Recent behavioral data have shown that lifelong bilingualism can maintain youthful cognitive control abilities in aging. Here, we provide the first direct evidence of a neural basis for the bilingual cognitive control boost in aging. Two experiments were conducted, using a perceptual task switching paradigm, and including a total of 110 participants. In Experiment 1, older adult bilinguals showed better perceptual switching performance than their monolingual peers. In Experiment 2, younger and older adult monolinguals and bilinguals completed the same perceptual task switching experiment while fMRI was performed. Typical age-related performance reductions and fMRI activation increases were observed. However, like younger adults, bilingual older adults outperformed their monolingual peers while displaying decreased activation in left lateral frontal cortex and cingulate cortex. Critically, this attenuation of age-related over-recruitment associated with bilingualism was directly correlated with better task switching performance. In addition, the lower BOLD response in frontal regions accounted for 82% of the variance in the bilingual task switching reaction time advantage. These results suggest that lifelong bilingualism offsets age-related declines in the neural efficiency for cognitive control processes.
Neuroimaging biomarkers that precede cognitive decline have the potential to aid early diagnosis of Alzheimer's disease (AD). A body of diffusion tensor imaging (DTI) work has demonstrated declines in white matter (WM) microstructure in AD and its typical prodromal state, amnestic mild cognitive impairment. The present review summarizes recent evidence suggesting that WM integrity declines are present in individuals at high AD-risk, prior to cognitive decline. The available data suggest that AD-risk is associated with WM integrity declines in a subset of tracts showing decline in symptomatic AD. Specifically, AD-risk has been associated with WM integrity declines in tracts that connect grey matter structures associated with memory function. These tracts include parahippocampal WM, the cinglum, the inferior fronto-occipital fasciculus, and the splenium of the corpus callosum. Preliminary evidence suggests that some AD-risk declines are characterized by increases of radial diffusivity, raising the possibility that a myelin-related pathology may contribute to AD onset. These findings justify future research aimed at a more complete understanding of the neurobiological bases of DTI-based declines in AD. With continued refinement of imaging methods, DTI holds promise as a method to aid identification of presymptomatic AD.
DTI; diffusion tensor imaging; APOE; presymptomatic; Alzheimer's; Alzheimer's risk
High cardiorespiratory fitness (CRF) is an important protective factor reducing the risk of cardiac-related disability and mortality. Recent research suggests that high CRF also has protective effects on the brain’s macrostructure and functional response. However, little is known about the potential relationship between CRF and the brain’s white matter (WM) microstructure. This study explored the relationship between a comprehensive measure of CRF (VO2 peak, total time on treadmill, and 1-minute heart rate recovery) and multiple diffusion tensor imaging measures of WM integrity. Participants were 26 healthy community dwelling seniors between the ages of 60 and 69 (mean = 64.79 years, SD = 2.8). Results indicated a positive correlation between comprehensive CRF and fractional anisotropy (FA) in a large portion of the corpus callosum. Both VO2 peak and total time on treadmill contributed significantly to explaining the variance in mean FA in this region. The CRF-FA relationship observed in the corpus callosum was primarily characterized by a negative correlation between CRF and radial diffusivity in the absence of CRF correlations with either axial diffusivity or mean diffusivity. Tractography results demonstrated that portions of the corpus callosum associated with CRF primarily involved those interconnecting frontal regions associated with high-level motor planning. These results suggest that high CRF may attenuate age-related myelin declines in portions of the corpus callosum that interconnect homologous premotor cortex regions involved in motor planning.
