Age-Related Brain Atrophy and the Positive Effects of Behavioral Enrichment in Middle-Aged Beagles.

Aging dogs serve as a valuable preclinical model for Alzheimer's disease (AD) due to their natural age-related development of ß-amyloid (Aß) plaques, human-like metabolism, and large brains that are ideal for studying structural brain aging trajectories from serial neuroimaging. Here we examined the effects of chronic treatment with the calcineurin inhibitor (CNI) tacrolimus or the nuclear factor of activated T cells (NFAT)-inhibiting compound Q134R on age-related canine brain atrophy from a longitudinal study in middle-aged beagles (36 females, 7 males) undergoing behavioral enrichment. Annual MRI was analyzed using modern, automated techniques for region-of-interest-based and voxel-based volumetric assessments. We found that the frontal lobe showed accelerated atrophy with age, while the caudate nucleus remained relatively stable. Remarkably, the hippocampus increased in volume in all dogs. None of these changes were influenced by tacrolimus or Q134R treatment. Our results suggest that behavioral enrichment can prevent atrophy and increase the volume of the hippocampus but does not prevent aging-associated prefrontal cortex atrophy.

Targeting Astrocyte Signaling Alleviates Cerebrovascular and Synaptic Function Deficits in a Diet-Based Mouse Model of Small Cerebral Vessel Disease.

Despite the indispensable role that astrocytes play in the neurovascular unit, few studies have investigated the functional impact of astrocyte signaling in cognitive decline and dementia related to vascular pathology. Diet-mediated induction of hyperhomocysteinemia (HHcy) recapitulates numerous features of vascular contributions to cognitive impairment and dementia (VCID). Here, we used astrocyte targeting approaches to evaluate astrocyte Ca2+ dysregulation and the impact of aberrant astrocyte signaling on cerebrovascular dysfunction and synapse impairment in male and female HHcy diet mice. Two-photon imaging conducted in fully awake mice revealed activity-dependent Ca2+ dysregulation in barrel cortex astrocytes under HHcy. Stimulation of contralateral whiskers elicited larger Ca2+ transients in individual astrocytes of HHcy diet mice compared with control diet mice. However, evoked Ca2+ signaling across astrocyte networks was impaired in HHcy mice. HHcy also was associated with increased activation of the Ca2+/calcineurin-dependent transcription factor NFAT4, which has been linked previously to the reactive astrocyte phenotype and synapse dysfunction in amyloid and brain injury models. Targeting the NFAT inhibitor VIVIT to astrocytes, using adeno-associated virus vectors, led to reduced GFAP promoter activity in HHcy diet mice and improved functional hyperemia in arterioles and capillaries. VIVIT expression in astrocytes also preserved CA1 synaptic function and improved spontaneous alternation performance on the Y maze. Together, the results demonstrate that aberrant astrocyte signaling can impair the major functional properties of the neurovascular unit (i.e., cerebral vessel regulation and synaptic regulation) and may therefore represent a promising drug target for treating VCID and possibly Alzheimer's disease and other related dementias.SIGNIFICANCE STATEMENT The impact of reactive astrocytes in Alzheimer's disease and related dementias is poorly understood. Here, we evaluated Ca2+ responses and signaling in barrel cortex astrocytes of mice fed with a B-vitamin deficient diet that induces hyperhomocysteinemia (HHcy), cerebral vessel disease, and cognitive decline. Multiphoton imaging in awake mice with HHcy revealed augmented Ca2+ responses in individual astrocytes, but impaired signaling across astrocyte networks. Stimulation-evoked arteriole dilation and elevated red blood cell velocity in capillaries were also impaired in cortex of awake HHcy mice. Astrocyte-specific inhibition of the Ca2+-dependent transcription factor, NFAT, normalized cerebrovascular function in HHcy mice, improved synaptic properties in brain slices, and stabilized cognition. Results suggest that astrocytes are a mechanism and possible therapeutic target for vascular-related dementia.

Tacrolimus Protects against Age-Associated Microstructural Changes in the Beagle Brain.

