Serial Cardiac Magnetic Resonance Imaging in Patients with Mitral Valve Prolapse-A Single-Center Retrospective Registry.

Background: Mitral valve prolapse (MVP) and mitral annular disjunction (MAD) are common valvular abnormalities that have been associated with ventricular arrhythmias (VA). Cardiac magnetic resonance imaging (CMR) has a key role in risk stratification of VA, including assessment of late gadolinium enhancement (LGE). Methods: Single-center retrospective analysis of patients with MVP or MAD who had >1 CMR and >1 24 h Holter registration available. Data are presented in detail, including evolution of VA and presence of LGE over time. Results: A total of twelve patients had repeated CMR and Holter registrations available, of which in four (33%) patients, it was conducted before and after minimal invasive mitral valve repair (MVR). After a median of 4.7 years, four out of eight (50%) patients without surgical intervention had new areas of LGE. New LGE was observed in the papillary muscles and the mid to basal inferolateral wall. In four patients, presenting with syncope or high-risk non-sustained ventricular tachycardia (VT), programmed ventricular stimulation was performed and in two (50%), sustained monomorphic VT was easily inducible. In two patients who underwent MVR, new LGE was observed in the basal inferolateral wall of which one presented with an increased burden of VA. Conclusions: In patients with MVP and MAD, repeat CMR may show new LGE in a small subset of patients, even shortly after MVR. A subgroup of patients who presented with an increase in VA burden showed new LGE upon repeat CMR. VA in patients with MVP and MAD are part of a heterogeneous spectrum that requires further investigation to establish risk stratification strategies.

Radiomics-based detection of acute myocardial infarction on noncontrast enhanced midventricular short-axis cine CMR images.

Cardiac magnetic resonance cine images are primarily used to evaluate functional consequences, whereas limited information is extracted from the noncontrast pixel-wise myocardial signal intensity pattern. In this study we want to assess whether characterizing this inherent contrast pattern of noncontrast-enhanced short axis (SAX) cine images via radiomics is sufficient to distinguish subjects with acute myocardial infarction (AMI) from controls. Cine balanced steady-state free-precession images acquired at 1.5 T from 99 AMI and 49 control patients were included. First, radiomic feature extraction of the left ventricular myocardium of end-diastolic (ED) and end-systolic (ES) frames was performed based on automated (AUTO) or manually corrected (MAN) segmentations. Next, top features were selected based on optimal classification results using a support vector machine (SVM) approach. The classification performances of the four radiomics models (using AUTO or MAN segmented ED or ES images), were measured by AUC, classification accuracy (CA), F1-score, sensitivity and specificity. The most accurate model was found when combining the features RunLengthNonUniformity, ClusterShade and Median obtained from the manually segmented ES images (CA = 0.846, F1 score = 0.847). ED analysis performed worse than ES, with lower CA and F1 scores (0.769 and 0.770, respectively). Manual correction of automated contours resulted in similar model features as the automated segmentations and did not improve classification results. A radiomics analysis can capture the inherent contrast in noncontrast mid-ventricular SAX cine images to distinguishing AMI from healthy subjects. The ES radiomics model was more accurate than the ED model. Manual correction of the autosegmentation did not provide significant classification improvements.

Use of Real-Time Cine MRI to Assess the Respirophasic Variation of the Inferior Vena Cava-Proof-of-Concept and Validation Against Transthoracic Echocardiography.

