Publications by authors named "Andras Jakab"

44 Publications

Delayed maturation of the structural brain connectome in neonates with congenital heart disease.

Brain Commun 2020 27;2(2):fcaa209. Epub 2020 Nov 27.

Centre for MR Research, University Children's Hospital Zurich, Zurich 8032, Switzerland.

There is emerging evidence for delayed brain development in neonates with congenital heart disease. We hypothesize that the perioperative development of the structural brain connectome is a proxy to such delays. Therefore, we set out to quantify the alterations and longitudinal pre- to post-operative changes in the connectome in congenital heart disease neonates relative to healthy term newborns and assess factors contributing to disturbed perioperative network development. In this prospective cohort study, 114 term neonates with congenital heart disease underwent cardiac surgery at the University Children's Hospital Zurich. Forty-six healthy term newborns were included as controls. Pre- and post-operative structural connectomes were derived from mean fractional anisotropy values of fibre pathways traced using diffusion MR tractography. Graph theory parameters calculated across a proportional cost threshold range were compared between groups by multi-threshold permutation correction adjusting for confounders. Network-based statistic was calculated for edgewise network comparison. White-matter injury volume was quantified on 3D T1-weighted images. Random coefficient mixed models with interaction terms of (i) cardiac subtype and (ii) injury volume with post-menstrual age at MRI, respectively, were built to assess modifying effects on network development. Pre- and post-operatively, at the global level, efficiency, indicative of network integration, was lower in heart disease neonates than controls. In contrast, local efficiency and transitivity, indicative of network segregation, were higher compared to controls (all  < 0.025 for one-sided -tests). Pre-operatively, these group differences were also found across multiple widespread nodes (all  < 0.025, accounting for multiple comparison), whereas post-operatively nodal differences were not evident. At the edge-level, the majority of weaker connections in heart disease neonates compared to controls involved inter-hemispheric connections (66.7% pre-operatively; 54.5% post-operatively). A trend showing a more rapid pre- to post-operative decrease in local efficiency was found in class I cardiac sub-type (biventricular defect without aortic arch obstruction) compared to controls. In congenital heart disease neonates, larger white-matter injury volume was associated with lower strength ( = 0.0026) and global efficiency ( = 0.0097). The maturation of the structural connectome is delayed in congenital heart disease neonates, with a pattern of lower structural integration and higher segregation compared to controls. Trend-level evidence indicated that normalized post-operative cardiac physiology in class I sub-types might improve structural network topology. In contrast, the burden of white-matter injury negatively impacts network strength and integration. Further research is needed to elucidate how aberrant structural network development in congenital heart disease represents neural correlates of later neurodevelopmental impairments.
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http://dx.doi.org/10.1093/braincomms/fcaa209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756099PMC
November 2020

The potential effect of instrumentation with different nickel titanium rotary systems on dentinal crack formation-An in vitro study.

PLoS One 2020 9;15(9):e0238790. Epub 2020 Sep 9.

Department of Oral Surgery, Faculty of Dentistry, University of Szeged, Szeged, Hungary.

The potential mechanical impact of different rotary systems used for root canal preparation has been a matter of debate for long. The aim of this study was to explore the incidence of dentinal cracks after root canal instrumentation with various rotary systems, in vitro. One hundred and eighty intact lower central incisors were selected and randomly divided into fourteen treatment groups (n = 12/group) and a control group (n = 12). After decoronation, the root canals were instrumented with fourteen different rotary systems (E3, E3 azure, NT2, Hyflex CM, Hyflex EDM, 2Shape, OneCurve, ProTaper Next, ProTaper Gold, WaveOne Gold, Mtwo, Reciproc Blue, TF adaptive, K3XF). All roots were horizontally sectioned at 3, 6, and 9 mm from the apex with a low-speed saw under water-cooling. The slices were then examined under stereomicroscope for dentinal cracks. No cracks were found in the control group. Cracks were found in all treatment groups, predominantly in the 3 mm slices. There was no statistically significant difference in the number of cracks when comparing the different systems to each other at any section level. At 3 mm, however, five of the studied systems, namely K3XF (p = 0.004), Protaper Next (p = 0.001), Reciproc Blue (p<0.001), TF adaptive (p = 0.050), and 2Shape (p = 0.009) presented a significantly higher number of cracks than the control group. Within the limitations of this study, instrumented canals presented dentinal cracks, while uninstrumented ones presented no cracks after sectioning. There seems to be no significant difference among the tested systems regarding crack formation in the instrumented root canal wall. Crack formation occurred irrespective of the motion of the rotary system (rotational or reciprocation). Further studies are needed to clarify the factors that contribute to crack formation in the case of each individual rotary system.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238790PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480847PMC
November 2020

Mental development is associated with cortical connectivity of the ventral and nonspecific thalamus of preterm newborns.

Brain Behav 2020 10 13;10(10):e01786. Epub 2020 Aug 13.

Department of Neonatology and Pediatric Intensive Care, University Children's Hospital Zurich, Zurich, Switzerland.

Introduction: The thalamus is a key hub for regulating cortical connectivity. Dysmaturation of thalamocortical networks that accompany white matter injury has been hypothesized as neuroanatomical correlate of late life neurocognitive impairment following preterm birth. Our objective was to find a link between thalamocortical connectivity measures at term equivalent age and two-year neurodevelopmental outcome in preterm infants.

Methods: Diffusion tensor MRI data of 58 preterm infants (postmenstrual age at birth, mean (SD), 29.71 (1.47) weeks) were used in the study. We utilized probabilistic diffusion tractography to trace connections between the cortex and thalami. Possible associations between connectivity strength, the length of the probabilistic fiber pathways, and developmental scores (Bayley Scales of Infant Development, Second Edition) were analyzed using multivariate linear regression models.

Results: We found strong correlation between mental developmental index and two complementary measures of thalamocortical networks: Connectivity strength projected to a cortical skeleton and pathway length emerging from thalamic voxels (partial correlation, R = .552 and R = .535, respectively, threshold-free cluster enhancement, corrected p-value < .05), while psychomotor development was not associated with thalamocortical connectivity. Post hoc stepwise linear regression analysis revealed that parental socioeconomic scale, postmenstrual age, and the duration of mechanical ventilation at the intensive care unit contribute to the variability of outcome.

Conclusions: Our findings independently validated previous observations in preterm infants, providing additional evidence injury or dysmaturation of tracts emerging from ventral-specific and various nonspecific thalamus projecting to late-maturing cortical regions are predictive of mental, but not psychomotor developmental outcomes.
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http://dx.doi.org/10.1002/brb3.1786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559616PMC
October 2020

Quantitative Hybrid Cardiac [F]FDG-PET-MRI Images for Assessment of Cardiac Repair by Preconditioned Cardiosphere-Derived Cells.

Mol Ther Methods Clin Dev 2020 Sep 15;18:354-366. Epub 2020 Jun 15.

Department of Cardiology, Medical University of Vienna, Vienna, Austria.