The overexpression of calcineurin leads to astrocyte hyperactivation, neuronal death, and inflammation, which are characteristics often associated with pathologic aging and Alzheimer's disease. In this study, we tested the hypothesis that tacrolimus, a calcineurin inhibitor, prevents age-associated microstructural atrophy, which we measured using higher-order diffusion MRI, in the middle-aged beagle brain (n = 30, male and female). We find that tacrolimus reduces hippocampal (p = 0.001) and parahippocampal (p = 0.002) neurite density index, as well as protects against an age-associated increase in the parahippocampal (p = 0.007) orientation dispersion index. Tacrolimus also protects against an age-related decrease in fractional anisotropy in the prefrontal cortex (p < 0.0001). We also show that these microstructural alterations precede cognitive decline and gross atrophy. These results support the idea that calcineurin inhibitors may have the potential to prevent aging-related pathology if administered at middle age.SIGNIFICANCE STATEMENT Hyperactive calcineurin signaling causes neuroinflammation and other neurobiological changes often associated with pathologic aging and Alzheimer's disease (AD). Controlling the expression of calcineurin before gross cognitive deficits are observable might serve as a promising avenue for preventing AD pathology. In this study, we show that the administration of the calcineurin inhibitor, tacrolimus, over 1 year prevents age- and AD-associated microstructural changes in the hippocampus, parahippocampal cortex, and prefrontal cortex of the middle-aged beagle brain, with no noticeable adverse effects. Tacrolimus is already approved by the Food and Drug Administration for use in humans to prevent solid organ transplant rejection, and our results bolster the promise of this drug to prevent AD and aging-related pathology.

Ironsmith: An automated pipeline for QSM-based data analyses.

Quantitative susceptibility mapping (QSM) is an MRI-based, computational method for anatomically localizing and measuring concentrations of specific biomarkers in tissue such as iron. Growing research suggests QSM is a viable method for evaluating the impact of iron overload in neurological disorders and on cognitive performance in aging. Several software toolboxes are currently available to reconstruct QSM maps from 3D GRE MR Images. However, few if any software packages currently exist that offer fully automated pipelines for QSM-based data analyses: from DICOM images to region-of-interest (ROI) based QSM values. Even less QSM-based software exist that offer quality control measures for evaluating the QSM output. Here, we address these gaps in the field by introducing and demonstrating the reliability and external validity of Ironsmith; an open-source, fully automated pipeline for creating and processing QSM maps, extracting QSM values from subcortical and cortical brain regions (89 ROIs) and evaluating the quality of QSM data using SNR measures and assessment of outlier regions on phase images. Ironsmith also features automatic filtering of QSM outlier values and precise CSF-only QSM reference masks that minimize partial volume effects. Testing of Ironsmith revealed excellent intra- and inter-rater reliability. Finally, external validity of Ironsmith was demonstrated via an anatomically selective relationship between motor performance and Ironsmith-derived QSM values in motor cortex. In sum, Ironsmith provides a freely-available, reliable, turn-key pipeline for QSM-based data analyses to support research on the impact of brain iron in aging and neurodegenerative disease.

Clinically relevant mitochondrial-targeted therapy improves chronic outcomes after traumatic brain injury.

Pioglitazone, an FDA-approved compound, has been shown to target the novel mitochondrial protein mitoNEET and produce short-term neuroprotection and functional benefits following traumatic brain injury. To expand on these findings, we now investigate the dose- and time-dependent effects of pioglitazone administration on mitochondrial function after experimental traumatic brain injury. We then hypothesize that optimal pioglitazone dosing will lead to ongoing neuroprotection and cognitive benefits that are dependent on pioglitazone-mitoNEET signalling pathways. We show that delayed intervention is significantly more effective than early intervention at improving acute mitochondrial bioenergetics in the brain after traumatic brain injury. In corroboration, we demonstrate that mitoNEET is more heavily expressed, especially near the cortical contusion, in the 18 h following traumatic brain injury. To explore whether these findings relate to ongoing pathological and behavioural outcomes, mice received controlled cortical impact followed by initiation of pioglitazone treatment at either 3 or 18 h post-injury. Mice with treatment initiation at 18 h post-injury exhibited significantly improved behaviour and tissue sparing compared to mice with pioglitazone initiated at 3 h post-injury. Further using mitoNEET knockout mice, we show that this therapeutic effect is dependent on mitoNEET. Finally, we demonstrate that delayed pioglitazone treatment improves serial motor and cognitive performance in conjunction with attenuated brain atrophy after traumatic brain injury. This study illustrates that mitoNEET is the critical target for delayed pioglitazone intervention after traumatic brain injury, mitochondrial-targeting is highly time-dependent after injury and there is an extended therapeutic window to effectively treat mitochondrial dysfunction after brain injury.