BACKGROUND: In clinical practice, the right heart filling status is assessed using the respirophasic variation of the inferior vena cava (IVC) assessed by transthoracic echocardiography (TTE) showing moderate correlations with the catheter-based reference standard. PURPOSE: To develop and validate a similar approach using MRI. STUDY TYPE: Prospective. POPULATION: 37 male elite cyclists (mean age 26 ± 4 years). FIELD STRENGTH/SEQUENCE: Real-time balanced steady-state free-precession cine sequence at 1.5 Tesla. ASSESSMENT: Respirophasic variation included assessment of expiratory size of the upper hepatic part of the IVC and degree of inspiratory collapse expressed as collapsibility index (CI). The IVC was studied either in long-axis direction (TTE) or using two transverse slices, separated by 30 mm (MRI) during operator-guided deep breathing. For MRI, in addition to the TTE-like diameter, IVC area and major and minor axis diameters were also assessed, together with the corresponding CIs. STATISTICAL TESTS: Repeated measures ANOVA test with Bonferroni correction. Intraclass correlation coefficient (ICC) and Bland-Altman analysis for intrareader and inter-reader agreement. A P value <0.05 was considered statistically significant. RESULTS: No significant differences in expiratory IVC diameter were found between TTE and MRI, i.e., 25 ± 4 mm vs. 25 ± 3 mm (P = 0.242), but MRI showed a higher CI, i.e., 76% ± 14% vs. 66% ± 14% (P < 0.05). As the IVC presented a noncircular shape, i.e., major and minor expiratory diameter of 28 ± 4 mm and 21 ± 4 mm, respectively, the CI varied according to the orientation, i.e., 63% ± 27% vs. 75% ± 16%, respectively. Alternatively, expiratory IVC area was 4.3 ± 1.1 cm2 and showed a significantly higher CI, i.e., 86% ± 14% than diameter-based CI (P < 0.05). All participants showed a CI >50% with MRI versus 35/37 (94%) with TTE. ICC values ranged 0.546-0.841 for MRI and 0.545-0.704 for TTE. CONCLUSION: Assessment of the respirophasic IVC variation is feasible with MRI. Adding this biomarker may be of particular use in evaluating heart failure patients. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

Effectiveness of the risk stratification proposed by the 2022 European Heart Rhythm Association Expert Consensus statement on arrhythmic mitral valve prolapse.

BACKGROUND: Recently, an expert consensus statement proposed indications where implantation of a primary prevention implantable cardioverter-defibrillator (ICD) may be reasonable in patients with mitral valve prolapse (MVP). The objective was to evaluate the proposed risk stratification by the expert consensus statement. METHODS: Consecutive patients with MVP without alternative arrhythmic substrates with cardiac magnetic resonance imaging (CMR) were included in a single-center retrospective registry. Arrhythmic MVP (AMVP) was defined as a total premature ventricular complex burden ≥5%, non-sustained ventricular tachycardia (VT), VT, or ventricular fibrillation. The end point was a composite of SCD, VT, inducible VT, and appropriate ICD shocks. RESULTS: In total, 169 patients (52.1% male, median age 51.4 years) were included and 99 (58.6%) were classified as AMVP. Multivariate logistic regression identified the presence of late gadolinium enhancement (OR 2.82, 95%CI 1.45-5.50) and mitral annular disjunction (OR 1.98, 95%CI 1.02-3.86) as only predictors of AMVP. According to the EHRA risk stratification, 5 patients with AMVP (5.1%) had a secondary prevention ICD indication, while in 69 patients (69.7%) the implantation of an ICD may be reasonable. During a median follow-up of 8.0 years (IQR 5.0-15.6), the incidence rate for the composite arrhythmic end point was 0.3%/year (95%CI 0.1-0.8). CONCLUSION: More than half of MVP patients referred for CMR met the AMVP diagnostic criteria. Despite low long-term event rates, in 70% of patients with AMVP the implantation of an ICD may be reasonable. Risk stratification of SCD in MVP remains an important knowledge gap and requires urgent investigation.

Exercise-induced myocardial T1 increase and right ventricular dysfunction in recreational cyclists: a CMR study.

PURPOSE: Although cardiac troponin I (cTnI) increase following strenuous exercise has been observed, the development of exercise-induced myocardial edema remains unclear. Cardiac magnetic resonance (CMR) native T1/T2 mapping is sensitive to the pathological increase of myocardial water content. Therefore, we evaluated exercise-induced acute myocardial changes in recreational cyclists by incorporating biomarkers, echocardiography and CMR. METHODS: Nineteen male recreational participants (age: 48 ± 5 years) cycled the 'L'étape du tour de France" (EDT) 2021' (175 km, 3600 altimeters). One week before the race, a maximal graded cycling test was conducted to determine individual heart rate (HR) training zones. One day before and 3-6 h post-exercise 3 T CMR and echocardiography were performed to assess myocardial native T1/T2 relaxation times and cardiac function, and blood samples were collected. All participants were asked to cycle 2 h around their anaerobic gas exchange threshold (HR zone 4). RESULTS: Eighteen participants completed the EDT stage in 537 ± 58 min, including 154 ± 61 min of cycling time in HR zone 4. Post-race right ventricular (RV) dysfunction with reduced strain and increased volumes (p < 0.05) and borderline significant left ventricular global longitudinal strain reduction (p = 0.05) were observed. Post-exercise cTnI (0.75 ± 5.1 ng/l to 69.9 ± 41.6 ng/l; p < 0.001) and T1 relaxation times (1133 ± 48 ms to 1182 ± 46 ms, p < 0.001) increased significantly with no significant change in T2 (p = 0.474). cTnI release correlated with increase in T1 relaxation time (p = 0.002; r = 0.703), post-race RV dysfunction (p < 0.05; r = 0.562) and longer cycling in HR zone 4 (p < 0.05; r = 0.607). CONCLUSION: Strenuous exercise causes early post-race cTnI increase, increased T1 relaxation time and RV dysfunction in recreational cyclists, which showed interdependent correlation. The long-term clinical significance of these changes needs further investigation. TRIAL REGISTRATION NUMBERS AND DATE: NCT04940650 06/18/2021. NCT05138003 06/18/2021.