Cardiosphere-derived cells (CDCs) are progenitor cells derived from heart tissue and have shown promising results in preclinical models. APOSEC, the secretome of irradiated peripheral blood mononuclear cells, has decreased infarct size in acute and chronic experimental myocardial infarction (MI). We enhanced the effect of CDCs with APOSEC preconditioning (apoCDC) and investigated the reparative effect in a translational pig model of reperfused MI. Supernatants of CDCs, assessed by proteomic analysis, revealed reduced production of extracellular matrix proteins after APOSEC preconditioning. In a porcine model of catheter-based reperfused anterior acute MI (AMI), CDCs with (apoCDC, n = 8) or without APOSEC preconditioning (CDC, n = 6) were infused intracoronary, 15 min after the start of reperfusion. Untreated AMI animals (n = 7) and sham procedures (n = 5) functioned as controls. 2-deoxy-2-(18 F)-fluoro-D-glucose-positron emission tomography-magnetic resonance imaging ([F]FDG-PET-MRI), with late enhancement after 1 month, showed reduced scar volume and lower transmurality of the infarcted area in CDC and apoCDC compared to AMI controls. Segmental quantitative PET images displayed indicated more residual viability in apoCDC. The left-ventricle (LV) ejection fraction was improved nonsignificantly to 45.8% ± 8.6% for apoCDC and 43.5% ± 7.1% for CDCs compared to 38.5% ± 4.4% for untreated AMI. Quantitative hybrid [F]FDG-PET-MRI demonstrated improved metabolic and functional recovery after CDC administration, whereas apoCDCs induced preservation of viability of the infarcted area.
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http://dx.doi.org/10.1016/j.omtm.2020.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341058PMC
September 2020

Diabetic neuropathy and other diabetic complications at the Diabetic Neuropathy Center of the University of Debrecen

Orv Hetil 2020 07;161(30):1243-1251

Általános Orvostudományi Kar, Anyagcsere Betegségek Nem Önálló Tanszék, Belgyógyászati Intézet,D Debreceni Egyetem, Debrecen, Nagyerdei krt. 98., 4032.

Introduction: The prevalence of diabetes mellitus is significantly increasing worldwide. Distal sensorimotor neuropathy (DSPN) is the most common and the earliest detectable microvascular complication. Due to its diverse clinical appearance and atypical symptoms, DSPN is often recognized in an advanced stage.

Aim And Method: In our study, the data of 431 patients who were examined using the Neurometer® between 2011 and 2018 at the Diabetic Neuropathy Center of the University of Debrecen were processed and the correlations between cardiovascular and microvascular complications, laboratory parameters and the severity of DSPN were investigated.

Results: The average age of patients was 63.4 years, 62% of them were women, and 92% had type 2 diabetes mellitus. The average duration of diabetes was 13.7 years. Cardiovascular disease (CVD) was diagnosed in 42% of the patients. The incidence of retinopathy was 12%, persistent microalbuminuria was 16%. Despite DSNP complaints, neuronal damage could not be detected in 19%; in the examined patients 49% had mild, 19% moderate and 13% severe neuropathy. Diabetes-related neurological damage was more serious in the presence of both diabetic retinopathy (p<0.001) and microalbuminuria (p<0.001). The incidence of these microvascular complications and the severity of DSPN showed a significant positive correlation (p<0.001). There was no correlation between the severity of peripheral neuropathy and the development of CVD, and we did not find any correlations between the severity of DSPN and CVD.

Conclusion: Based on our investigation, correlation between the progression of diabetic neuropathy and cardiovascular complications was not found, although the progression of diabetic neuropathy indicated the development of other microvascular diseases. Peripheral neurological examination using the Neurometer® is appropriate for controlling the DSPN status and the establishment of the severity of neuropathy determines the quality of life in diabetic patients. Among these patients, the risk of CVD can be assessed by Ewing's test for autonomic nervous system function. Orv Hetil. 2020; 161(30): 1243-1251.
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http://dx.doi.org/10.1556/650.2020.31799DOI Listing
July 2020

Inhibition is associated with whole-brain structural brain connectivity on network level in school-aged children born very preterm and at term.

Neuroimage 2020 09 19;218:116937. Epub 2020 May 19.

Department of Neonatology and Pediatric Intensive Care, University Children's Hospital Zurich, Switzerland; Children's Research Center, University Children's Hospital Zurich, Switzerland. Electronic address:

Inhibition abilities are often impaired in children born very preterm. In typically-developing individuals, inhibition has been associated with structural brain connectivity (SC). As SC is frequently altered following preterm birth, this study investigated whether aberrant SC underlies inhibition deficits in school-aged children born very preterm. In a group of 67 very preterm participants aged 8-13 years and 69 term-born peers, inhibition abilities were assessed with two tasks. In a subgroup of 50 very preterm and 62 term-born participants, diffusion tensor imaging (DTI) data were collected. Using network-based statistics (NBS), mean fractional anisotropy (FA) was compared between groups. Associations of FA and inhibition abilities were explored through linear regression. The composite score of inhibition abilities was lower in the very preterm group (M ​= ​-0.4, SD ​= ​0.8) than in the term-born group (M ​= ​0.0, SD ​= ​0.8) but group differences were not significant when adjusting for age, sex and socio-economic status (β ​= ​-0.13, 95%-CI [-0.30, 0.04], p ​= ​0.13). In the very preterm group, FA was significantly lower in a network comprising thalamo-frontal, thalamo-temporal, frontal, cerebellar and intra-hemispheric connections than in the term-born group (t ​= ​5.21, lowest p-value ​= ​0.001). Irrespective of birth status, a network comprising parietal, cerebellar and subcortical connections was positively associated with inhibition abilities (t ​= ​4.23, lowest p-value ​= ​0.02). Very preterm birth results in long-term alterations of SC at network-level. As networks underlying inhibition abilities do not overlap with those differing between the groups, FA may not be adequate to explain inhibition problems in very preterm children. Future studies should combine complementary measures of brain connectivity to address neural correlates of inhibition abilities.
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http://dx.doi.org/10.1016/j.neuroimage.2020.116937DOI Listing
September 2020

Creative music therapy to promote brain function and brain structure in preterm infants: A randomized controlled pilot study.

Neuroimage Clin 2020 13;25:102171. Epub 2020 Jan 13.

Department of Neonatology and Pediatric Intensive Care, Children's University Hospital of Zurich, Steinwiesstrasse 75, 8032 Zürich, Switzerland; Children's Research Center, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032 Zürich, Switzerland.

Cognitive and neurobehavioral problems are among the most severe adverse outcomes in very preterm infants. Such neurodevelopmental impairments may be mitigated through nonpharmacological interventions such as creative music therapy (CMT), an interactive, resource- and needs-oriented approach that provides individual social contact and musical stimulation. The aim was to test the feasibility of a study investigating the role of CMT and to measure the short- and medium-term effects of CMT on structural and functional brain connectivity with MRI. In this randomized, controlled clinical pilot feasibility trial, 82 infants were randomized to either CMT or standard care. A specially trained music therapist provided CMT via infant-directed humming and singing in lullaby style. To test the short-term effects of CMT on brain structure and function, diffusion tensor imaging data and resting-state functional imaging data were acquired. Clinical feasibility was achieved despite moderate parental refusal mainly in the control group after randomization. 40 infants remained as final cohort for the MRI analysis. Structural brain connectivity appears to be moderately affected by CMT, structural connectomic analysis revealed increased integration in the posterior cingulate cortex only. Lagged resting-state MRI analysis showed lower thalamocortical processing delay, stronger functional networks, and higher functional integration in predominantly left prefrontal, supplementary motor, and inferior temporal brain regions in infants treated with CMT. This trial provides unique evidence that CMT has beneficial effects on functional brain activity and connectivity in networks underlying higher-order cognitive, socio-emotional, and motor functions in preterm infants. Our results indicate the potential of CMT to improve long-term neurodevelopmental outcomes in children born very preterm.
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http://dx.doi.org/10.1016/j.nicl.2020.102171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974781PMC
January 2021

Developmental Pathoconnectomics and Advanced Fetal MRI.

