloid progenitors (MPCs). Principal component analysis was used to identify and characterize the LAIPs, which were then used to generate individual profiles for MFC-MRD monitoring. Furthermore, we investigated the relationship between the expression patterns of LAIPs and the different subtypes of AML. The MFC-MRD study was performed by identifying residual AML populations that matched with the LAIPs at diagnosis. To further validate this approach, the presence of MRD was also assessed by qPCR (qPCR-MRD). Finally, we studied the association between MFC-MRD and progression-free survival (PFS). Results: The strategy used in this study allowed us to describe more than 300 different LAIPs and facilitated the association of specific phenotypes with certain subtypes of AML. The MFC-MRD monitoring based on LAIPs with good/strong specificity was applicable to virtually all patients and showed a good correlation with qPCR-MRD and PFS. Conclusions: The described methodology provides an objective method to identify and characterize LAIPs. Furthermore, it provides a theoretical basis to develop highly sensitive MFC-MRD strategies.

Impact of Individual Comorbidities on Survival of Patients with Myelofibrosis.

The comorbidity burden is an important risk factor for overall survival (OS) in several hematological malignancies. This observational prospective study was conducted to evaluate the impact of individual comorbidities on survival in a multicenter series of 668 patients with primary myelofibrosis (PMF) or MF secondary to polycythemia vera (PPV-MF) or essential thrombocythemia (PET-MF). Hypertension (hazard ratio (HR) = 4.96, p < 0.001), smoking (HR = 5.08, p < 0.001), dyslipidemia (HR = 4.65, p < 0.001) and hepatitis C virus (HCV) (HR = 4.26, p = 0.015) were most adversely associated with OS. Diabetes (HR = 3.01, p < 0.001), pulmonary disease (HR = 3.13, p < 0.001) and renal dysfunction (HR = 1.82, p = 0.037) were also associated with an increased risk of death. Multivariate analysis showed that pulmonary disease (HR = 2.69, p = 0.001), smoking (HR = 3.34, p < 0.001), renal dysfunction (HR = 2.08, p = 0.043) and HCV (HR = 11.49, p = 0.001) had a negative impact on OS. When ruxolitinib exposure was included in the model, the effect of each comorbidity on survival was modified. Therefore, individual comorbidities should be taken into account in determining the survival prognosis for patients with MF.

Self-Perceived Emotional Intelligence Levels in Nursing Students in Times of a Pandemic: Multivariate Representation.

Self-perceived emotional intelligence in healthcare personnel is not just an individual skill but a work tool, which is even more necessary in times of crisis. This article aimed to determine emotional intelligence as perceived by students studying nursing at the University of Colima, Mexico, a year after the start of the COVID-19 pandemic. A cross-sectional survey of an academic year stratified population of 349 students was conducted, using the Trait Meta-Mood Scale-24 instrument. A global descriptive analysis was performed for each school year. Additionally, an ANOVA was performed, and a Multiple Correspondence Analysis was executed. It is essential to highlight the high percentages for emotional attention within the results. However, a large percentage of students required improvement in emotional attention, clarity, and repair. According to their school year, significant differences were observed among student groups within the three emotional intelligence subscales (p < 0.05). Second-year students had low levels in the three subscales of emotional intelligence, while fourth-year students had adequate levels. We established that the scores were different depending on the school year, with a significant decrease in second-year students. The implementation of educational programs could aid in the development of emotional skills in students from the health field, especially in times of crisis.

Relationship between inferior frontal sulcal hyperintensities on brain MRI, ageing and cerebral small vessel disease.

Raised signal in cerebrospinal fluid (CSF) on fluid-attenuated inversion recovery (FLAIR) may indicate raised CSF protein or debris and is seen in inferior frontal sulci on routine MRI. To explore its clinical relevance, we assessed the association of inferior frontal sulcal hyperintensities (IFSH) on FLAIR with demographics, risk factors, and small vessel disease markers in three cohorts (healthy volunteers, n=44; mild stroke patients, n=105; older community-dwelling participants from Lothian birth cohort 1936, n=101). We collected detailed clinical data, scanned all subjects on the same 3T MRI scanner and 3-dimensional FLAIR sequence and developed a scale to rate IFSH. In adjusted analyses, the IFSH score increased with age (per 10-year increase; OR 1.69; 95% CI, 1.42-2.02), and perivascular spaces score in centrum semiovale in stroke patients (OR 1.73; 95% CI, 1.13-2.69). Since glymphatic CSF clearance declines with age and drains partially via the cribriform plate to the nasal lymphatics, IFSH on 3T MRI may be a non-invasive biomarker of altered CSF clearance and justifies further research in larger, more diverse samples.