Fitness; Diffusion Tensor Imaging; White Matter; Brain Imaging; Aging; Exercise
The exact biochemical steps of xylan backbone synthesis remain elusive. In Arabidopsis, three non-redundant genes from two glycosyltransferase (GT) families, IRX9 and IRX14 from GT43 and IRX10 from GT47, are candidates for forming the xylan backbone. In other plants, evidence exists that different tissues express these three genes at widely different levels, which suggests that diversity in the makeup of the xylan synthase complex exists. Recently we have profiled the transcripts present in the developing mucilaginous tissue of psyllium (Plantago ovata Forsk). This tissue was found to have high expression levels of an IRX10 homolog, but very low levels of the two GT43 family members. This contrasts with recent wheat endosperm tissue profiling that found a relatively high abundance of the GT43 family members. We have performed an in-depth analysis of all GTs genes expressed in four developmental stages of the psyllium mucilagenous layer and in a single stage of the psyllium stem using RNA-Seq. This analysis revealed several IRX10 homologs, an expansion in GT61 (homologs of At3g18170/At3g18180), and several GTs from other GT families that are highly abundant and specifically expressed in the mucilaginous tissue. Our current hypothesis is that the four IRX10 genes present in the mucilagenous tissues have evolved to function without the GT43 genes. These four genes represent some of the most divergent IRX10 genes identified to date. Conversely, those present in the psyllium stem are very similar to those in other eudicots. This suggests these genes are under selective pressure, likely due to the synthesis of the various xylan structures present in mucilage that has a different biochemical role than that present in secondary walls. The numerous GT61 family members also show a wide sequence diversity and may be responsible for the larger number of side chain structures present in the psyllium mucilage.
xylan; psyllium; secondary cell wall; irx; glycosyltransferase; mucilage
With a large percentage of clinical trials still using paper forms as the primary data collection tool, there is much potential for increasing efficiency through web-based data collection systems, especially for large-scale multi-center trials. This paper presents OnWARD, an ontology-driven, secure, rapidly-deployed, web-based framework supporting data capture for large-scale multi-center clinical research. Our approach is developed using the agile methodology to provide a flexible, user-centered dynamic form generator, which can be quickly deployed and customized for any clinical study without the need of deep technical expertise. Because of the flexible framework, the data management system can be extended to accommodate a large variety of data types, including genetic, genomic and proteomic data. In this paper, we demonstrate the initial deployment of OnWARD for a Phase II multi-center clinical trial after a development period of merely three months. The study utilizes 23 clinical report forms containing more than 1500 data points. Preliminary evaluation results show that OnWARD exceeded expectations of the clinical investigators in efficiency, flexibility and ease in setting up.
ontology; clinical research form; dynamic form; web-based data entry
The human capacities for overcoming prepotent actions and flexibly switching between tasks represent cornerstones of cognitive control. Functional neuroimaging has implicated a diverse set of brain regions contributing to each of these cognitive control processes. However, the extent to which attentional switching and response conflict draw on shared or distinct neural mechanisms remains unclear. The current study examined the neural correlates of response conflict and attentional switching using event-related functional magnetic resonance imaging (fMRI) and a fully randomized 2×2 design. We manipulated an arrow-word version of the Stroop task to measure conflict and switching in the context of a single task decision, in response to a common set of stimuli. Under these common conditions, both behavioral and imaging data showed significant main effects of conflict and switching but no interaction. However, conjunction analyses identified frontal regions involved in both switching and response conflict, including the dorsal anterior cingulate cortex (dACC) and left inferior frontal junction. In addition, connectivity analyses demonstrated task-dependent functional connectivity patterns between dACC and inferior temporal cortex for attentional switching and between dACC and posterior parietal cortex for response conflict. These results suggest that the brain makes use of shared frontal regions, but can dynamically modulate the connectivity patterns of some of those regions, to deal with attentional switching and response conflict.
Cognitive control; Attentional switching; Response conflict; Prefrontal cortex; fMRI; functional connectivity
One of our highest evolved functions as human beings is our capacity to switch between multiple tasks effectively. A body of research has identified a distributed frontoparietal network of brain regions which contribute to task switching. However, relatively less is known about whether some brain regions may contribute to switching in a domain-general manner while others may be more preferential for different kinds of switching. To explore this issue, we conducted three meta-analyses focusing on different types of task switching frequently used in the literature (perceptual, response, and context switching), and created a conjunction map of these distinct switch types. A total of 36 switching studies with 562 activation coordinates were analyzed using the activation likelihood estimation method. Common areas associated with switching across switch type included the inferior frontal junction and posterior parietal cortex. In contrast, domain-preferential activation was observed for perceptual switching in the dorsal portion of the premotor cortex and for context switching in frontopolar cortex. Our results suggest that some regions within the frontoparietal network contribute to domain-general switching processes while others contribute to more domain-preferential processes, according to the type of task switch performed.