Authors:
András Jakab

Top Magn Reson Imaging 2019 Oct;28(5):275-284

Centre for MR Research, University Children's Hospital of Zürich, Zurich, Switzerland.

Developmental pathoconnectomics is an emerging field that aims to unravel the events leading to and outcome from disrupted brain connectivity development. Advanced magnetic resonance imaging (MRI) technology enables the portrayal of human brain connectivity before birth and has the potential to offer novel insights into normal and pathological human brain development. This review gives an overview of the currently used MRI techniques for connectomic imaging, with a particular focus on recent studies that have successfully translated these to the in utero or postmortem fetal setting. Possible mechanisms of how pathologies, maternal, or environmental factors may interfere with the emergence of the connectome are considered. The review highlights the importance of advanced image post processing and the need for reproducibility studies for connectomic imaging. Further work and novel data-sharing efforts would be required to validate or disprove recent observations from in utero connectomic studies, which are typically limited by low case numbers and high data drop out. Novel knowledge with regard to the ontogenesis, architecture, and temporal dynamics of the human brain connectome would lead to the more precise understanding of the etiological background of neurodevelopmental and mental disorders. To achieve this goal, this review considers the growing evidence from advanced fetal connectomic imaging for the increased vulnerability of the human brain during late gestation for pathologies that might lead to impaired connectome development and subsequently interfere with the development of neural substrates serving higher cognition.
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http://dx.doi.org/10.1097/RMR.0000000000000220DOI Listing
October 2019

Postoperative brain volumes are associated with one-year neurodevelopmental outcome in children with severe congenital heart disease.

Sci Rep 2019 07 26;9(1):10885. Epub 2019 Jul 26.

Children's Research Centre, University Children's Hospital Zurich, Zürich, Switzerland.

Children with congenital heart disease (CHD) remain at risk for neurodevelopmental impairment despite improved perioperative care. Our prospective cohort study aimed to determine the relationship between perioperative brain volumes and neurodevelopmental outcome in neonates with severe CHD. Pre- and postoperative cerebral MRI was acquired in term born neonates with CHD undergoing neonatal cardiopulmonary bypass surgery. Brain volumes were measured using an atlas prior-based automated method. One-year neurodevelopmental outcome was assessed with the Bayley-III. CHD infants (n = 77) had lower pre- and postoperative total and regional brain volumes compared to controls (n = 44, all p < 0.01). CHD infants had poorer cognitive and motor outcome (p ≤ 0.0001) and a trend towards lower language composite score compared to controls (p = 0.06). Larger total and selected regional postoperative brain volumes were found to be associated with better cognitive and language outcomes (all p < 0.04) at one year. This association was independent of length of intensive care unit stay for total, cortical, temporal, frontal and cerebellar volumes. Therefore, reduced cerebral volume in CHD neonates undergoing bypass surgery may serve as a biomarker for impaired outcome.
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http://dx.doi.org/10.1038/s41598-019-47328-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659678PMC
July 2019

Liposomal doxorubicin attenuates cardiotoxicity via induction of interferon-related DNA damage resistance.

Cardiovasc Res 2020 04;116(5):970-982

Department of Cardiology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.

Aims: The clinical application of doxorubicin (DOX) is severely compromised by its cardiotoxic effects, which limit the therapeutic index and the cumulative dose. Liposomal encapsulation of DOX (Myocet®) provides a certain protective effect against cardiotoxicity by reducing myocardial drug accumulation. We aimed to evaluate transcriptomic responses to anthracyclines with different cardiotoxicity profiles in a translational large animal model for identifying potential alleviation strategies.

Methods And Results: We treated domestic pigs with either DOX, epirubicin (EPI), or liposomal DOX and compared the cardiac, laboratory, and haemodynamic effects with saline-treated animals. Cardiotoxicity was encountered in all groups, reflected by an increase of plasma markers N-terminal pro-brain-natriuretic peptide and Troponin I and an impact on body weight. High morbidity of EPI-treated animals impeded further evaluation. Cardiac magnetic resonance imaging with gadolinium late enhancement and transthoracic echocardiography showed stronger reduction of the left and right ventricular systolic function and stronger myocardial fibrosis in DOX-treated animals than in those treated with the liposomal formulation. Gene expression profiles of the left and right ventricles were analysed by RNA-sequencing and validated by qPCR. Interferon-stimulated genes (ISGs), linked to DNA damage repair and cell survival, were downregulated by DOX, but upregulated by liposomal DOX in both the left and right ventricle. The expression of cardioprotective translocator protein (TSPO) was inhibited by DOX, but not its liposomal formulation. Cardiac fibrosis with activation of collagen was found in all treatment groups.

Conclusions: All anthracycline-derivatives resulted in transcriptional activation of collagen synthesis and processing. Liposomal packaging of DOX-induced ISGs in association with lower cardiotoxicity, which is of high clinical importance in anticancer treatment. Our study identified potential mechanisms for rational development of strategies to mitigate anthracycline-induced cardiomyopathy.
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http://dx.doi.org/10.1093/cvr/cvz192DOI Listing
April 2020

Effect of Ischemic Preconditioning and Postconditioning on Exosome-Rich Fraction microRNA Levels, in Relation with Electrophysiological Parameters and Ventricular Arrhythmia in Experimental Closed-Chest Reperfused Myocardial Infarction.

Int J Mol Sci 2019 Apr 30;20(9). Epub 2019 Apr 30.

Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, 1090 Vienna, Austria.

We investigated the antiarrhythmic effects of ischemic preconditioning (IPC) and postconditioning (PostC) by intracardiac electrocardiogram (ECG) and measured circulating microRNAs (miRs) that are related to cardiac conduction. Domestic pigs underwent 90-min. percutaneous occlusion of the mid left anterior coronary artery, followed by reperfusion. The animals were divided into three groups: acute myocardial infarction (AMI, = 7), ischemic preconditioning-acute myocardial infarction (IPC-AMI) ( = 9), or AMI-PostC ( = 5). IPC was induced by three 5-min. episodes of repetitive ischemia/reperfusion cycles (rI/R) before AMI. PostC was induced by six 30-s rI/R immediately after induction of reperfusion 90 min after occlusion. Before the angiographic procedure, a NOGA endocardial mapping catheter was placed again the distal anterior ventricular endocardium to record the intracardiac electrogram (R-amplitude, ST-Elevation, ST-area under the curve (AUC), QRS width, and corrected QT time (QTc)) during the entire procedure. An arrhythmia score was calculated. Cardiac MRI was performed after one-month. IPC led to significantly lower ST-elevation, heart rate, and arrhythmia score during ischemia. PostC induced a rapid recovery of R-amplitude, decrease in QTc, and lower arrhythmia score during reperfusion. Slightly higher levels of miR-26 and miR-133 were observed in AMI compared to groups IPC-AMI and AMI-PostC. Significantly lower levels of miR-1, miR-208, and miR-328 were measured in the AMI-PostC group as compared to animals in group AMI and IPC-AMI. The arrhythmia score was not significantly associated with miRNA plasma levels. Cardiac MRI showed significantly smaller infarct size in the IPC-AMI group when compared to the AMI and AMI-PostC groups. Thus, IPC led to better left ventricular ejection fraction at one-month and it exerted antiarrhythmic effects during ischemia, whereas PostC exhibited antiarrhythmic properties after reperfusion, with significant downregulaton of ischemia-related miRNAs.
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http://dx.doi.org/10.3390/ijms20092140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540096PMC
April 2019

Left temporal plane growth predicts language development in newborns with congenital heart disease.