Diffusion-weighted imaging lesions and risk of recurrent stroke after intracerebral haemorrhage.

OBJECTIVE: To determine whether the presence of diffusion-weighted imaging-positive (DWI+) lesions is associated with recurrent stroke after intracerebral haemorrhage (ICH). METHODS: The REstart or STop Antithrombotics Randomised Trial (RESTART) assessed the effect of restarting versus avoiding antiplatelet therapy after ICH on major vascular events for up to 5 years. We rated DWI sequences of MRI done before randomisation for DWI+ lesion presence, masked to outcome and antiplatelet use. Cox proportional hazards regression models were used to quantify associations. RESULTS: Of 537 participants in RESTART, 247 (median (IQR) age 75.7 (69.6-81.1) years; 170 men (68.8%); 120 started vs 127 avoided antiplatelet therapy) had DWI sequences on brain MRI at a median of 57 days (IQR 19-103) after ICH, of whom 73 (30%) had one or more DWI+ lesion. During a median follow-up of 2 years (1-3), 18 participants had recurrent ICH and 21 had ischaemic stroke. DWI+ lesion presence was associated with all stroke, (adjusted HR 2.2 (95% CI 1.1 to 4.2)) and recurrent ICH (4.8 (95% CI 1.8 to 13.2)), but not ischaemic stroke (0.9 (95% CI 0.3 to 2.5)). DWI+ lesion presence (0.5 (95% CI 0.2 to 1.3)) vs absence (0.6 (95% CI 0.3 to 1.5), pinteraction=0.66) did not modify the effect of antiplatelet therapy on a composite outcome of recurrent stroke. CONCLUSIONS: DWI+ lesion presence in ICH survivors is associated with recurrent ICH, but not with ischaemic stroke. We found no evidence of modification of effects of antiplatelet therapy on recurrent stroke after ICH by DWI+ lesion presence. These findings provide a new perspective on the significance of DWI+ lesions, which may be markers of microvascular mechanisms associated with recurrent ICH. TRIAL REGISTRATION NUMBER: ISRCTN71907627.

The gut microbiome of COVID-19 recovered patients returns to uninfected status in a minority-dominated United States cohort.

To investigate the relationship between intestinal microbiota and SARS-CoV-2-mediated pathogenicity in a United States, majority African American cohort. We prospectively collected fecal samples from 50 SARS-CoV-2 infected patients, 9 SARS-CoV-2 recovered patients, and 34 uninfected subjects seen by the hospital with unrelated respiratory medical conditions (controls). 16S rRNA sequencing and qPCR analysis was performed on fecal DNA/RNA. The fecal microbial composition was found to be significantly different between SARS-CoV-2 patients and controls (PERMANOVA FDR-P = .004), independent of antibiotic exposure. Peptoniphilus, Corynebacterium and Campylobacter were identified as the three most significantly enriched genera in COVID-19 patients compared to controls. Actively infected patients were also found to have a different gut microbiota than recovered patients (PERMANOVA FDR-P = .003), and the most enriched genus in infected patients was Campylobacter, with Agathobacter and Faecalibacterium being enriched in the recovered patients. No difference in microbial community structure between recovered patients and uninfected controls was observed, nor a difference in alpha diversity between the three groups. 24 of the 50 COVID-19 patients (48%) tested positive via RT-qPCR for fecal SARS-CoV-2 RNA. A significant difference in gut microbial composition between SARS-CoV-2 positive and negative samples was observed, with Klebsiella and Agathobacter being enriched in the positive cohort. No significant associations between microbiome composition and disease severity was found. The intestinal microbiota is sensitive to the presence of SARS-CoV-2, with increased relative abundance of genera (Campylobacter, Klebsiella) associated with gastrointestinal (GI) disease. Further studies are needed to investigate the functional impact of SARS-CoV-2 on GI health.

Comparison of structural MRI brain measures between 1.5 and 3 T: Data from the Lothian Birth Cohort 1936.