Cognitive control; Task switching; Meta-analysis; Switch type; Perceptual switching; Response switching; Context switching
Adolescents are predisposed to short sleep duration and irregular sleep patterns due to certain host characteristics (e.g., age, pubertal status, gender, ethnicity, socioeconomic class, and neighborhood distress) and health-related variables (e.g., ADHD, asthma, birth weight, and BMI). The aim of the current study was to investigate the relationship between such variables and actigraphic measures of sleep duration and variability.
Cross-sectional study of 247 adolescents (48.5% female, 54.3% ethnic minority, mean age of 13.7 years) involved in a larger community-based cohort study.
Significant univariate predictors of sleep duration included gender, minority ethnicity, neighborhood distress, parent income, and BMI. In multivariate models, gender, minority status, and BMI were significantly associated with sleep duration (all p<.05), with girls, non-minority adolescents, and those of a lower BMI obtaining more sleep. Univariate models demonstrated that age, minority ethnicity, neighborhood distress, parent education, parent income, pubertal status, and BMI were significantly related to variability in total sleep time. In the multivariate model, age, minority status, and BMI were significantly related to variability in total sleep time (all p<.05), with younger adolescents, non-minority adolescents, and those of a lower BMI obtaining more regular sleep.
These data show differences in sleep patterns in population sub-groups of adolescents which may be important in understanding pediatric health risk profiles. Subgroups that may particularly benefit from interventions aimed at improving sleep patterns include boys, overweight, and minority adolescents.
This study investigated the effect of a high-volume compared to a low-volume resistance training session on maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP). Twenty male subjects with resistance training experience (6.2 ± 3.2 y), in a crossover trial, completed two resistance training protocols (high-volume: 5 sets per exercise; low-volume: 2 sets per exercise) and a control session (no exercise) on 3 separate occasions. MIP and MEP decreased by 13.6% (p < 0.01) and 14.7% (p < 0.01) respectively from pre-session MIP and MEP, following the high-volume session. MIP and MEP were unaffected following the low-volume or the control sessions. MIP returned to pre-session values after 40 minutes, whereas MEP remained significantly reduced after 60 minutes post-session by 9.2% compared to pre-session (p < 0.01). The findings suggest that the high-volume session significantly decreased MIP and MEP post-session, implicating a substantially increased demand on the respiratory muscles and that adequate recovery is mandatory following this mode of training.
Respiratory muscular strength performance is acutely diminished following a high-volume whole-body resistance training session.
Greater ventilatory requirements and generation of IAP during the high-volume resistance training session may have contributed to the increased demand placed on the respiratory muscles.
Protracted return of respiratory muscular strength performance to baseline levels may have implications for individuals prior to engaging in subsequent exercise bouts.
Respiratory pressures; core stability; hyperventilation; intra-abdominal pressure; Valsalva maneuver
The Ensembl project (http://www.ensembl.org) provides genome resources for chordate genomes with a particular focus on human genome data as well as data for key model organisms such as mouse, rat and zebrafish. Five additional species were added in the last year including gibbon (Nomascus leucogenys) and Tasmanian devil (Sarcophilus harrisii) bringing the total number of supported species to 61 as of Ensembl release 64 (September 2011). Of these, 55 species appear on the main Ensembl website and six species are provided on the Ensembl preview site (Pre!Ensembl; http://pre.ensembl.org) with preliminary support. The past year has also seen improvements across the project.
The human ability to flexibly alternate between tasks represents a central component of cognitive control. Neuroimaging studies have linked task switching with a diverse set of prefrontal cortex (PFC) regions but the contributions of these regions to various forms of cognitive flexibility remains largely unknown. Here, subjects underwent functional brain imaging while they completed a paradigm which selectively induced stimulus, response, or cognitive set switches in the context of a single task decision performed on a common set of stimuli. Behavioral results indicated comparable reaction time costs associated with each switch type. Domain-general task switching activation was observed in the inferior frontal junction and posterior parietal cortex, suggesting core roles for these regions in switching such as updating and representing task sets. In contrast, multiple domain-preferential PFC activations were observed across lateral and medial PFC, with progressively more rostral regions recruited as switches became increasingly abstract. Specifically, highly abstract cognitive set switches recruited anterior-PFC regions, moderately abstract response switches recruited mid-PFC regions, and highly constrained stimulus switches recruited posterior-PFC regions. These results demonstrate a functional organization across lateral and medial PFC according to the level of abstraction associated with acts of cognitive flexibility.