Apical papillary muscle displacement is a prevalent feature and a phenotypic precursor of apical hypertrophic cardiomyopathy.

AIMS: Papillary muscle (PM) abnormalities are considered part of the phenotypic spectrum of hypertrophic cardiomyopathy (HCM). The aim of this study was to evaluate the presence and frequency of PM displacement in different HCM phenotypes. METHODS AND RESULTS: We retrospectively analysed cardiovascular magnetic resonance (CMR) findings in 156 patients (25% females, median age 57 years). Patients were divided into three groups: septal hypertrophy (Sep-HCM, n = 70, 45%), mixed hypertrophy (Mixed-HCM, n = 48, 31%), and apical hypertrophy (Ap-HCM, n = 38, 24%). Fifty-five healthy subjects were enrolled as controls. Apical PM displacement was observed in 13% of controls and 55% of patients, which was most common in the Ap-HCM group, followed by the Mixed-HCM and Sep-HCM groups (respectively: inferomedial PM 92 vs. 65 vs. 13%, P < 0.001; anterolateral PM 61 vs. 40 vs. 9%, P < 0.001). Significant differences in PM displacement were found when comparing healthy controls with patients with Ap- and Mixed-HCM subtypes but not when comparing them with patients with the Sep-HCM subtype. T-wave inversion in the inferior and lateral leads was more frequent in patients with Ap-HCM (100 and 65%, respectively) when compared with Mixed-HCM (89 and 29%, respectively) and Sep-HCM (57 and 17%, respectively; P < 0.001 for both). Eight patients with Ap-HCM had prior CMR examinations because of T-wave inversion [median interval 7 (3-8) years], and in the first CMR study, none showed apical hypertrophy [median apical wall thickness 8 (7-9) mm], while all of them presented with apical PM displacement. CONCLUSION: Apical PM displacement is part of the phenotypic Ap-HCM spectrum and may precede the development of hypertrophy. These observations suggest a potential pathogenetic, mechanical link between apical PM displacement and Ap-HCM.

Role of Cardiovascular Magnetic Resonance to Assess Cardiovascular Inflammation.

Cardiovascular inflammatory diseases still represent a challenge for physicians. Inflammatory cardiomyopathy, pericarditis, and large vessels vasculitis can clinically mimic a wide spectrum of diseases. While the underlying etiologies are varied, the common physio-pathological process is characterized by vasodilation, exudation, leukocytes infiltration, cell damage, and fibrosis. Cardiovascular magnetic resonance (CMR) allows the visualization of some of these diagnostic targets. CMR provides not only morphological and functional assessment but also tissue catheterization revealing edema, hyperemia, tissue injury, and reparative fibrosis through T2 weighted images, early and late gadolinium enhancement, and parametric mapping techniques. Recent developments showed the role of CMR in the identification of ongoing inflammation also in other CV diseases like myocardial infarction, atherosclerosis, arrhythmogenic and hypertrophic cardiomyopathy. Future developments of CMR, aiming at the specific assessment of immune cell infiltration, will give deeper insight into cardiovascular inflammatory diseases.

Magnetic resonance relaxometry of the liver - a new imaging biomarker to assess right heart failure in pulmonary hypertension.