Cortical iron disrupts functional connectivity networks supporting working memory performance in older adults.

Excessive brain iron negatively affects working memory and related processes but the impact of cortical iron on task-relevant, cortical brain networks is unknown. We hypothesized that high cortical iron concentration may disrupt functional circuitry within cortical networks supporting working memory performance. Fifty-five healthy older adults completed an N-Back working memory paradigm while functional magnetic resonance imaging (fMRI) was performed. Participants also underwent quantitative susceptibility mapping (QSM) imaging for assessment of non-heme brain iron concentration. Additionally, pseudo continuous arterial spin labeling scans were obtained to control for potential contributions of cerebral blood volume and structural brain images were used to control for contributions of brain volume. Task performance was positively correlated with strength of task-based functional connectivity (tFC) between brain regions of the frontoparietal working memory network. However, higher cortical iron concentration was associated with lower tFC within this frontoparietal network and with poorer working memory performance after controlling for both cerebral blood flow and brain volume. Our results suggest that high cortical iron concentration disrupts communication within frontoparietal networks supporting working memory and is associated with reduced working memory performance in older adults.

Differential Effects of Isoproterenol on Regional Myocardial Mechanics in Rat Using Three-Dimensional Cine DENSE Cardiovascular Magnetic Resonance.

The present study assessed the acute effects of isoproterenol on left ventricular (LV) mechanics in healthy rats with the hypothesis that ß-adrenergic stimulation influences the mechanics of different myocardial regions of the LV wall in different ways. To accomplish this, magnetic resonance images were obtained in the LV of healthy rats with or without isoproterenol infusion. The LV contours were divided into basal, midventricular, and apical regions. Additionally, the midventricular myocardium was divided into three transmural layers with each layer partitioned into four segments (i.e., septal, inferior, lateral, and anterior). Peak systolic strains and torsion were quantified for each region. Isoproterenol significantly increased peak systolic radial strain and circumferential-longitudinal (CL) shear strain, as well as ventricular torsion, throughout the basal, midventricle, and apical regions. In the midventricle, isoproterenol significantly increased peak systolic radial strain, and induced significant increases in peak systolic circumferential strain and longitudinal strain in the septum. Isoproterenol consistently increased peak systolic CL shear strain in all midventricular segments. Ventricular torsion was significantly increased in nearly all segments except the inferior subendocardium. The effects of isoproterenol on LV systolic mechanics (i.e., three-dimensional (3D) strains and torsion) in healthy rats depend on the region. This region dependency is also strain component-specific. These results provide insight into the regional response of LV mechanics to ß-adrenergic stimulation in rats and could act as a baseline for future studies on subclinical abnormalities associated with the inotropic response in heart disease.

Regional quantification of myocardial mechanics in rat using 3D cine DENSE cardiovascular magnetic resonance.

Rat models have assumed an increasingly important role in cardiac research. However, a detailed profile of regional cardiac mechanics, such as strains and torsion, is lacking for rats. We hypothesized that healthy rat left ventricles (LVs) exhibit regional differences in cardiac mechanics, which are part of normal function. In this study, images of the LV were obtained with 3D cine displacement encoding with stimulated echoes (DENSE) cardiovascular magnetic resonance in 10 healthy rats. To evaluate regional cardiac mechanics, the LV was divided into basal, mid-ventricular, and apical regions. The myocardium at the mid-LV was further partitioned into four wall segments (i.e. septal, inferior, lateral, and anterior) and three transmural layers (i.e. sub-endocardium, mid-myocardium, and sub-epicardium). The six Lagrangian strain components (i.e. Err , Ecc , Ell , Ecl , Erl , and Ecr ) were computed from the 3D displacement field and averaged within each region of interest. Torsion was quantified using the circumferential-longitudinal shear angle. While peak systolic Ecl differed between the mid-ventricle and apex, the other five components of peak systolic strain were similar across the base, mid-ventricle, and apex. In the mid-LV myocardium, Ecc decreased gradually from the sub-endocardial to the sub-epicardial layer. Ell demonstrated significant differences between the four wall segments, with the largest magnitude in the inferior segment. Err was uniform among the four wall segments. Ecl varied along the transmural direction and among wall segments, whereas Erl differed only among the wall segments. Erc was not associated with significant variations. Torsion also varied along the transmural direction and among wall segments. These results provide fundamental insights into the regional contractile function of healthy rat hearts, and form the foundation for future studies on regional changes induced by disease or treatments.