Brain 2019 05;142(5):1270-1281

Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.

Congenital heart defects are the most common congenital anomalies, accounting for a third of all congenital anomaly cases. While surgical correction dramatically improved survival rates, the lag behind normal neurodevelopment appears to persist. Deficits in higher cognitive functions are particularly common, including developmental delay in communication and oral-motor apraxia. It remains unclear whether the varying degree of cognitive developmental delay is reflected in variability in brain growth patterns. To answer this question, we aimed to investigate whether the rate of regional brain growth is correlated with later life neurodevelopment. Forty-four newborns were included in our study, of whom 33 were diagnosed with dextro-transposition of the great arteries and 11 with other forms of severe congenital heart defects. During the first month of life, neonates underwent corrective or palliative cardiovascular bypass surgery, pre- and postoperative cerebral MRI were performed 18.7 ± 7.03 days apart. MRI was performed in natural sleep on a 3.0 T scanner using an 8-channel head coil, fast spin-echo T2-weighted anatomical sequences were acquired in three planes. Based on the principles of deformation-based morphometry, we calculated brain growth rate maps reflecting average daily growth occurring between pre- and postoperative brain images. An explorative, whole-brain, threshold-free cluster enhancement analysis revealed strong correlation between the growth rate of the Heschl's gyrus, anterior planum temporale and language score at 12 months of age, corrected for demographic variables (P = 0.018, t = 5.656). No significant correlation was found between brain growth rates and motor or cognitive scores. Post hoc analysis showed that the length of hospitalization interacted with this correlation, longer hospitalization resulted in faster enlargement of the internal CSF spaces. Our longitudinal cohort study provides evidence for the early importance of left-dominant perisylvian regions in auditory and language development before direct postnatal exposure to native language. In congenital heart disease patients, the perioperative period results in a critical variability of brain growth rate in this region, which is a reliable neural correlate of language development at 1 year of age.
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http://dx.doi.org/10.1093/brain/awz067DOI Listing
May 2019

Transcriptional Alterations by Ischaemic Postconditioning in a Pig Infarction Model: Impact on Microvascular Protection.

Int J Mol Sci 2019 Jan 15;20(2). Epub 2019 Jan 15.

Department of Cardiology, Medical University of Vienna, A-1090 Vienna, Austria.

Although the application of cardioprotective ischaemia/reperfusion (I/R) stimuli after myocardial infarction (MI) is a promising concept for salvaging the myocardium, translation to a clinical scenario has not fulfilled expectations. We have previously shown that in pigs, ischaemic postconditioning (IPostC) reduces myocardial oedema and microvascular obstruction (MVO), without influencing myocardial infarct size. In the present study, we analyzed the mechanisms underlying the IPostC-induced microvascular protection by transcriptomic analysis, followed by pathway analysis. Closed-chest reperfused MI was induced by 90 min percutaneous balloon occlusion of the left anterior descending coronary artery, followed by balloon deflation in anaesthetised pigs. Animals were randomised to IPostC ( = 8), MI (non-conditioned, = 8), or Control (sham-operated, = 4) groups. After three hours or three days follow-up, myocardial tissue samples were harvested and subjected to RNA-seq analysis. Although the transcriptome analysis revealed similar expression between IPostC and MI in transcripts involved in cardioprotective pathways, we identified gene expression changes responding to IPostC at the three days follow-up. Focal adhesion signaling, downregulated genes participating in cardiomyopathy and activation of blood cells may have critical consequences for microvascular protection. Specific analyses of the gene subsets enriched in the endothelium of the infarcted area, revealed strong deregulation of transcriptional functional clusters, DNA processing, replication and repair, cell proliferation, and focal adhesion, suggesting sustentative function in the endothelial cell layer protection and integrity. The spatial and time-dependent transcriptome analysis of porcine myocardium supports a protective effect of IPostC on coronary microvasculature post-MI.
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http://dx.doi.org/10.3390/ijms20020344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358966PMC
January 2019

Tracing the structural origins of atypical language representation: consequences of prenatal mirror-imaged brain asymmetries in a dizygotic twin couple.

Brain Struct Funct 2018 Nov 30;223(8):3757-3767. Epub 2018 Jul 30.

Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

We investigated the predictive value of prenatal superior temporal sulcus (STS) depth asymmetry in a special case of a female dizygotic twin that showed inverted prenatal asymmetry of this structure. For this purpose, we performed a follow-up investigation in this former fetus at the age of seven, where we assessed the functional language lateralization using task-based and resting-state functional magnetic resonance imaging (fMRI). As control group we employed her twin brother, who showed a typical folding pattern prenatally, as well as a complementary set of four age-matched children that had fetal MRI of their brains and typical STS depth asymmetry. We could show that the twin with the atypical fetal asymmetry of the STS also showed significantly differing rightward language lateralization in the frontal and temporal lobes. Additionally, resting-state data suggest a stronger connectivity between inferior frontal gyri in this case. The twin showed normal cognitive development. This result gives a first glimpse into the STS' atypical asymmetry being a very early morphological marker for later language lateralization.
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http://dx.doi.org/10.1007/s00429-018-1717-yDOI Listing
November 2018

Microvascular perfusion of the placenta, developing fetal liver, and lungs assessed with intravoxel incoherent motion imaging.

J Magn Reson Imaging 2018 07 27;48(1):214-225. Epub 2017 Dec 27.

Department of Diagnostic Imaging, University Children's Hospital, Zurich, Switzerland.

Background: In utero intravoxel incoherent motion magnetic resonance imaging (IVIM-MRI) provides a novel method for examining microvascular perfusion fraction and diffusion in the developing human fetus.

Purpose: To characterize gestational changes in the microvascular perfusion fraction of the placenta, fetal liver, and lungs using IVIM-MRI.

Study Type: Retrospective, cross-sectional study.

Subjects: Fifty-five datasets from 33 singleton pregnancies were acquired (17-36 gestational weeks).

Field Strength/sequence: In utero diffusion-weighted echo-planar imaging at 1.5T and 3.0T with b-factors ranging from 0 to 900 s/mm in 16 steps.

Assessment: Using the IVIM principle, microvascular perfusion fraction (f), pseudodiffusion (D*), and diffusion coefficients (d) were estimated for the placenta, liver, and lungs with a biexponential model. A free-form nonlinear deformation algorithm was used to correct for the frame-by-frame motion of the fetal organs and the placenta. The IVIM parameters were then compared to a Doppler ultrasound-based assessment of the umbilical artery resistance index.