BACKGROUND: Right heart failure (RHF) in pulmonary hypertension (PH) patients is manifested by increased right atrial (RA) pressure. We hypothesized liver relaxation times measured at cardiovascular magnetic resonance (CMR) can be used to noninvasively assess increased right-sided filling pressure. METHODS: Forty-five consecutive patients, that is, 37 PH patients and 8 chronic thromboembolic pulmonary disease patients without PH underwent right heart catheterization and CMR. CMR findings were compared to 40 control subjects. Native T1, T2, and extracellular volume (ECV) liver values were measured on the cardiac maps. RESULTS: Patients with increased RA pressure (i.e.,≥8 mm Hg)(n = 19, RA+ group) showed higher NT-proBNP and CRP values, lower LVEF, MAPSE values, larger atrial size, and higher native T1 and T2 values of the myocardium than patients with normal RA pressure (RA- group, n = 26). Liver T1, T2 and ECV was significantly higher in RA+ than RA- patients and controls, that is, T1: 684 ± 129 ms vs 563 ± 72 ms and 540 ± 34 ms; T2: 60 ± 10 ms vs 49 ± 6 ms and 46 ± 4 ms; ECV: 36 ± 8% vs 29 ± 4% and 30 ± 3%. A positive correlation was found between liver T1, T2 and ECV and RA pressure, that is, r2 of 0.61, 0.82, and 0.58, respectively (p < 0.001). ROC analysis to depict increased RA pressure showed an AUC of 0.847, 0.904, 0.816, and 0.645 for liver T1, T2, NT-proNBP and gamma-glutamyl transpeptidase, respectively. Excellent intra- and inter-observer agreement was found for assessment of T1/T2/ECV liver values. CONCLUSIONS: Assessment of liver relaxation times as part of a comprehensive CMR exam in PH patients may provide valuable information with regard to the presence of passive liver congestion.

Prenatal Radiation Exposure Leads to Higher-Order Telencephalic Dysfunctions in Adult Mice That Coincide with Reduced Synaptic Plasticity and Cerebral Hypersynchrony.

Higher-order telencephalic circuitry has been suggested to be especially vulnerable to irradiation or other developmentally toxic impact. This report details the adult effects of prenatal irradiation at a sensitive time point on clinically relevant brain functions controlled by telencephalic regions, hippocampus (HPC), and prefrontal cortex (PFC). Pregnant C57Bl6/J mice were whole-body irradiated at embryonic day 11 (start of neurogenesis) with X-ray intensities of 0.0, 0.5, or 1.0 Gy. Female offspring completed a broad test battery of HPC-/PFC-controlled tasks that included cognitive performance, fear extinction, exploratory, and depression-like behaviors. We examined neural functions that are mechanistically related to these behavioral and cognitive changes, such as hippocampal field potentials and long-term potentiation, functional brain connectivity (by resting-state functional magnetic resonance imaging), and expression of HPC vesicular neurotransmitter transporters (by immunohistochemical quantification). Prenatally exposed mice displayed several higher-order dysfunctions, such as decreased nychthemeral activity, working memory defects, delayed extinction of threat-evoked response suppression as well as indications of perseverative behavior. Electrophysiological examination indicated impaired hippocampal synaptic plasticity. Prenatal irradiation also induced cerebral hypersynchrony and increased the number of glutamatergic HPC terminals. These changes in brain connectivity and plasticity could mechanistically underlie the irradiation-induced defects in higher telencephalic functions.

Synthetic Antiferromagnetic Gold Nanoparticles as Bimodal Contrast Agents in MRI and CT-An Experimental In Vitro and In Vivo Study.

The use of multimodal contrast agents can potentially overcome the intrinsic limitations of individual imaging methods. We have validated synthetic antiferromagnetic nanoparticles (SAF-NPs) as bimodal contrast agents for in vitro cell labeling and in vivo cell tracking using magnetic resonance imaging (MRI) and computed tomography (CT). SAF-NP-labeled cells showed high contrast in MRI phantom studies (r2* = 712 s-1 mM-1), while pelleted cells showed clear contrast enhancement in CT. After intravenous SAF-NP injection, nanoparticles accumulated in the liver and spleen, as visualized in vivo by significant MRI contrast enhancement. Intravenous injection of SAF-NP-labeled cells resulted in cell accumulation in the lungs, which was clearly detectable by using CT but not by using MRI. SAF-NPs proved to be very efficient cell labeling agents for complementary MRI- and CT-based cell tracking. Bimodal monitoring of SAF-NP labeled cells is in particular of interest for applications where the applied imaging methods are not able to visualize the particles and/or cells in all organs.

Left ventricular remodelling in mitral valve prolapse patients: implications of apical papillary muscle insertion.