Optimal configuration of respiratory navigator gating for the quantification of left ventricular strain using spiral cine displacement encoding with stimulated echoes (DENSE) MRI.

PURPOSE: To determine the optimal respiratory navigator gating configuration for the quantification of left ventricular strain using spiral cine displacement encoding with stimulated echoes (DENSE) MRI. MATERIALS AND METHODS: Two-dimensional spiral cine DENSE was performed on a 3 Tesla MRI using two single-navigator configurations (retrospective, prospective) and a combined "dual-navigator" configuration in 10 healthy adults and 20 healthy children. The adults also underwent breathhold DENSE as a reference standard for comparisons. Peak left ventricular strains, signal-to-noise ratio (SNR), and navigator efficiency were compared. Subjects also underwent dual-navigator gating with and without visual feedback to determine the effect on navigator efficiency. RESULTS: There were no differences in circumferential, radial, and longitudinal strains between navigator-gated and breathhold DENSE (P = 0.09-0.95) (as confidence intervals, retrospective: [-1.0%-1.1%], [-7.4%-2.0%], [-1.0%-1.2%]; prospective: [-0.6%-2.7%], [-2.8%-8.3%], [-0.3%-2.9%]; dual: [-1.6%-0.5%], [-8.3%-3.2%], [-0.8%-1.9%], respectively). The dual configuration maintained SNR compared with breathhold acquisitions (16 versus 18, P = 0.06). SNR for the prospective configuration was lower than for the dual navigator in adults (P = 0.004) and children (P < 0.001). Navigator efficiency was higher (P < 0.001) for both retrospective (54%) and prospective (56%) configurations compared with the dual configuration (35%). Visual feedback improved the dual configuration navigator efficiency to 55% (P < 0.001). CONCLUSION: When quantifying left ventricular strains using spiral cine DENSE MRI, a dual navigator configuration results in the highest SNR in adults and children. In adults, a retrospective configuration has good navigator efficiency without a substantial drop in SNR. Prospective gating should be avoided because it has the lowest SNR. Visual feedback represents an effective option to maintain navigator efficiency while using a dual navigator configuration. LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:786-794.

Using a respiratory navigator significantly reduces variability when quantifying left ventricular torsion with cardiovascular magnetic resonance.

BACKGROUND: Left ventricular (LV) torsion is an important indicator of cardiac function that is limited by high inter-test variability (50% of the mean value). We hypothesized that this high inter-test variability is partly due to inconsistent breath-hold positions during serial image acquisitions, which could be significantly improved by using a respiratory navigator for cardiovascular magnetic resonance (CMR) based quantification of LV torsion. METHODS: We assessed respiratory-related variability in measured LV torsion with two distinct experimental protocols. First, 17 volunteers were recruited for CMR with cine displacement encoding with stimulated echoes (DENSE) in which a respiratory navigator was used to measure and then enforce variability in end-expiratory position between all LV basal and apical acquisitions. From these data, we quantified the inter-test variability of torsion in the absence and presence of enforced end-expiratory position variability, which established an upper bound for the expected torsion variability. For the second experiment (in 20 new, healthy volunteers), 10 pairs of cine DENSE basal and apical images were each acquired from consecutive breath-holds and consecutive navigator-gated scans (with a single acceptance position). Inter-test variability of torsion was compared between the breath-hold and navigator-gated scans to quantify the variability due to natural breath-hold variation. To demonstrate the importance of these variability reductions, we quantified the reduction in sample size required to detect a clinically meaningful change in LV torsion with the use of a respiratory navigator. RESULTS: The mean torsion was 3.4 ± 0.2°/cm. From the first experiment, enforced variability in end-expiratory position translated to considerable variability in measured torsion (0.56 ± 0.34°/cm), whereas inter-test variability with consistent end-expiratory position was 57% lower (0.24 ± 0.16°/cm, p < 0.001). From the second experiment, natural respiratory variability from consecutive breath-holds translated to a variability in torsion of 0.24 ± 0.10°/cm, which was significantly higher than the variability from navigator-gated scans (0.18 ± 0.06°/cm, p = 0.02). By using a respiratory navigator with DENSE, theoretical sample sizes were reduced from 66 to 16 and 26 to 15 as calculated from the two experiments. CONCLUSIONS: A substantial portion (22-57%) of the inter-test variability of LV torsion can be reduced by using a respiratory navigator to ensure a consistent breath-hold position between image acquisitions.