Cognitive control; Task switching; Prefrontal cortex; Stimulus switching; Response switching; Set switching
The Ensembl project (http://www.ensembl.org) seeks to enable genomic science by providing high quality, integrated annotation on chordate and selected eukaryotic genomes within a consistent and accessible infrastructure. All supported species include comprehensive, evidence-based gene annotations and a selected set of genomes includes additional data focused on variation, comparative, evolutionary, functional and regulatory annotation. The most advanced resources are provided for key species including human, mouse, rat and zebrafish reflecting the popularity and importance of these species in biomedical research. As of Ensembl release 59 (August 2010), 56 species are supported of which 5 have been added in the past year. Since our previous report, we have substantially improved the presentation and integration of both data of disease relevance and the regulatory state of different cell types.
Objective This study examined associations among adolescent sleepiness, sleep duration, variability in sleep duration, and psychological functioning (symptoms of anxiety, depression, externalizing behaviors, and perceived health). Methods This was a cross-sectional analysis of data from a community-based cohort study of sleep and health. Participants were 247 adolescents (48.6% female, 54.3% ethnic minority, mean age of 13.7 years). Sleep duration and variability in sleep duration were measured by actigraphy and sleepiness was measured by adolescent questionnaire. Primary outcomes were measured by parent, teacher, and adolescent questionnaires. Results Sleepiness was associated with higher scores on measures of anxiety (Adjusted partial r2 = .28, p < .001), depression (Adjusted partial r2 = .23, p < .001), and perceived health (indicating more negative outcomes) (Adjusted partial r2 = .19, p < .01). Significant associations between sleep duration or variability in sleep duration with psychological variables were not found. Conclusions Findings highlight the inter-relationships between sleepiness and psychological functioning and the potential importance of addressing sleepiness in health and psychological evaluations of adolescents.
adolescents; sleep; psychosocial functioning.
Although there is mounting evidence that childhood obesity is a risk factor for incident asthma, it remains unclear if there is a distinct “asthma-obesity” phenotype. This study characterized body composition, obesity related co-morbidities, and traditional risk factors for asthma in a cohort of children referred for asthma management in a pulmonary clinic. We hypothesized that children with asthma and obesity would have distinct risk factors and co-morbidities, particularly with respect to metabolic and sleep abnormalities.
Participants and Methods
116 asthmatic children ages 4 to 18 years underwent comprehensive measurements of common asthma risk factors as well as measurements of obesity-related morbidities, including lung function tests, atopy, and assessments of sleep (overnight oximetry and actigraphy), physical activity (accelerometry), and metabolism. Characteristics of children who were obese (BMI ≥ 95th percentile) were compared to those who were not obese (BMI < 95th percentile).
Obesity was present in 44% of participants. Obese participants had similar rates of atopy and family history of atopy, lung function, and asthma control at enrollment as their non-obese peers. A significantly higher proportion of obese participants had metabolic syndrome (23% vs 0%) and habitual snoring (60% vs 33%) compared to non-obese participants; insufficient sleep and nocturnal desaturations tended to be more prevalent among obese subjects.
Obesity and obesity related co-morbidities were common in a referral population of children with asthma. The specific influence of metabolic abnormalities on asthma morbidity and management is still uncertain and likely will need to be addressed in prospective studies.
The purpose of this work is to demonstrate rapid intradermal delivery of up to 1.5 mL of formulation using a hollow microneedle delivery device designed for self-application.
3M’s hollow Microstructured Transdermal System (hMTS) was applied to domestic swine to demonstrate delivery of a variety of formulations including small molecule salts and proteins. Blood samples were collected after delivery and analyzed via HPLC or ELISA to provide a PK profile for the delivered drug. Site evaluations were conducted post delivery to determine skin tolerability.