Multi-scanner MRI studies are reliant on understanding the apparent differences in imaging measures between different scanners. We provide a comprehensive analysis of T1 -weighted and diffusion MRI (dMRI) structural brain measures between a 1.5 T GE Signa Horizon HDx and a 3 T Siemens Magnetom Prisma using 91 community-dwelling older participants (aged 82 years). Although we found considerable differences in absolute measurements (global tissue volumes were measured as ~6-11% higher and fractional anisotropy [FA] was 33% higher at 3 T than at 1.5 T), between-scanner consistency was good to excellent for global volumetric and dMRI measures (intraclass correlation coefficient [ICC] range: .612-.993) and fair to good for 68 cortical regions (FreeSurfer) and cortical surface measures (mean ICC: .504-.763). Between-scanner consistency was fair for dMRI measures of 12 major white matter tracts (mean ICC: .475-.564), and the general factors of these tracts provided excellent consistency (ICC ≥ .769). Whole-brain structural networks provided good to excellent consistency for global metrics (ICC ≥ .612). Although consistency was poor for individual network connections (mean ICCs: .275-.280), this was driven by a large difference in network sparsity (.599 vs. .334), and consistency was improved when comparing only the connections present in every participant (mean ICCs: .533-.647). Regression-based k-fold cross-validation showed that, particularly for global volumes, between-scanner differences could be largely eliminated (R2 range .615-.991). We conclude that low granularity measures of brain structure can be reliably matched between the scanners tested, but caution is warranted when combining high granularity information from different scanners.

Sources of systematic error in DCE-MRI estimation of low-level blood-brain barrier leakage.

PURPOSE: Dynamic contrast-enhanced (DCE) -MRI with Patlak model analysis is increasingly used to quantify low-level blood-brain barrier (BBB) leakage in studies of pathophysiology. We aimed to investigate systematic errors due to physiological, experimental, and modeling factors influencing quantification of the permeability-surface area product PS and blood plasma volume vp , and to propose modifications to reduce the errors so that subtle differences in BBB permeability can be accurately measured. METHODS: Simulations were performed to predict the effects of potential sources of systematic error on conventional PS and vp quantification: restricted BBB water exchange, reduced cerebral blood flow, arterial input function (AIF) delay and B1+ error. The impact of targeted modifications to the acquisition and processing were evaluated, including: assumption of fast versus no BBB water exchange, bolus versus slow injection of contrast agent, exclusion of early data from model fitting and B1+ correction. The optimal protocol was applied in a cohort of recent mild ischaemic stroke patients. RESULTS: Simulation results demonstrated substantial systematic errors due to the factors investigated (absolute PS error ≤ 4.48 × 10-4 min-1 ). However, these were reduced (≤0.56 × 10-4 min-1 ) by applying modifications to the acquisition and processing pipeline. Processing modifications also had substantial effects on in-vivo normal-appearing white matter PS estimation (absolute change ≤ 0.45 × 10-4 min-1 ). CONCLUSION: Measuring subtle BBB leakage with DCE-MRI presents unique challenges and is affected by several confounds that should be considered when acquiring or interpreting such data. The evaluated modifications should improve accuracy in studies of neurodegenerative diseases involving subtle BBB breakdown.

Rationale and design of a longitudinal study of cerebral small vessel diseases, clinical and imaging outcomes in patients presenting with mild ischaemic stroke: Mild Stroke Study 3.

BACKGROUND: Cerebral small vessel disease is a major cause of dementia and stroke, visible on brain magnetic resonance imaging. Recent data suggest that small vessel disease lesions may be dynamic, damage extends into normal-appearing brain and microvascular dysfunctions include abnormal blood-brain barrier leakage, vasoreactivity and pulsatility, but much remains unknown regarding underlying pathophysiology, symptoms, clinical features and risk factors of small vessel disease.Patients and Methods: The Mild Stroke Study 3 is a prospective observational cohort study to identify risk factors for and clinical implications of small vessel disease progression and regression among up to 300 adults with non-disabling stroke. We perform detailed serial clinical, cognitive, lifestyle, physiological, retinal and brain magnetic resonance imaging assessments over one year; we assess cerebrovascular reactivity, blood flow, pulsatility and blood-brain barrier leakage on magnetic resonance imaging at baseline; we follow up to four years by post and phone. The study is registered ISRCTN 12113543. SUMMARY: Factors which influence direction and rate of change of small vessel disease lesions are poorly understood. We investigate the role of small vessel dysfunction using advanced serial neuroimaging in a deeply phenotyped cohort to increase understanding of the natural history of small vessel disease, identify those at highest risk of early disease progression or regression and uncover novel targets for small vessel disease prevention and therapy.

Cerebral small vessel disease genomics and its implications across the lifespan.

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.

The Application of Optical Coherence Tomography Angiography in Cerebral Small Vessel Disease, Ischemic Stroke, and Dementia: A Systematic Review.