AIMS: Mitral valve prolapse (MVP) causes left ventricular (LV) remodelling even in the absence of significant mitral regurgitation. To evaluate whether apical insertion of the papillary muscle (PM) influences the pattern and severity of MVP-related LV remodelling. METHODS AND RESULTS: All MVP patients who underwent CMR at our institution between December 2008 and December 2019 were included, thoroughly reviewed and grouped according to apical/non-apical PM insertion. Apical PM insertion was found in 53/92 patients (58%) and associated with mitral leaflet thickening (P < 0.01) and a trend towards higher prevalence of mitral annular disjunction (P = 0.05). Whereas no differences in ventricular volumes or ejection fraction were found, patients with apical PM insertion showed more lateral wall remodelling with mid lateral wall thinning [2.1 (1.8-2.5) vs. 4.0 (3.5-5.0) mm, P < 0.01], increased LV eccentricity and a lower GCS at this level (15 ± 3% vs. 20 ± 3%, P < 0.01). In long-axis direction, increased end-diastolic mid lateral wall angulation was found (i.e. angle <155° measured in the thinnest point of the mid lateral wall in four-chamber view) with a higher angle variation during systole (25 ± 11° vs. 17 ± 8°, P < 0.01). Remarkably, PM fibrosis was significantly more frequent in patients with apical PM insertion (i.e. 66% vs. 28%, P < 0.01). Finally, a higher burden of premature ventricular complexes (>5%) and non-sustained ventricular tachyarrhythmias was found in patients with apical PM insertion: 53% vs. 25% (P = 0.04) and 38% vs. 18% (P = 0.04), respectively. CONCLUSION: Apical PM insertion is part of the phenotypic spectrum of MVP, impacts significantly LV remodelling, and potentially may be related to increased ventricular arrhythmogenicity.

Noninvasive assessment of congestive hepatopathy in patients with constrictive pericardial physiology using MR relaxometry.

BACKGROUND: Constrictive pericarditis represents a treatable cause of mainly right heart failure (RHF), characterized by increased filling pressures and congestive hepatopathy. We hypothesized assessment of T1 and T2 liver relaxation times enables to depict liver congestion, and thus to diagnose RHF. METHODS: Cardiovascular magnetic resonance imaging (CMR) was performed in 45 pericarditis patients i.e., 25 with constrictive physiology (CP+), 20 with normal physiology (CP-), and 30 control subjects. CMR included morphologic and functional assessment of the heart and pericardium. Liver relaxation times were measured on T1 and T2 cardiac maps. RESULTS: CP+ and CP- patients were predominantly male, but CP+ patients were on average 13 years older than CP- patients (p = 0.003). T1 and T2 Liver values were significantly higher in CP+ than in CP- patients and controls, i.e. T1: 765 ± 102 ms vs 581 ± 56 ms and 537 ± 30 ms (both p < 0.001); T2: 63 ± 13 ms vs 50 ± 4 ms and 46 ± 4 ms (both p < 0.001). Extracellular volume (ECV) liver values were also increased, i.e. 42 ± 7% CP+ vs 31 ± 3% CP- and 30 ± 3% control (both p < 0.001). Using a cut-off right atrial pressure of >5 mmHg to discriminate between normal and increased pressure, native T1 liver yielded the highest AUC (0.926) at ROC analysis with a sensitivity of 79.3% and specificity of 95.6%. Gamma-glutamyl transpeptidase correlated well withT1 liver (r2 = 0.43) and ECV liver (r2 = 0.30). Excellent intra- and inter-reader agreement was found for T1, T2 and ECV measurement of the liver. CONCLUSIONS: Assessment of liver relaxation times in pericarditis patients provide valuable information on the presence of concomitant congestive hepatopathy, reflecting RHF.

Assessment of Right-Sided Heart Failure in Patients with Dilated Cardiomyopathy using Magnetic Resonance Relaxometry of the Liver.