Cerebral amyloid angiopathy in Down syndrome and sporadic and autosomal-dominant Alzheimer's disease.

INTRODUCTION: We aimed to investigate if cerebral amyloid angiopathy (CAA) is more frequent in genetically determined than in sporadic early-onset forms of Alzheimer's disease (AD) (early-onset AD [EOAD]). METHODS: Neuroimaging features of CAA, apolipoprotein (APOE), and cerebrospinal fluid amyloid ß (Aß) 40 levels were studied in subjects with Down syndrome (DS, n = 117), autosomal-dominant AD (ADAD, n = 29), sporadic EOAD (n = 42), and healthy controls (n = 68). RESULTS: CAA was present in 31%, 38%, and 12% of cognitively impaired DS, symptomatic ADAD, and sporadic EOAD subjects and in 13% and 4% of cognitively unimpaired DS individuals and healthy controls, respectively. APOE ε4 genotype was borderline significantly associated with CAA in sporadic EOAD (P = .06) but not with DS or ADAD. There were no differences in Aß040 levels between groups or between subjects with and without CAA. DISCUSSION: CAA is more frequently found in genetically determined AD than in sporadic EOAD. Cerebrospinal fluid Aß40 levels are not a useful biomarker for CAA in AD.

White Matter Hyperintensity Associations with Cerebral Blood Flow in Elderly Subjects Stratified by Cerebrovascular Risk.

OBJECTIVE: This study aims to add clarity to the relationship between deep and periventricular brain white matter hyperintensities (WMHs), cerebral blood flow (CBF), and cerebrovascular risk in older persons. METHODS: Deep white matter hyperintensity (dWMH) and periventricular white matter hyperintensity (pWMH) and regional gray matter (GM) and white matter (WM) blood flow from arterial spin labeling were quantified from magnetic resonance imaging scans of 26 cognitively normal elderly subjects stratified by cerebrovascular disease (CVD) risk. Fluid-attenuated inversion recovery images were acquired using a high-resolution 3-dimensional (3-D) sequence that reduced partial volume effects seen with slice-based techniques. RESULTS: dWMHs but not pWMHs were increased in patients at high risk of CVD; pWMHs but not dWMHs were associated with decreased regional cortical (GM) blood flow. We also found that blood flow in WM is decreased in regions of both pWMH and dWMH, with a greater degree of decrease in pWMH areas. CONCLUSIONS: WMHs are usefully divided into dWMH and pWMH regions because they demonstrate differential effects. 3-D regional WMH volume is a potentially valuable marker for CVD based on associations with cortical CBF and WM CBF.

How do negative emotions impair self-control? A neural model of negative urgency.

Self-control often fails when people experience negative emotions. Negative urgency represents the dispositional tendency to experience such self-control failure in response to negative affect. Neither the neural underpinnings of negative urgency nor the more general phenomenon of self-control failure in response to negative emotions are fully understood. Previous theorizing suggests that an insufficient, inhibitory response from the prefrontal cortex may be the culprit behind such self-control failure. However, we entertained an alternative hypothesis: negative emotions lead to self-control failure because they excessively tax inhibitory regions of the prefrontal cortex. Using fMRI, we compared the neural activity of people high in negative urgency with controls on an emotional, inhibitory Go/No-Go task. While experiencing negative (but not positive or neutral) emotions, participants high in negative urgency showed greater recruitment of inhibitory brain regions than controls. Suggesting a compensatory function, inhibitory accuracy among participants high in negative urgency was associated with greater prefrontal recruitment. Greater activity in the anterior insula on negatively-valenced, inhibitory trials predicted greater substance abuse one month and one year after the MRI scan among individuals high in negative urgency. These results suggest that, among people whose negative emotions often lead to self-control failure, excessive reactivity of the brain's regulatory resources may be the culprit.

Cardiorespiratory fitness modifies the relationship between myocardial function and cerebral blood flow in older adults.

A growing body of evidence indicates that cardiorespiratory fitness attenuates some age-related cerebral declines. However, little is known about the role that myocardial function plays in this relationship. Brain regions with high resting metabolic rates, such as the default mode network (DMN), may be especially vulnerable to age-related declines in myocardial functions affecting cerebral blood flow (CBF). This study explored the relationship between a measure of myocardial mechanics, global longitudinal strain (GLS), and CBF to the DMN. In addition, we explored how cardiorespiratory affects this relationship. Participants were 30 older adults between the ages of 59 and 69 (mean age=63.73years, SD=2.8). Results indicated that superior cardiorespiratory fitness and myocardial mechanics were positively associated with DMN CBF. Moreover, results of a mediation analysis revealed that the relationship between GLS and DMN CBF was accounted for by individual differences in fitness. Findings suggest that benefits of healthy heart function to brain function are modified by fitness.