Up to 1.5 mL of formulation was infused into swine at a max rate of approximately 0.25 mL/min. A red blotch, the size of the hMTS array, was observed immediately after patch removal, but had faded so as to be almost indistinguishable 10 min post-patch removal. One-mL deliveries of commercial formulations of naloxone hydrochloride and human growth hormone and a formulation of equine anti-tetanus toxin were completed in swine. With few notable differences, the resulting PK profiles were similar to those achieved following subcutaneous injection of these formulations.
3M’s hMTS can provide rapid, intradermal delivery of 300–1,500 µL of liquid formulations of small molecules salts and proteins, compounds not typically compatible with passive transdermal delivery.
transdermal drug delivery; microneedles; intradermal; hollow microstructures; MTS
Gene expression arrays are valuable and widely used tools for biomedical research. Today's commercial arrays attempt to measure the expression level of all of the genes in the genome. Effectively translating the results from the microarray into a biological interpretation requires an accurate mapping between the probesets on the array and the genes that they are targeting. Although major array manufacturers provide annotations of their gene expression arrays, the methods used by various manufacturers are different and the annotations are difficult to keep up to date in the rapidly changing world of biological sequence databases.
We have created a consistent microarray annotation protocol applicable to all of the major array manufacturers. We constantly keep our annotations updated with the latest Ensembl Gene predictions, and thus cross-referenced with a large number of external biomedical sequence database identifiers. We show that these annotations are accurate and address in detail reasons for the minority of probesets that cannot be annotated. Annotations are publicly accessible through the Ensembl Genome Browser and programmatically through the Ensembl Application Programming Interface. They are also seamlessly integrated into the BioMart data-mining tool and the biomaRt package of BioConductor.
Consistent, accurate and updated gene expression array annotations remain critical for biological research. Our annotations facilitate accurate biological interpretation of gene expression profiles.
We present the design and implementation of VISAGE (VISual AGgregator and Explorer), a query interface for clinical research. We follow a user-centered development approach and incorporate visual, ontological, searchable and explorative features in three interrelated components: Query Builder, Query Manager and Query Explorer. The Query Explorer provides novel on-line data mining capabilities for purposes such as hypothesis generation or cohort identification. The VISAGE query interface has been implemented as a significant component of Physio-MIMI, an NCRR-funded, multi-CTSA-site pilot project. Preliminary evaluation results show that VISAGE is more efficient for query construction than the i2b2 web-client.
Ensembl (http://www.ensembl.org) integrates genomic information for a comprehensive set of chordate genomes with a particular focus on resources for human, mouse, rat, zebrafish and other high-value sequenced genomes. We provide complete gene annotations for all supported species in addition to specific resources that target genome variation, function and evolution. Ensembl data is accessible in a variety of formats including via our genome browser, API and BioMart. This year marks the tenth anniversary of Ensembl and in that time the project has grown with advances in genome technology. As of release 56 (September 2009), Ensembl supports 51 species including marmoset, pig, zebra finch, lizard, gorilla and wallaby, which were added in the past year. Major additions and improvements to Ensembl since our previous report include the incorporation of the human GRCh37 assembly, enhanced visualisation and data-mining options for the Ensembl regulatory features and continued development of our software infrastructure.
Previously published data from the Cleveland Children’s Sleep and Health Study (CCSHS) demonstrated that preterm infants are especially vulnerable both to sleep disordered breathing (SDB) and its neurocognitive sequelae at age 8–11 years. In this analysis, we aimed to identify the components of the neonatal medical history associated with childhood SDB among children born prematurely.
This analysis focuses on the 383 children in the population-based CCSHS cohort who were born <37 weeks gestational age and who had technically acceptable sleep studies performed at ages 8–11 years (92% of all preterm children). Logistic regression was used to evaluate the associations between candidate perinatal and neonatal risk factors and the presence of childhood SDB by sleep study.
Twenty-eight preterm children (7.3%) met the definition for SDB at age 8–11 years. Having a single mother and mild maternal pre-eclampsia were strongly associated with SDB in unadjusted and race-adjusted models. Unadjusted analyses also identified xanthine use and CPR and/or intubation in the delivery room as potential risk-factors for SDB. We did not find a significant link between traditional markers of severity of neonatal illness -- such as gestational age, birth weight, intraventricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD), or duration of ventilation -- and childhood SDB at school age.