In non-ischemic dilated cardiomyopathy (DC) patients at risk of developing right heart failure (RHF), early depiction of congestive heart failure (CHF) is pivotal to inform about the hemodynamic status and tailor medical therapy. We hypothesized increased liver relaxation times measured at routine cardiovascular magnetic resonance (CMR), reflecting passive hepatic congestion, may be a valuable imaging biomarker to depict congestive heart failure. The study cohort consisted of DC patients with LV dysfunction (i.e., ejection fraction <35%) with (n = 48) and without (n = 46) right ventricular dysfunction (RVD), defined as a right ventricular ejection fraction <35%, and >45%, respectively, and a control group (n = 40). Native T1, T2, and extracellular volume (ECV) liver values were measured on routinely acquired cardiac maps. DC+RVD patients had higher C-reactive protein, troponin I and NT-pro BNP values, and worse LV functional parameters than DC-RVD patients (all p <0.001). T1, T2 and ECV Liver values were significantly higher in DC+RVD compared to DC-RVD patients and controls, that is, T1: 675 ± 88 ms verses 538 ± 39 ms and 540 ± 34 ms; T2: 54± 8 ms versus 45 ± 5 ms and 46 ± 4 ms; ECV: 36 ± 7% versus 29 ± 4% and 30 ± 3% (all p <0.001). Gamma-glutamyltranspeptidase (GGT) correlated moderately but significantly with native T1 (r2 = 0.34), T2 (r2 = 0.27), and ECV liver (r2 = 0.23) (all p <0.001). Using right atrial (RA) pressure, as surrogate measure of RHF (i.e., RA pressure >5 mm Hg), native T1 liver yielded at ROC analysis the highest area under the curve (0.906), significantly higher than ECV liver (0.813), GGT (0.806), T2 liver (0.797), total bilirubin (0.737) and alkaline phosphatase (0.561)(p = 0.04). A T1 value of 617 ms yielded a sensitivity of 79.5% and specificity of 91.0% to depict RHF. Excellent intra-/inter-observer agreement was found for assessment of native T1/T2/ECV liver values. In conclusion, in DC patients, assessment of liver relaxation times acquired on a cardiovascular magnetic resonance exam, may provide valuable information with regard to the presence of RHF.

Heterogeneous Effects of Calorie Content and Nutritional Components Underlie Dietary Influence on Pancreatic Cancer Susceptibility.

Pancreatic cancer is a rare but fatal form of cancer, the fourth highest in absolute mortality. Known risk factors include obesity, diet, and type 2 diabetes; however, the low incidence rate and interconnection of these factors confound the isolation of individual effects. Here, we use epidemiological analysis of prospective human cohorts and parallel tracking of pancreatic cancer in mice to dissect the effects of obesity, diet, and diabetes on pancreatic cancer. Through longitudinal monitoring and multi-omics analysis in mice, we found distinct effects of protein, sugar, and fat dietary components, with dietary sugars increasing Mad2l1 expression and tumor proliferation. Using epidemiological approaches in humans, we find that dietary sugars give a MAD2L1 genotype-dependent increased susceptibility to pancreatic cancer. The translation of these results to a clinical setting could aid in the identification of the at-risk population for screening and potentially harness dietary modification as a therapeutic measure.

Non-invasive characterization of amyotrophic lateral sclerosis in a hTDP-43A315T mouse model: A PET-MR study.

Currently TAR DNA binding protein 43 (TDP-43) pathology, underlying Amyotrophic Lateral Sclerosis (ALS), remains poorly understood which hinders both clinical diagnosis and drug discovery efforts. To better comprehend the disease pathophysiology, positron emission tomography (PET) and multi-parametric magnetic resonance imaging (mp-MRI) provide a non-invasive mode to investigate molecular, structural, and neurochemical abnormalities in vivo. For the first time, we report the findings of a longitudinal PET-MR study in the TDP-43A315T ALS mouse model, investigating disease-related changes in the mouse brain. 2-deoxy-2-[18F]fluoro-D-glucose [18F]FDG PET showed significantly lowered glucose metabolism in the motor and somatosensory cortices of TDP-43A315T mice whereas metabolism was elevated in the region covering the bilateral substantia nigra, reticular and amygdaloid nucleus between 3 and 7 months of age, as compared to non-transgenic controls. MR spectroscopy data showed significant changes in glutamate + glutamine (Glx) and choline levels in the motor cortex and hindbrain of TDP-43A315T mice compared to controls. Cerebral blood flow (CBF) measurements, using an arterial spin labelling approach, showed no significant age- or group-dependent changes in brain perfusion. Diffusion MRI indices demonstrated transient changes in different motor areas of the brain in TDP-43A315T mice around 14 months of age. Cytoplasmic TDP-43 proteinaceous inclusions were observed in the brains of symptomatic, 18-month-old mice, but not in non-symptomatic transgenic or wild-type mice. Our results reveal that disease- and age-related functional and neurochemical alterations, together with limited structural changes, occur in specific brain regions of transgenic TDP-43A315T mice, as compared to their healthy counterparts. Altogether these findings shed new light on TDP-43A315T disease pathogenesis and may prove useful for clinical management of ALS.