Advanced cardiac chemical exchange saturation transfer (cardioCEST) MRI for in vivo cell tracking and metabolic imaging.

An improved pre-clinical cardiac chemical exchange saturation transfer (CEST) pulse sequence (cardioCEST) was used to selectively visualize paramagnetic CEST (paraCEST)-labeled cells following intramyocardial implantation. In addition, cardioCEST was used to examine the effect of diet-induced obesity upon myocardial creatine CEST contrast. CEST pulse sequences were designed from standard turbo-spin-echo and gradient-echo sequences, and a cardiorespiratory-gated steady-state cine gradient-echo sequence. In vitro validation studies performed in phantoms composed of 20 mM Eu-HPDO3A, 20 mM Yb-HPDO3A, or saline demonstrated similar CEST contrast by spin-echo and gradient-echo pulse sequences. Skeletal myoblast cells (C2C12) were labeled with either Eu-HPDO3A or saline using a hypotonic swelling procedure and implanted into the myocardium of C57B6/J mice. Inductively coupled plasma mass spectrometry confirmed cellular levels of Eu of 2.1 × 10(-3) ng/cell in Eu-HPDO3A-labeled cells and 2.3 × 10(-5) ng/cell in saline-labeled cells. In vivo cardioCEST imaging of labeled cells at ±15 ppm was performed 24 h after implantation and revealed significantly elevated asymmetric magnetization transfer ratio values in regions of Eu-HPDO3A-labeled cells when compared with surrounding myocardium or saline-labeled cells. We further utilized the cardioCEST pulse sequence to examine changes in myocardial creatine in response to diet-induced obesity by acquiring pairs of cardioCEST images at ±1.8 ppm. While ventricular geometry and function were unchanged between mice fed either a high-fat diet or a corresponding control low-fat diet for 14 weeks, myocardial creatine CEST contrast was significantly reduced in mice fed the high-fat diet. The selective visualization of paraCEST-labeled cells using cardioCEST imaging can enable investigation of cell fate processes in cardioregenerative medicine, or multiplex imaging of cell survival with imaging of cardiac structure and function and additional imaging of myocardial creatine.

Cardiac remodeling and dysfunction in childhood obesity: a cardiovascular magnetic resonance study.

BACKGROUND: Obesity affects nearly one in five children and is associated with increased risk of premature death. Obesity-related heart disease contributes to premature death. We aimed to use cardiovascular magnetic resonance (CMR) to comprehensively characterize the changes in cardiac geometry and function in obese children. METHODS AND RESULTS: Forty-one obese/overweight (age 12 ± 3 years, 56 % female) and 29 healthy weight children (age 14 ± 3 years, 41 % female) underwent CMR, including both standard cine imaging and displacement encoded imaging, for a complete assessment of left ventricular (LV) structure and function. After adjusting for age, LV mass index was 23 % greater (27 ± 4 g/m(2.7) vs 22 ± 3 g/m(2.7), p <0.001) and the LV myocardium was 10 % thicker (5.6 ± 0.8 mm vs 5.1 ± 0.8 mm, p <0.001) in the obese/overweight children. This evidence of cardiac remodeling was present in obese children as young as age 8. Twenty four percent of obese/overweight children had concentric hypertrophy, 59 % had normal geometry and 17 % had either eccentric hypertrophy or concentric remodeling. LV mass index, thickness, ejection fraction and peak longitudinal and circumferential strains all correlated with epicardial adipose tissue after adjusting for height and gender (all p <0.05). Peak longitudinal and circumferential strains showed a significant relationship with the type of LV remodeling, and were most impaired in children with concentric hypertrophy (p <0.001 and p = 0.003, respectively). CONCLUSIONS: Obese children show evidence of significant cardiac remodeling and dysfunction, which begins as young as age 8. Obese children with concentric hypertrophy and impaired strain may represent a particularly high risk subgroup that demands further investigation.

An interactive videogame designed to improve respiratory navigator efficiency in children undergoing cardiovascular magnetic resonance.