Statistical Tests: Pearson product-moment correlation coefficient (PMCC) to reveal outlier corrected correlations between Doppler and IVIM parameters. Gestational age-related changes were assessed using linear regression analysis (LR).

Results: Placental f (0.29 ± 0.08) indicates high blood volume in the microvascular compartment, moderately increased during gestation (LR, R = 0.338), and correlated negatively with the umbilical artery resistance index (PMCC, R = -0.457). The f of the liver decreased sharply during gestation (LR, R = -0.436). Lung maturation was characterized by increasing perfusion fraction (LR, R = 0.547), and we found no gestational changes in d and D* values (LR, R = -0.013 and R = 0.051, respectively). The Doppler measurements of the umbilical artery and middle cerebral artery did not correlate with the IVIM parameters of the lungs and liver.

Data Conclusion: Gestational age-associated changes of the placental, liver, and lung IVIM parameters likely reflect changes in placental and fetal circulation, and characterize the trajectory of microstructural and functional maturation of the fetal vasculature.

Level Of Evidence: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2017.
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http://dx.doi.org/10.1002/jmri.25933DOI Listing
July 2018

Porcine model of progressive cardiac hypertrophy and fibrosis with secondary postcapillary pulmonary hypertension.

J Transl Med 2017 10 6;15(1):202. Epub 2017 Oct 6.

Department of Cardiology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Background: Meaningful translational large animal models for cardiac diseases are indispensable for studying disease mechanisms, development of novel therapeutic strategies, and evaluation of potential drugs.

Methods: For induction of heart failure, cardiac hypertrophy and fibrosis, a bare metal stent was implanted in the descending aorta of growing pigs (n = 7), inducing pressure stress on the left ventricle (group HYPI). The constant stent size in growing pigs resulted in antegrade partial obstruction of the aortic flow with a gradual increase in afterload. Five pigs with sham intervention served as control. Serial haemodynamic, pressure-volume loop measurements and transthoracic echocardiography (TTE) were performed to detect developing pressure overload of the LV and cardiac MRI with late enhancement for measuring LV and RV mass and ejection fraction.

Results: At 5-month follow-up, CT and contrast aortography, and intraluminal echocardiography confirmed aortic isthmus stenosis with a mean trans-stenotic gradient of 64 ± 13.9 mmHg. Invasive haemodynamic measurements revealed a secondary increase in pulmonary artery pressure (44.6 ± 5.1 vs 25.9 ± 6.2 mmHg, HYPI vs control, p < 0.05). TTE and ex vivo analyses confirmed severe concentric LV hypertrophy (mean circumferential wall thickness, 19.4 ± 3.1, n = 7 vs 11.4 ± 1.0 mm, n = 5, HYPI vs controls, p < 0.05). The LV and RV mass increased significantly, paralleled by increased isovolumic relaxation constant (tau). Histological analyses confirmed substantial fibrosis and myocyte hypertrophy in both LV and RV. Expressions of ANP, BNP, and miRNA-29a were up-regulated, while SERCA2a and miRNA-1 were down-regulated. Plasma NGAL levels increased gradually, while the elevation of NT-proBNP was detected only at the 5-month FUP.

Conclusion: These data prove that percutaneous artificial aortic stenosis in pigs is useful for inducing clinically relevant progredient heart failure based on myocardial hypertrophy and fibrosis.
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http://dx.doi.org/10.1186/s12967-017-1299-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5639584PMC
October 2017

Intrinsic remote conditioning of the myocardium as a comprehensive cardiac response to ischemia and reperfusion.

Oncotarget 2017 Sep 12;8(40):67227-67240. Epub 2017 Jun 12.

Department of Cardiology, Medical University of Vienna, Vienna, Austria.

We have previously shown that distal anterior wall ischemia/reperfusion induces gene expression changes in the proximal anterior myocardial area, involving genes responsible for cardiac remodeling. Here we investigated the molecular signals of the ischemia non-affected remote lateral and posterior regions and present gene expression profiles of the entire left ventricle by using our novel and straightforward method of 2D and 3D image reconstruction. Five or 24h after repetitive 10min ischemia/reperfusion without subsequent infarction, pig hearts were explanted and myocardial samples from 52 equally distributed locations of the left ventricle were collected. Expressional changes of seven genes of interest (HIF-1α; caspase-3, transcription factor GATA4; myocyte enhancer factor 2C /MEF2c/; hexokinase 2 /HK2/; clusterin /CLU/ and excision repair cross-complementation group 4 /ERCC4/) were measured by qPCR. 2D and 3D gene expression maps were constructed by projecting the fold changes on the NOGA anatomical mapping coordinates. Caspase-3, GATA4, HK2, CLU, and ERCC4 were up-regulated region-specifically in the ischemic zone at 5 h post ischemia/reperfusion injury. Overexpression of GATA4, clusterin and ERCC4 persisted after 24 h. HK2 showed strong up-regulation in the ischemic zone and down-regulation in remote areas at 5 h, and was severely reduced in all heart regions at 24 h. These results indicate a quick onset of regulation of apoptosis-related genes, which is partially reversed in the late phase of ischemia/reperfusion cardioprotection, and highlight variations between ischemic and unaffected myocardium over time. The NOGA 2D and 3D construction system is an attractive method to visualize expressional variations in the myocardium.
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http://dx.doi.org/10.18632/oncotarget.18438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620169PMC
September 2017

diffusion tensor imaging of the fetal brain: A reproducibility study.

Neuroimage Clin 2017 9;15:601-612. Epub 2017 Jun 9.

Department of Diagnostic Imaging, University Children's Hospital, Zürich, Switzerland.

Our purpose was to evaluate the within-subject reproducibility of diffusion tensor imaging (DTI) metrics and the visibility of major white matter structures. Images for 30 fetuses (20-33. postmenstrual weeks, normal neurodevelopment: 6 cases, cerebral pathology: 24 cases) were acquired on 1.5 T or 3.0 T MRI. DTI with 15 diffusion-weighting directions was repeated three times for each case, TR/TE: 2200/63 ms, voxel size: 1 ∗ 1 mm, slice thickness: 3-5 mm, b-factor: 700 s/mm. Reproducibility was evaluated from structure detectability, variability of DTI measures using the coefficient of variation (CV), image correlation and structural similarity across repeated scans for six selected structures. The effect of age, scanner type, presence of pathology was determined using Wilcoxon rank sum test. White matter structures were detectable in the following percentage of fetuses in at least two of the three repeated scans: corpus callosum genu 76%, splenium 64%, internal capsule, posterior limb 60%, brainstem fibers 40% and temporooccipital association pathways 60%. The mean CV of DTI metrics ranged between 3% and 14.6% and we measured higher reproducibility in fetuses with normal brain development. Head motion was negatively correlated with reproducibility, this effect was partially ameliorated by motion-correction algorithm using image registration. Structures on 3.0 T had higher variability both with- and without motion correction. Fetal DTI is reproducible for projection and commissural bundles during mid-gestation, however, in 16-30% of the cases, data were corrupted by artifacts, resulting in impaired detection of white matter structures. To achieve robust results for the quantitative analysis of diffusivity and anisotropy values, fetal-specific image processing is recommended and repeated DTI is needed to ensure the detectability of fiber pathways.
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http://dx.doi.org/10.1016/j.nicl.2017.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477067PMC
April 2018

In vivo MRI and ex vivo histological assessment of the cardioprotection induced by ischemic preconditioning, postconditioning and remote conditioning in a closed-chest porcine model of reperfused acute myocardial infarction: importance of microvasculature.