These results represent a first step in identifying prenatal and neonatal characteristics which place preterm infants at higher risk for childhood SDB. The strong association between mild pre-eclampsia and childhood SDB underscores the importance of research aimed at understanding in utero risk factors for neurorespiratory development.
sleep disordered breathing (SDB); obstructive sleep apnea (OSA); pre-eclampsia; snoring; neonate
Increased variability in ventilation may contribute to the pathogenesis of obstructive sleep apnea (OSA) by promoting ventilatory instability, fluctuations of neuromuscular output to the upper airway, and pharyngeal collapsibility. We assessed the association of a measure of ventilatory variability measured at the wake-sleep transition with OSA and associated covariates.
485 participants in the Cleveland Family Study underwent overnight polysomnography with independent derivation of the Ventilatory Variability Index and the Apnea Hypopnea Index. The Ventilatory Variability Index was calculated from the variability in the power spectrum of the abdominal inductance signal over a 2-minute period beginning at sleep onset.
The Ventilatory Variability Index was strongly correlated with the Apnea Hypopnea Index (r=0.43, p<0.001). After adjusting for age, body mass index, sex, and race, the Ventilatory Variability Index remained significantly associated with Apnea Hypopnea Index (p<0.001). The adjusted odds ratio for obstructive sleep apnea (Apnea Hypopnea Index ≥ 15) with each half standard deviation increase in Ventilatory Variability Index was 1.41 [1.25–1.59]. In a subgroup analysis of obese snorers, to limit analyses to those with a presumed anatomic predisposition for apnea, Ventilatory Variability Index remained associated with an elevated Apnea Hypopnea Index.
Increased ventilatory variability may be a useful phenotype in characterizing obstructive sleep apnea.
Sleep apnea syndromes; sleep disordered breathing; polysomnography; apnea
DNA methylation is an indispensible epigenetic modification of mammalian genomes. Consequently there is great interest in strategies for genome-wide/whole-genome DNA methylation analysis, and immunoprecipitation-based methods have proven to be a powerful option. Such methods are rapidly shifting the bottleneck from data generation to data analysis, necessitating the development of better analytical tools. Until now, a major analytical difficulty associated with immunoprecipitation-based DNA methylation profiling has been the inability to estimate absolute methylation levels. Here we report the development of a novel cross-platform algorithm – Bayesian Tool for Methylation Analysis (Batman) – for analyzing Methylated DNA Immunoprecipitation (MeDIP) profiles generated using arrays (MeDIP-chip) or next-generation sequencing (MeDIP-seq). The latter is an approach we have developed to elucidate the first high-resolution whole-genome DNA methylation profile (DNA methylome) of any mammalian genome. MeDIP-seq/MeDIP-chip combined with Batman represent robust, quantitative, and cost-effective functional genomic strategies for elucidating the function of DNA methylation.
Rationale: Metabolic syndrome (MetS) affects 4 to 10% of adolescents. Risk factors include overweight, male sex, and Hispanic ethnicity. Although sleep-disordered breathing (SDB) has been implicated as a risk factor for MetS in adults, its association with SDB in adolescents is unknown.
Objectives: To define the association of SDB with MetS in adolescents.
Methods: Standardized measurements of SDB, anthropometry and bioassays, were made in 270 adolescents, aged 13.6 ± 0.7 years. MetS was identified if threshold levels were exceeded in three of five areas: waist circumference, blood pressure, triglyceride level, high-density lipoprotein cholesterol level, and glucose levels.
Measurements and Main Results: Although 70% of children with SDB (apnea–hypopnea index ⩾ 5) were overweight and 59% had MetS, 16% of children without SDB had MetS. Twenty-five percent of those with MetS had SDB. After adjusting for age, race, sex, and preterm status, children with SDB had a 6.49 (95% confidence interval, 2.52, 16.70) increased odds of MetS compared with children without SDB. Indices of SDB stress associated with MetS included respiratory event frequency, degree of oxygen desaturation, and sleep efficiency. Analyses of individual metabolic parameters showed that, after adjustment for body mass index, SDB was associated with systolic and diastolic blood pressure, low-density lipoprotein cholesterol, and fasting insulin levels.