BACKGROUND: Advanced cardiovascular magnetic resonance (CMR) acquisitions often require long scan durations that necessitate respiratory navigator gating. The tradeoff of navigator gating is reduced scan efficiency, particularly when the patient's breathing patterns are inconsistent, as is commonly seen in children. We hypothesized that engaging pediatric participants with a navigator-controlled videogame to help control breathing patterns would improve navigator efficiency and maintain image quality. METHODS: We developed custom software that processed the Siemens respiratory navigator image in real-time during CMR and represented diaphragm position using a cartoon avatar, which was projected to the participant in the scanner as visual feedback. The game incentivized children to breathe such that the avatar was positioned within the navigator acceptance window (±3 mm) throughout image acquisition. Using a 3T Siemens Tim Trio, 50 children (Age: 14 ± 3 years, 48 % female) with no significant past medical history underwent a respiratory navigator-gated 2D spiral cine displacement encoding with stimulated echoes (DENSE) CMR acquisition first with no feedback (NF) and then with the feedback game (FG). Thirty of the 50 children were randomized to undergo extensive off-scanner training with the FG using a MRI simulator, or no off-scanner training. Navigator efficiency, signal-to-noise ratio (SNR), and global left-ventricular strains were determined for each participant and compared. RESULTS: Using the FG improved average navigator efficiency from 33 ± 15 to 58 ± 13 % (p < 0.001) and improved SNR by 5 % (p = 0.01) compared to acquisitions with NF. There was no difference in navigator efficiency (p = 0.90) or SNR (p = 0.77) between untrained and trained participants for FG acquisitions. Circumferential and radial strains derived from FG acquisitions were slightly reduced compared to NF acquisitions (-16 ± 2 % vs -17 ± 2 %, p < 0.001; 40 ± 10 % vs 44 ± 11 %, p = 0.005, respectively). There were no differences in longitudinal strain (p = 0.38). CONCLUSIONS: Use of a respiratory navigator feedback game during navigator-gated CMR improved navigator efficiency in children from 33 to 58 %. This improved efficiency was associated with a 5 % increase in SNR for spiral cine DENSE. Extensive off-scanner training was not required to achieve the improvement in navigator efficiency.

Left ventricular mechanical dysfunction in diet-induced obese mice is exacerbated during inotropic stress: a cine DENSE cardiovascular magnetic resonance study.

BACKGROUND: Obesity is a risk factor for cardiovascular disease. There is evidence of impaired left ventricular (LV) function associated with obesity, which may relate to cardiovascular mortality, but some studies have reported no dysfunction. Ventricular function data are generally acquired under resting conditions, which could mask subtle differences and potentially contribute to these contradictory findings. Furthermore, abnormal ventricular mechanics (strains, strain rates, and torsion) may manifest prior to global changes in cardiac function (i.e., ejection fraction) and may therefore represent more sensitive markers of cardiovascular disease. This study evaluated LV mechanics under both resting and stress conditions with the hypothesis that the LV mechanical dysfunction associated with obesity is exacerbated with stress and manifested at earlier stages of disease compared to baseline. METHODS: C57BL/6J mice were randomized to a high-fat or control diet (60 %, 10 % kcal from fat, respectively) for varying time intervals (n = 7 - 10 subjects per group per time point, 100 total; 4 - 55 weeks on diet). LV mechanics were quantified under baseline (resting) and/or stress conditions (40 µg/kg/min continuous infusion of dobutamine) using cine displacement encoding with stimulated echoes (DENSE) with 7.4 ms temporal resolution on a 7 T Bruker ClinScan. Peak strain, systolic strain rates, and torsion were quantified. A linear mixed model was used with Benjamini-Hochberg adjustments for multiple comparisons. RESULTS: Reductions in LV peak longitudinal strain at baseline were first observed in the obese group after 42 weeks, with no differences in systolic strain rates or torsion. Conversely, reductions in longitudinal strain and circumferential and radial strain rates were seen under inotropic stress conditions after only 22 weeks on diet. Furthermore, stress cardiovascular magnetic resonance (CMR) evaluation revealed supranormal values of LV radial strain and torsion in the obese group early on diet, followed by later deficits. CONCLUSIONS: Differences in left ventricular mechanics in obese mice are exacerbated under stress conditions. Stress CMR demonstrated a broader array of mechanical dysfunction and revealed these differences at earlier time points. Thus, it may be important to evaluate cardiac function in the setting of obesity under stress conditions to fully elucidate the presence of ventricular dysfunction.