J Transl Med 2017 04 1;15(1):67. Epub 2017 Apr 1.

Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.

Background: Cardioprotective value of ischemic post- (IPostC), remote (RIC) conditioning in acute myocardial infarction (AMI) is unclear in clinical trials. To evaluate cardioprotection, most translational animal studies and clinical trials utilize necrotic tissue referred to the area at risk (AAR) by magnetic resonance imaging (MRI). However, determination of AAR by MRI' may not be accurate, since MRI-indices of microvascular damage, i.e., myocardial edema and microvascular obstruction (MVO), may be affected by cardioprotection independently from myocardial necrosis. Therefore, we assessed the effect of IPostC, RIC conditioning and ischemic preconditioning (IPreC; positive control) on myocardial necrosis, edema and MVO in a clinically relevant, closed-chest pig model of AMI.

Methods And Results: Acute myocardial infarction was induced by a 90-min balloon occlusion of the left anterior descending coronary artery (LAD) in domestic juvenile female pigs. IPostC (6 × 30 s ischemia/reperfusion after 90-min occlusion) and RIC (4 × 5 min hind limb ischemia/reperfusion during 90-min LAD occlusion) did not reduce myocardial necrosis as assessed by late gadolinium enhancement 3 days after reperfusion and by ex vivo triphenyltetrazolium chloride staining 3 h after reperfusion, however, the positive control, IPreC (3 × 5 min ischemia/reperfusion before 90-min LAD occlusion) did. IPostC and RIC attenuated myocardial edema as measured by cardiac T2-weighted MRI 3 days after reperfusion, however, AAR measured by Evans blue staining was not different among groups, which confirms that myocardial edema is not a measure of AAR, IPostC and IPreC but not RIC decreased MVO.

Conclusion: We conclude that IPostC and RIC interventions may protect the coronary microvasculature even without reducing myocardial necrosis.
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http://dx.doi.org/10.1186/s12967-017-1166-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5376486PMC
April 2017

Sequential activation of different pathway networks in ischemia-affected and non-affected myocardium, inducing intrinsic remote conditioning to prevent left ventricular remodeling.

Sci Rep 2017 03 7;7:43958. Epub 2017 Mar 7.

Department of Cardiology, Medical University of Vienna, Vienna, Austria.

We have analyzed the pathway networks of ischemia-affected and remote myocardial areas after repetitive ischemia/reperfusion (r-I/R) injury without ensuing myocardial infarction (MI) to elaborate a spatial- and chronologic model of cardioprotective gene networks to prevent left ventricular (LV) adverse remodeling. Domestic pigs underwent three cycles of 10/10 min r-I/R by percutaneous intracoronary balloon inflation/deflation in the mid left anterior descending artery, without consecutive MI. Sham interventions (n = 8) served as controls. Hearts were explanted at 5 h (n = 6) and 24 h (n = 6), and transcriptomic profiling of the distal (ischemia-affected) and proximal (non-affected) anterior myocardial regions were analyzed by next generation sequencing (NGS) and post-processing with signaling pathway impact and pathway network analyses. In ischemic region, r-I/R induced early activation of Ca-, adipocytokine and insulin signaling pathways with key regulator STAT3, which was also upregulated in the remote areas together with clusterin (CLU) and TNF-alpha. During the late phase of cardioprotection, antigen immunomodulatory pathways were activated with upregulation of STAT1 and CASP3 and downregulation of neprilysin in both zones, suggesting r-I/R induced intrinsic remote conditioning. The temporo-spatially differently activated pathways revealed a global myocardial response, and neprilysin and the STAT family as key regulators of intrinsic remote conditioning for prevention of adverse remodeling.
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http://dx.doi.org/10.1038/srep43958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339807PMC
March 2017

Safety and efficacy of cardiopoietic stem cells in the treatment of post-infarction left-ventricular dysfunction - From cardioprotection to functional repair in a translational pig infarction model.

Biomaterials 2017 04 23;122:48-62. Epub 2016 Nov 23.

Institute for Regenerative Medicine (IREM), University of Zurich, Zurich, Switzerland; Wyss Translational Center Zurich, ETH and University of Zurich, Zurich, Switzerland; Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, USA.

To date, clinical success of cardiac cell-therapies remains limited. To enhance the cardioreparative properties of stem cells, the concept of lineage-specification through cardiopoietic-guidance has been recently suggested. However, so far, only results from murine studies and from a clinical pilot-trial in chronic heart-failure (CHF) are available, while systematic evidence of its therapeutic-efficacy is still lacking. Importantly, also no data from large animals or for other indications are available. Therefore, we here investigate the therapeutic-efficacy of human cardiopoietic stem cells in the treatment of post-infarction LV-dysfunction using a translational pig-model. Using growth-factor priming, lineage-specification of human bone-marrow derived MSCs was achieved to generate cardiopoietic stem cells according to GMP-compliant protocols. Thereafter, pigs with post-infarction LV-dysfunction (sub-acute phase;1-month) were randomized to either receive transcatheter NOGA 3D electromechanical-mapping guided intramyocardial transplantation of cardiopoietic cells or saline (control). After 30days, cardiac MRI (cMRI) was performed for functional evaluation and in-vivo cell-tracking. This approach was coupled with a comprehensive post-mortem cell-fate and mode-of-repair analysis. Cardiopoietic cell therapy was safe and ejection-fraction was significantly higher when compared to controls (p = 0.012). It further prevented maladaptive LV-remodeling and revealed a significantly lower relative and total infarct-size (p = 0.043 and p = 0.012). As in-vivo tracking and post-mortem analysis displayed only limited intramyocardial cardiopoietic cell-integration, the significant induction of neo-angiogenesis (∼40% higher; p = 0.003) and recruitment of endogenous progenitors (∼2.5x higher; p = 0.008) to the infarct border-zone appeared to be the major modes-of-repair. This is the first report using a pre-clinical large animal-model to demonstrate the safety and efficacy of cardiopoietic stem cells for the treatment of post-infarction LV-dysfunction to prevent negative LV-remodeling and subsequent CHF. It further provides insight into post-delivery cardiopoietic cell-fate and suggests the mechanisms of cardiopoietic cell-induced cardiac-repair. The adoption of GMP-/GLP-compliant methodologies may accelerate the translation into a phase-I clinical-trial in patients with post-ischemic LV-dysfunction broadening the current indication of this interesting cell-type.
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http://dx.doi.org/10.1016/j.biomaterials.2016.11.029DOI Listing
April 2017

Intra-voxel incoherent motion MRI of the living human foetus: technique and test-retest repeatability.

Eur Radiol Exp 2017 22;1(1):26. Epub 2017 Dec 22.

3Department of Diagnostic Imaging, University Children's Hospital, Steinwiesstrasse 75, 8032 Zurich, Switzerland.