T1 mapping performance and measurement repeatability: results from the multi-national T1 mapping standardization phantom program (T1MES).

BACKGROUND: The T1 Mapping and Extracellular volume (ECV) Standardization (T1MES) program explored T1 mapping quality assurance using a purpose-developed phantom with Food and Drug Administration (FDA) and Conformité Européenne (CE) regulatory clearance. We report T1 measurement repeatability across centers describing sequence, magnet, and vendor performance. METHODS: Phantoms batch-manufactured in August 2015 underwent 2 years of structural imaging, B0 and B1, and "reference" slow T1 testing. Temperature dependency was evaluated by the United States National Institute of Standards and Technology and by the German Physikalisch-Technische Bundesanstalt. Center-specific T1 mapping repeatability (maximum one scan per week to minimum one per quarter year) was assessed over mean 358 (maximum 1161) days on 34 1.5 T and 22 3 T magnets using multiple T1 mapping sequences. Image and temperature data were analyzed semi-automatically. Repeatability of serial T1 was evaluated in terms of coefficient of variation (CoV), and linear mixed models were constructed to study the interplay of some of the known sources of T1 variation. RESULTS: Over 2 years, phantom gel integrity remained intact (no rips/tears), B0 and B1 homogenous, and "reference" T1 stable compared to baseline (% change at 1.5 T, 1.95 ± 1.39%; 3 T, 2.22 ± 1.44%). Per degrees Celsius, 1.5 T, T1 (MOLLI 5s(3s)3s) increased by 11.4 ms in long native blood tubes and decreased by 1.2 ms in short post-contrast myocardium tubes. Agreement of estimated T1 times with "reference" T1 was similar across Siemens and Philips CMR systems at both field strengths (adjusted R2 ranges for both field strengths, 0.99-1.00). Over 1 year, many 1.5 T and 3 T sequences/magnets were repeatable with mean CoVs < 1 and 2% respectively. Repeatability was narrower for 1.5 T over 3 T. Within T1MES repeatability for native T1 was narrow for several sequences, for example, at 1.5 T, Siemens MOLLI 5s(3s)3s prototype number 448B (mean CoV = 0.27%) and Philips modified Look-Locker inversion recovery (MOLLI) 3s(3s)5s (CoV 0.54%), and at 3 T, Philips MOLLI 3b(3s)5b (CoV 0.33%) and Siemens shortened MOLLI (ShMOLLI) prototype 780C (CoV 0.69%). After adjusting for temperature and field strength, it was found that the T1 mapping sequence and scanner software version (both P < 0.001 at 1.5 T and 3 T), and to a lesser extent the scanner model (P = 0.011, 1.5 T only), had the greatest influence on T1 across multiple centers. CONCLUSION: The T1MES CE/FDA approved phantom is a robust quality assurance device. In a multi-center setting, T1 mapping had performance differences between field strengths, sequences, scanner software versions, and manufacturers. However, several specific combinations of field strength, sequence, and scanner are highly repeatable, and thus, have potential to provide standardized assessment of T1 times for clinical use, although temperature correction is required for native T1 tubes at least.

Left ventricular global myocardial strain assessment: Are CMR feature-tracking algorithms useful in the clinical setting?