2D cine DENSE with low encoding frequencies accurately quantifies cardiac mechanics with improved image characteristics.

BACKGROUND: Displacement Encoding with Stimulated Echoes (DENSE) encodes displacement into the phase of the magnetic resonance signal. The encoding frequency (ke) maps the measured phase to tissue displacement while the strength of the encoding gradients affects image quality. 2D cine DENSE studies have used a ke of 0.10 cycles/mm, which is high enough to remove an artifact-generating echo from k-space, provide high sensitivity to tissue displacements, and dephase the blood pool. However, through-plane dephasing can remove the unwanted echo and dephase the blood pool without relying on high ke. Additionally, the high sensitivity comes with the costs of increased phase wrapping and intra-voxel dephasing. We hypothesized that ke below 0.10 cycles/mm can be used to improve image characteristics and provide accurate measures of cardiac mechanics. METHODS: Spiral cine DENSE images were obtained for 10 healthy subjects and 10 patients with a history of heart disease on a 3 T Siemens Trio. A mid-ventricular short-axis image was acquired with different ke: 0.02, 0.04, 0.06, 0.08, and 0.10 cycles/mm. Peak twist, circumferential strain, and radial strain were compared between acquisitions employing different ke using Bland-Altman analyses and coefficients of variation. The percentage of wrapped pixels in the phase images at end-systole was calculated for each ke. The dephasing of the blood signal and signal to noise ratio (SNR) were also calculated and compared. RESULTS: Negligible differences were seen in strains and twist for all ke between 0.04 and 0.10 cycles/mm. These differences were of the same magnitude as inter-test differences. Specifically, the acquisitions with 0.04 cycles/mm accurately quantified cardiac mechanics and had zero phase wrapping. Compared to 0.10 cycles/mm, the acquisitions with 0.04 cycles/mm had 9 % greater SNR and negligible differences in blood pool dephasing. CONCLUSIONS: For 2D cine DENSE with through-plane dephasing, the encoding frequency can be lowered to 0.04 cycles/mm without compromising the quantification of twist or strain. The amount of wrapping can be reduced with this lower value to greatly simplify the input to unwrapping algorithms. The strain and twist results from studies using different encoding frequencies can be directly compared.

Validation of in vivo 2D displacements from spiral cine DENSE at 3T.

BACKGROUND: Displacement Encoding with Stimulated Echoes (DENSE) encodes displacement into the phase of the magnetic resonance signal. Due to the stimulated echo, the signal is inherently low and fades through the cardiac cycle. To compensate, a spiral acquisition has been used at 1.5T. This spiral sequence has not been validated at 3T, where the increased signal would be valuable, but field inhomogeneities may result in measurement errors. We hypothesized that spiral cine DENSE is valid at 3T and tested this hypothesis by measuring displacement errors at both 1.5T and 3T in vivo. METHODS: Two-dimensional spiral cine DENSE and tagged imaging of the left ventricle were performed on ten healthy subjects at 3T and six healthy subjects at 1.5T. Intersection points were identified on tagged images near end-systole. Displacements from the DENSE images were used to project those points back to their origins. The deviation from a perfect grid was used as a measure of accuracy and quantified as root-mean-squared error. This measure was compared between 3T and 1.5T with the Wilcoxon rank sum test. Inter-observer variability of strains and torsion quantified by DENSE and agreement between DENSE and harmonic phase (HARP) were assessed by Bland-Altman analyses. The signal to noise ratio (SNR) at each cardiac phase was compared between 3T and 1.5T with the Wilcoxon rank sum test. RESULTS: The displacement accuracy of spiral cine DENSE was not different between 3T and 1.5T (1.2 ± 0.3 mm and 1.2 ± 0.4 mm, respectively). Both values were lower than the DENSE pixel spacing of 2.8 mm. There were no substantial differences in inter-observer variability of DENSE or agreement of DENSE and HARP between 3T and 1.5T. Relative to 1.5T, the SNR at 3T was greater by a factor of 1.4 ± 0.3. CONCLUSIONS: The spiral cine DENSE acquisition that has been used at 1.5T to measure cardiac displacements can be applied at 3T with equivalent accuracy. The inter-observer variability and agreement of DENSE-derived peak strains and torsion with HARP is also comparable at both field strengths. Future studies with spiral cine DENSE may take advantage of the additional SNR at 3T.