Background: Our purpose was to test the within-subject (test-retest) reproducibility of the perfusion fraction, diffusion coefficient, and pseudo-diffusion coefficient measurements in various foetus organs and in the placenta based on the intra-voxel incoherent motion (IVIM) principle.

Methods: In utero diffusion-weighted IVIM magnetic resonance imaging (MRI) was performed in 15 pregnant women (pregnancy age 21-36 weeks) on 1.5-T and 3.0-T clinical scanners with b-factors in the range of 0-900 s/mm in 16 steps. A bi-exponential model was fitted on the volume-averaged diffusion values. Perfusion fraction (f), diffusion coefficient (d), and pseudo-diffusion coefficient (D*) were calculated. Within-subject reproducibility was evaluated as test-retest variability (VAR %) of the IVIM parameters in the foetal frontal cortex, frontal white matter, cerebellum, lungs, kidneys, liver, and in the placenta.

Results: For the foetal lungs, liver and the placenta, test-retest variability was in the range of 14-20% for f, 12-14% for d, and 17-25% for D*. The diffusion coefficients of the investigated brain regions were moderately to highly reproducible (VAR 5-15%). However, f and D* showed inferior reproducibility compared to corresponding measures for the lungs, liver, and placenta. The IVIM parameters of the foetal kidney were revealed to be highly variable across scans.

Conclusions: IVIM MRI potentially provides a novel method for examining microvascular perfusion and diffusion in the developing human foetus. However, reproducibility of perfusion and diffusion parameters depends greatly upon data quality, foetal and maternal movements, and foetal-specific image post-processing.
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http://dx.doi.org/10.1186/s41747-017-0031-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5909359PMC
December 2017

Cloud-Based Evaluation of Anatomical Structure Segmentation and Landmark Detection Algorithms: VISCERAL Anatomy Benchmarks.

IEEE Trans Med Imaging 2016 11 9;35(11):2459-2475. Epub 2016 Jun 9.

Variations in the shape and appearance of anatomical structures in medical images are often relevant radiological signs of disease. Automatic tools can help automate parts of this manual process. A cloud-based evaluation framework is presented in this paper including results of benchmarking current state-of-the-art medical imaging algorithms for anatomical structure segmentation and landmark detection: the VISCERAL Anatomy benchmarks. The algorithms are implemented in virtual machines in the cloud where participants can only access the training data and can be run privately by the benchmark administrators to objectively compare their performance in an unseen common test set. Overall, 120 computed tomography and magnetic resonance patient volumes were manually annotated to create a standard Gold Corpus containing a total of 1295 structures and 1760 landmarks. Ten participants contributed with automatic algorithms for the organ segmentation task, and three for the landmark localization task. Different algorithms obtained the best scores in the four available imaging modalities and for subsets of anatomical structures. The annotation framework, resulting data set, evaluation setup, results and performance analysis from the three VISCERAL Anatomy benchmarks are presented in this article. Both the VISCERAL data set and Silver Corpus generated with the fusion of the participant algorithms on a larger set of non-manually-annotated medical images are available to the research community.
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http://dx.doi.org/10.1109/TMI.2016.2578680DOI Listing
November 2016

Long-Term Outcome of Combined (Percutaneous Intramyocardial and Intracoronary) Application of Autologous Bone Marrow Mononuclear Cells Post Myocardial Infarction: The 5-Year MYSTAR Study.

PLoS One 2016 20;11(10):e0164908. Epub 2016 Oct 20.

Department of Cardiology, Internal Medicine II, Medical University of Vienna, Vienna, Austria.

Objective: The long-term (5-year) outcome of early (3-6 weeks after acute myocardial infarction [AMI], BM-MNC Early group) and late (3-4 months after AMI, BM-MNC Late group) combined (percutaneous intramyocardial and intracoronary) delivery of autologous bone marrow mononuclear cells (BM-MNCs) was evaluated in patients with ejection fractions (EF) between 30-45% post-AMI.

Methods: Major adverse cardiac and cerebrovascular events (MACCE) and hospitalization were recorded. Left (LV) and right (RV) ventricular function were measured by transthoracic echocardiography. Cardiac magnetic resonance imaging (MRI) and myocardial single photon emission computed tomography was performed in a subgroup of patients. Pre-cell therapy myocardial voltage values of treated areas (assessed by NOGA mapping) were correlated with clinical outcome.

Results: Five-year MACCE incidences (7.4%. vs 24.1%) and the composite of all adverse events (11.1% vs 27.6%) were not different between the Early and Late treatment groups. The significant LV-EF increase at 1-year follow-up was preserved at the 5-year control (from baseline to 5-year: 5.3%, 95% CI:0.5-10.1, and 5.7%, 95% CI:1.7-9.6, p<0.05 in the Early and Late groups, respectively), with no significant changes between 1- and 5-year follow-ups. Similarly, RVEF increased significantly from baseline to the 5-year follow-up (Early group: 5.4%, 95% CI:1.0-9.6; and Late group: 8.4%, 95% CI:4.5-12.3). Lower baseline levels of myocardial viability of the treated cardiac area (6.3±2.4 vs 8.2±3.0 mV, p<0.05) were associated with incidence of MACCE.

Conclusions: Percutaneous combined delivery of autologous BM-MNCs is feasible and safe after 5 years, and may result in sustained improvement of cardiac function at 5 years in patients with low EF post-AMI (Clinicaltrials.gov NCT01395212).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0164908PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5072601PMC
June 2017

Feasibility of Diffusion Tractography for the Reconstruction of Intra-Thalamic and Cerebello-Thalamic Targets for Functional Neurosurgery: A Multi-Vendor Pilot Study in Four Subjects.

Front Neuroanat 2016 12;10:76. Epub 2016 Jul 12.

Center for Magnetic Resonance Imaging Research, University Children's Hospital Zürich, Switzerland.

Functional stereotactic neurosurgery by means of deep brain stimulation or ablation provides an effective treatment for movement disorders, but the outcome of surgical interventions depends on the accuracy by which the target structures are reached. The purpose of this pilot study was to evaluate the feasibility of diffusion tensor imaging (DTI) based probabilistic tractography of deep brain structures that are commonly used for pre- and perioperative targeting for functional neurosurgery. Three targets were reconstructed based on their significance as intervention sites or as a no-go area to avoid adverse side effects: the connections propagating from the thalamus to (1) primary and supplementary motor areas, (2) to somatosensory areas and the cerebello-thalamic tract (CTT). We evaluated the overlap of the reconstructed connectivity based targets with corresponding atlas based data, and tested the inter-subject and inter-scanner variability by acquiring repeated DTI from four volunteers, and on three MRI scanners with similar sequence parameters. Compared to a 3D histological atlas of the human thalamus, moderate overlaps of 35-50% were measured between connectivity- and atlas based volumes, while the minimal distance between the centerpoints of atlas and connectivity targets was 2.5 mm. The variability caused by the MRI scanner was similar to the inter-subject variability, except for connections with the postcentral gyrus where it was higher. While CTT resolved the anatomically correct trajectory of the tract individually, high volumetric variability was found across subjects and between scanners. DTI can be applied in the clinical, preoperative setting to reconstruct the CTT and to localize subdivisions within the lateral thalamus. In our pilot study, such subdivisions moderately matched the borders of the ventrolateral-posteroventral (VLpv) nucleus and the ventral-posterolateral (VPL) nucleus. Limitations of the currently used standard DTI protocols were exacerbated by large scanner-to-scanner variability of the connectivity-based targets.
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http://dx.doi.org/10.3389/fnana.2016.00076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940380PMC
July 2016

Validation of In utero Tractography of Human Fetal Commissural and Internal Capsule Fibers with Histological Structure Tensor Analysis.