OBJECTIVES: Myocardial strains can be calculated using cardiovascular magnetic resonance (CMR) feature-tracking (FT) algorithms. They show excellent intra- and inter-observer agreement but rather disappointing inter-vendor agreement. Currently, it is unknown how well CMR-FT-based strain values agree with manually obtained strain values. METHODS: In 45 subjects (15 controls, 15 acute myocardial infarction, 15 non-ischemic dilated cardiomyopathy), end-systolic manually derived strains were compared to four CMR-FT software packages. Global radial strain (GRS), global circumferential strain (GCS) and global longitudinal strain (GLS) were determined. Intra- and inter-observer agreement and agreement between manual and CMR-FT analysis were calculated. Statistical analysis included Bland-Altman plots, intra-class correlation coefficient (ICC) and coefficient of variation (CV). RESULTS: Manual contouring yielded excellent intra-observer (ICC 0.903 (GRS) to 0.995 (GCS)) and inter-observer agreement (ICC 0.915 (GRS) to 0.966 (GCS)) with CV ranging 4.7% (GCS) to 20.7% (GRS) and 12.7% (GCS) to 20.0% (GRS), for intra-observer and inter-observer agreement, respectively. Agreement between manual and CMR-FT strain values ranged from poor to excellent, with best agreement for GCS (ICC 0.857-0.935) and intermediate for GLS (ICC 0.591-0.914), while ICC values for GRS ranged widely (ICC 0.271-0.851). In particular, two software packages showed a strong trend toward systematic underestimation of myocardial strain in radial and longitudinal direction, correlating poorly to moderately with manual contouring, i.e., GRS (ICC 0.271, CV 25.2%) and GLS (ICC 0.591, CV 17.6%). CONCLUSION: Some CMR-FT values agree poorly with manually derived strains, emphasizing to be cautious to use these software packages in the clinical setting. In particular, radial and longitudinal strain tends to be underestimated when using manually derived strains as reference.

Prognostic value of cardiovascular magnetic resonance in patients with biopsy-proven systemic sarcoidosis.

OBJECTIVES: As prognosis in sarcoidosis is determined by cardiac involvement, the objective was to study the added value of cardiovascular magnetic resonance (CMR) in risk stratification. METHODS: In 114 patients (48 ± 12 years/52% male) with biopsy-proven sarcoidosis, we studied the value of clinical and CMR-derived parameters to predict future events, using sustained ventricular tachycardia, ventricular fibrillation, aborted cardiac death, implantable cardioverter-defibrillator (ICD) placement with appropriate shocks, hospitalization for heart failure, and death as composite endpoint. Median follow-up after CMR was 3.1 years (1.1-5.7 years). RESULTS: The ejection fraction (EF) was 58.2 ± 9.1% and 54.7 ± 10.8% for left ventricle (LV) and right ventricle (RV), respectively. LV late gadolinium enhancement (LGE) was present in 40 patients (35%) involving 5.1% of the LV mass (IQR, 3.0-12.0%), with concomitant RV involvement in 12 patients (11%). T2-weighting imaging and/or T2 mapping showed active disease in 14 patients. The composite endpoint was reached in 34 patients, with 7 deaths in the LGE-positive group (17.5%), versus two deaths in the LGE-negative group (2.7%) (p = 0.015). At univariate analysis, RVEF (p = 0.009), pulmonary arterial pressure (p = 0.002), and presence of LGE (p < 0.001) and LGE (% of LV) (p < 0.001) were significant. At multivariate analysis, only presence of LGE and LGE (% of LV) was significant (both p = 0.03). At Kaplan-Meier, presence of LGE and an LGE of 3% predicted event-free survival and patient survival. We found no difference in active versus inactive disease with regard to patient survival. CONCLUSION: Myocardial enhancement at LGE-CMR adds independent prognostic value in risk stratification sarcoidosis patients. In contrast, clinical as well as functional cardiac parameters lack discriminative power. KEY POINTS: • Sarcoidosis often affects the heart. • Comprehensive CMR, including T2 imaging and LGE enhancement CMR, allows to depict both active and inactive myocardial damage. • Patient prognosis in sarcoidosis is determined by the presence and severity of myocardial involvement at LGE CMR.

Quantitative Assessment of Age-Associated Alterations in Brain Vasculature in Wild-Type Mice and in Bigenic Mice that Model Alzheimer's Disease.

PURPOSE: Vascular dysfunction is a major hallmark of Alzheimer's disease (AD). However, studies that investigated vascular dysfunction in mice modeling AD using magnetic resonance angiography (MRA) are typically limited to qualitative and/or scoring-based paradigms, which are labor-intensive and observer-dependent. PROCEDURES: We developed and validated a semi-automatic MRA processing pipeline and applied this to high-resolution in vivo MRA images acquired on a 9.4T small animal MRI scanner. We assessed vascular morphology at 3, 6, and 12 months in wild-type (WT) and bigenic (APP.V717IxTau.P301L: biAT) mice. RESULTS: Vessel radius or length can increase with age regardless of genotype depending on the respective vessel. We also observed significantly lower internal carotid artery length in biAT mice compared to WT. CONCLUSIONS: The results demonstrate that even subtle changes in vessel morphology can be noninvasively quantified. This is of great interest for AD, but also to other models of neurodegenerative diseases involving macrovascular dysfunction.