Conclusions: A majority of adolescents with SDB are overweight and meet criteria for MetS. The close association between MetS and SDB and their putative interacting pathophysiologies suggests a need to develop screening, prevention, and treatment strategies for both disorders in high-risk, overweight adolescents.
sleep apnea; metabolic syndrome; obesity
To prospectively determine if pulsed arterial spin-labeling perfusion magnetic resonance (MR) imaging depicts regional cerebral hypoperfusion in subjects with Alzheimer disease (AD) and mild cognitive impairment (MCI), compared with perfusion in cognitively normal (CN) subjects, that is consistent with results of fluorodeoxyglucose (FDG) positron emission tomography (PET) and hexamethyl-propyleneamine oxime (HMPAO) single photon emission computed tomography (SPECT) studies of similar populations.
MATERIALS AND METHODS
Institutional review board approval and informed consent were obtained. Twenty subjects with AD (13 men, seven women; mean age, 72.9 years), 18 with MCI (nine men, nine women; mean age, 73.3 years), and 23 CN subjects (10 men, 13 women; mean age, 72.9 years) underwent arterial spin-labeling and volumetric T1-weighted structural MR imaging. Perfusion images were coregistered to structural images, corrected for partial volume effects (PVEs) with information from the structural image to determine tissue content of perfusion voxels, and normalized to a study-specific template. Analyses of perfusion differences between groups, with and without corrections for PVEs, were performed on a voxel-by-voxel basis with a one-tailed fixed-effects analysis of covariance model adjusted for age. In addition, tests were performed with and without accounting for global perfusion.
The AD group showed significant regional hypoperfusion, compared with the CN group, in the right inferior parietal cortex extending into the bilateral posterior cingulate gyri (P < .001), bilateral superior and middle frontal gyri (P < .001), and left inferior parietal lobe (P = .007). When PVEs from underlying cortical gray matter atrophy were accounted for, the AD group still showed hypoperfusion in the right inferior parietal lobe extending into the bilateral posterior cingulate gyri (P < .001) and left (P = .003) and right (P = .012) middle frontal gyri. With a more liberal voxel-level threshold of P < .01, the MCI group showed significant regional hypoperfusion relative to the CN group in the inferior right parietal lobe (P = .046), similar to the region of greatest significance in the AD group.
Arterial spin-labeling MR imaging showed regional hypoperfusion with AD, in brain regions similar to those seen in FDG PET and HMPAO SPECT studies of similar populations; this hypoperfusion persists after accounting for underlying cortical gray matter atrophy.
The immunosuppressive agent cyclosporin A (CsA), a calcineurin inhibitor which blocks T cell activation has provided the pharmacologic foundation for organ transplantation. CsA exerts additional effects on non-immune cell populations and may adversely effect microvascular endothelial cells, contributing to chronic rejection, a long-term clinical complication and significant cause of mortality in solid-organ transplants, including patients with small bowel allografts. Growth of new blood vessels, or angiogenesis, is a critical homeostatic mechanism in organs and tissues, and regulates vascular populations in response to physiologic requirements. We hypothesized that CsA would inhibit the angiogenic capacity of human gut microvessels. Primary cultures of human intestinal microvascular endothelial cells (HIMEC) were used to evaluate CsA's effect on four in vitro measures of angiogenesis, including endothelial stress fiber assembly, migration, proliferation and tube formation, in response to the endothelial growth factor VEGF. We characterized the effect of CsA on intracellular signaling mechanisms following VEGF stimulation. CsA affected all VEGF induced angiogenic events assessed in HIMEC. CsA differentially inhibited signaling pathways which mediated distinct steps of the angiogenic process. CsA blocked VEGF induced nuclear translocation of the transcription factor NFAT, activation of p44/42 MAPK, and partially inhibited JNK and p38 MAPK. CsA differentially affected signaling cascades in a dose dependent fashion and completely blocked expression of COX-2, which was integrally linked to HIMEC angiogenesis. These data suggest that CsA inhibits the ability of microvascular endothelial cells to undergo angiogenesis, impairing vascular homeostatic mechanisms and contributing to the vasculopathy associated with chronic rejection.