Objective: To investigate the application of optical coherence tomography angiography (OCTA) in cerebral small vessel disease (SVD), ischemic stroke and dementia. Methods: We conducted a systematic search in MEDLINE (from inception) and EMBASE (from 1980) to end 2019 for human studies that measured retinal parameters in cerebral SVD, ischemic stroke, and dementia using OCTA. Results: Fourteen articles (n = 989) provided relevant data. Ten studies included patients with Alzheimer disease (AD) and mild cognitive impairment (n = 679), two investigated pre-symptomatic AD participants (n = 154), and two investigated monogenic SVD patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (n = 32) and Fabry disease (n = 124). Methods to reduce bias and risk factor adjustment were poorly reported. Substantial methodological variations between studies precluded a formal meta-analysis. Quantitative measurements revealed significant yet inconclusive changes in foveal avascular zone, perfusion density, and vessel density (VD) in AD, presymptomatic AD, and SVD patients. Two (n = 160) of three studies (n = 192) showed association between decreased VD and increased white matter hyperintensities. In three (n = 297) of seven studies (n = 563), better cognitive function was associated with increased VD. One study (n = 52) suggested increased VD was associated with increased ganglion cell-inner plexiform layer thickness in AD yet with no covariate adjustment. Conclusions: Changes in retinal microvasculature identified using OCTA are associated with monogenic SVD and different stages of AD, but data are limited and partly confounded by methodological differences. Larger studies with risk factors adjustment and more consistent OCTA methods are needed to fully exploit this technology. PROSPERO registration number: CRD42020166929.

Relationship Between Venules and Perivascular Spaces in Sporadic Small Vessel Diseases.

Background and Purpose- Perivascular spaces (PVS) around venules may help drain interstitial fluid from the brain. We examined relationships between suspected venules and PVS visible on brain magnetic resonance imaging. Methods- We developed a visual venular quantification method to examine the spatial relationship between venules and PVS. We recruited patients with lacunar stroke or minor nondisabling ischemic stroke and performed brain magnetic resonance imaging and retinal imaging. We quantified venules on gradient echo or susceptibility-weighted imaging and PVS on T2-weighted magnetic resonance imaging in the centrum semiovale and then determined overlap between venules and PVS. We assessed associations between venular count and patient demographic characteristics, vascular risk factors, small vessel disease features, retinal vessels, and venous sinus pulsatility. Results- Among 67 patients (69% men, 69.0±9.8 years), only 4.6% (range, 0%-18%) of venules overlapped with PVS. Total venular count increased with total centrum semiovale PVS count in 55 patients after accounting for venule-PVS overlap (ß=0.468 [95% CI, 0.187-0.750]) and transverse sinus pulsatility (ß=0.547 [95% CI, 0.309-0.786]) and adjusting for age, sex, and systolic blood pressure. Conclusions- Despite increases in both visible PVS and suspected venules, we found minimal spatial overlap between them in patients with sporadic small vessel disease, suggesting that most magnetic resonance imaging-visible centrum semiovale PVS are periarteriolar rather than perivenular.

Fluctuating asymmetry in brain structure and general intelligence in 73-year-olds.

Fluctuating body asymmetry is theorized to indicate developmental instability, and to have small positive associations with low socioeconomic status (SES). Previous studies have reported small negative associations between fluctuating body asymmetry and cognitive functioning, but relationships between fluctuating brain asymmetry and cognitive functioning remain unclear. The present study investigated the association between general intelligence (a latent factor derived from a factor analysis on 13 cognitive tests) and the fluctuating asymmetry of four structural measures of brain hemispheric asymmetry: cortical surface area, cortical volume, cortical thickness, and white matter fractional anisotropy. The sample comprised members of the Lothian Birth Cohort 1936 (LBC1936, N = 636, mean age = 72.9 years). Two methods were used to calculate structural hemispheric asymmetry: in the first method, regions contributed equally to the overall asymmetry score; in the second method, regions contributed proportionally to their size. When regions contributed equally, cortical thickness asymmetry was negatively associated with general intelligence (ß = -0.18,p < .001). There was no association between cortical thickness asymmetry and childhood SES, suggesting that other mechanisms are involved in the thickness asymmetry-intelligence association. Across all cortical metrics, asymmetry of regions identified by the parieto-frontal integration theory (P-FIT) was not more strongly associated with general intelligence than non-P-FIT asymmetry. When regions contributed proportionally, there were no associations between general intelligence and any of the asymmetry measures. The implications of these findings, and of different methods of calculating structural hemispheric asymmetry, are discussed.

The striatum, the hippocampus, and short-term memory binding: Volumetric analysis of the subcortical grey matter's role in mild cognitive impairment.

BACKGROUND: Deficits in short-term memory (STM) binding are a distinguishing feature of preclinical stages leading to Alzheimer's disease (AD). However, the neuroanatomical correlates of conjunctive STM binding are largely unexplored. Here we examine the possible association between the volumes of hippocampi, parahippocampal gyri, and grey matter within the subcortical structures - all found to have foci that seemingly correlate with basic daily living activities in AD patients - with cognitive tests related to conjunctive STM binding. MATERIALS AND METHODS: Hippocampal, thalamic, parahippocampal and corpus striatum volumes were semi-automatically quantified in brain magnetic resonance images from 25 cognitively normal people and 21 patients with Mild Cognitive Impairment (MCI) at high risk of AD progression, who undertook a battery of cognitive tests and the short-term memory binding test. Associations were assessed using linear regression models and group differences were assessed using the Mann-Whitney U test. RESULTS: Hippocampal and parahippocampal gyrus volumes differed between MCI and control groups. Although the grey matter volume in the globus pallidus (r = -0.71, p < 0.001) and parahippocampal gyry (r = -0.63, p < 0.05) correlated with a STM binding task in the MCI group, only the former remained associated with STM binding deficits in MCI patients, after correcting for age, gender and years of education (ß = -0.56,P = 0.042) although with borderline significance. CONCLUSIONS: Loss of hippocampal volume plays no role in the processing of STM binding. Structures within the basal ganglia, namely the globus pallidus, could be part of the extrahippocampal network supporting binding. Replication of this study in large samples is now needed.

[Peak expiratory flow vs. spirometry for the diagnosis of asthma in adults]. / Flujometría versus espirometría para el diagnóstico de asma en adultos.

BACKGROUND: The diagnosis of asthma is confirmed with a spirometry: FEV1 ratio (forced expiratory volume in one second)/FVC (forced vital capacity) <80% with reversibility (FEV1 >12% or 200 mL) after using salbutamol. The peak expiratory flow is cheap and easy to use; it measures the forced expiratory flow, of which reversibility > 20% suggests asthma. OBJECTIVE: To know the sensitivity, specificity, and the positive and negative predictive values of the flowmeter. METHODS: A cross-sectional, observational, comparative study. Individuals aged >18 years without contraindications for spirometry were included. They underwent spirometry and peak expiratory flow, and the ACT (Asthma Control Test) questionnaire was applied to them. Sensitivity, specificity, positive predictive value and negative predictive value of the flowmetry were calculated. ROC curve was carried out in order to know the cut-off point of greater sensitivity and specificity. RESULTS: Of 150 patients, 66% were male; the median age was 38 years. According to the guidelines of GINA 2018 (Global Initiative for Asthma); 58.7% were controlled. The sensitivity of the peak expiratory flow was 47%, and the specificity was 87%, with a positive predictive value of 54.8% and a negative predictive value of 84%. The peak expiratory flow showed higher specificity with FEV1 <59%. The cut-off point of greater sensitivity and specificity was a reversibility of 8%, with an area under the curve of 0.70. CONCLUSIONS: The flowmeter has got greater sensitivity in airway obstructions; it is useful when a spirometer is not available.

Antecedentes: El diagnóstico de asma se confirma con espirometría: VEF1 (volumen espiratorio forzado del primer segundo)/CVF (capacidad vital forzada) < 80 %, con reversibilidad (VEF1 >12 % o 200 mL) tras utilizar salbutamol. El flujómetro es barato y fácil de utilizar, mide el flujo espiratorio forzado, cuya reversibilidad > 20 % sugiere asma. Objetivo: Conocer sensibilidad, especificidad y valores predictivos positivos y negativo del flujómetro. Métodos: Estudio transversal, observacional, comparativo. Se incluyó a individuos > 18 años sin contraindicaciones para espirometría, quienes fueron sometidos a espirometría y flujometría y se les aplicó el Asthma Control Test. Se calculó sensibilidad, especificidad y valores predictivos positivo y negativo de la flujometría. Se realizó curva ROC para conocer el punto de corte de mayor sensibilidad y especificidad. Resultados: De 150 pacientes, 66 % fue del sexo masculino; la mediana de edad fue de 38 años. Conforme los criterios de Global Initiative for Asthma 2018, 58.7 % estaba controlado. La sensibilidad de la flujometría fue de 47 %, la especificidad de 87 %, valor predictivo positivo de 54.8 % y negativo de 84 %. La flujometría mostró mayor especificidad con VEF1 < 59 %. El punto de corte de mayor sensibilidad y especificidad fue una reversibilidad de 8 %, con área bajo la curva de 0.70. Conclusiones: El flujómetro tiene mayor sensibilidad en obstrucciones de vía aérea; es de utilidad cuando no se cuenta con un espirómetro.