Front Neuroanat 2015 24;9:164. Epub 2015 Dec 24.

Division of Neuroradiology and Musculoskeletal Radiology, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna Vienna, Austria.

Diffusion tensor imaging (DTI) and tractography offer the unique possibility to visualize the developing white matter macroanatomy of the human fetal brain in vivo and in utero and are currently under investigation for their potential use in the diagnosis of developmental pathologies of the human central nervous system. However, in order to establish in utero DTI as a clinical imaging tool, an independent comparison between macroscopic imaging and microscopic histology data in the same subject is needed. The present study aimed to cross-validate normal as well as abnormal in utero tractography results of commissural and internal capsule fibers in human fetal brains using postmortem histological structure tensor (ST) analysis. In utero tractography findings from two structurally unremarkable and five abnormal fetal brains were compared to the results of postmortem ST analysis applied to digitalized whole hemisphere sections of the same subjects. An approach to perform ST-based deterministic tractography in histological sections was implemented to overcome limitations in correlating in utero tractography to postmortem histology data. ST analysis and histology-based tractography of fetal brain sections enabled the direct assessment of the anisotropic organization and main fiber orientation of fetal telencephalic layers on a micro- and macroscopic scale, and validated in utero tractography results of corpus callosum and internal capsule fiber tracts. Cross-validation of abnormal in utero tractography results could be achieved in four subjects with agenesis of the corpus callosum (ACC) and in two cases with malformations of internal capsule fibers. In addition, potential limitations of current DTI-based in utero tractography could be demonstrated in several brain regions. Combining the three-dimensional nature of DTI-based in utero tractography with the microscopic resolution provided by histological ST analysis may ultimately facilitate a more complete morphologic characterization of axon guidance disorders at prenatal stages of human brain development.
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http://dx.doi.org/10.3389/fnana.2015.00164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4689804PMC
January 2016

Fetal Cerebral Magnetic Resonance Imaging Beyond Morphology.

Semin Ultrasound CT MR 2015 Dec 14;36(6):465-75. Epub 2015 Jun 14.

Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria.

The recent technological advancement of fast magnetic resonance imaging (MRI) sequences allowed the inclusion of diffusion tensor imaging, functional MRI, and proton MR spectroscopy in prenatal imaging protocols. These methods provide information beyond morphology and hold the key to improving several fields of human neuroscience and clinical diagnostics. Our review introduces the fundamental works that enabled these imaging techniques, and also highlights the most recent contributions to this emerging field of prenatal diagnostics, such as the structural and functional connectomic approach. We introduce the advanced image processing approaches that are extensively used to tackle fetal or maternal movement-related image artifacts, and which are necessary for the optimal interpretation of such imaging data.
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http://dx.doi.org/10.1053/j.sult.2015.06.003DOI Listing
December 2015

MIDA: A Multimodal Imaging-Based Detailed Anatomical Model of the Human Head and Neck.

PLoS One 2015 22;10(4):e0124126. Epub 2015 Apr 22.

Division of Biomedical Physics, Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, 20993, United States of America.

Computational modeling and simulations are increasingly being used to complement experimental testing for analysis of safety and efficacy of medical devices. Multiple voxel- and surface-based whole- and partial-body models have been proposed in the literature, typically with spatial resolution in the range of 1-2 mm and with 10-50 different tissue types resolved. We have developed a multimodal imaging-based detailed anatomical model of the human head and neck, named "MIDA". The model was obtained by integrating three different magnetic resonance imaging (MRI) modalities, the parameters of which were tailored to enhance the signals of specific tissues: i) structural T1- and T2-weighted MRIs; a specific heavily T2-weighted MRI slab with high nerve contrast optimized to enhance the structures of the ear and eye; ii) magnetic resonance angiography (MRA) data to image the vasculature, and iii) diffusion tensor imaging (DTI) to obtain information on anisotropy and fiber orientation. The unique multimodal high-resolution approach allowed resolving 153 structures, including several distinct muscles, bones and skull layers, arteries and veins, nerves, as well as salivary glands. The model offers also a detailed characterization of eyes, ears, and deep brain structures. A special automatic atlas-based segmentation procedure was adopted to include a detailed map of the nuclei of the thalamus and midbrain into the head model. The suitability of the model to simulations involving different numerical methods, discretization approaches, as well as DTI-based tensorial electrical conductivity, was examined in a case-study, in which the electric field was generated by transcranial alternating current stimulation. The voxel- and the surface-based versions of the models are freely available to the scientific community.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0124126PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4406723PMC
April 2016

Disrupted developmental organization of the structural connectome in fetuses with corpus callosum agenesis.

Neuroimage 2015 May 26;111:277-88. Epub 2015 Feb 26.

Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Computational Imaging Research Lab (CIR) Vienna, Austria; Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA, USA.

Agenesis of the corpus callosum is a model disease for disrupted connectivity of the human brain, in which the pathological formation of interhemispheric fibers results in subtle to severe cognitive deficits. Postnatal studies suggest that the characteristic abnormal pathways in this pathology are compensatory structures that emerge via neural plasticity. We challenge this hypothesis and assume a globally different network organization of the structural interconnections already in the fetal acallosal brain. Twenty fetuses with isolated corpus callosum agenesis with or without associated malformations were enrolled and fiber connectivity among 90 brain regions was assessed using in utero diffusion tensor imaging and streamline tractography. Macroscopic scale connectomes were compared to 20 gestational age-matched normally developing fetuses with multiple granularity of network analysis. Gradually increasing connectivity strength and tract diffusion anisotropy during gestation were dominant in antero-posteriorly running paramedian and antero-laterally running aberrant pathways, and in short-range connections in the temporoparietal regions. In fetuses with associated abnormalities, more diffuse reduction of cortico-cortical and cortico-subcortical connectivity was observed than in cases with isolated callosal agenesis. The global organization of anatomical networks consisted of less segregated nodes in acallosal brains, and hubs of dense connectivity, such as the thalamus and cingulate cortex, showed reduced network centrality. Acallosal fetal brains show a globally altered connectivity network structure compared to normals. Besides the previously described Probst and sigmoid bundles, we revealed a prenatally differently organized macroconnectome, dominated by increased connectivity. These findings provide evidence that abnormal pathways are already present during at early stages of fetal brain development in the majority of cerebral white matter.
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http://dx.doi.org/10.1016/j.neuroimage.2015.02.038DOI Listing
May 2015

A computational model for bipolar deep brain stimulation of the subthalamic nucleus.

Annu Int Conf IEEE Eng Med Biol Soc 2014 ;2014:6258-61

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been shown to reduce some of the symptoms of advanced, levodopa-responsive Parkinson's disease that are not adequately controlled with medication. However, the precise mechanism of the therapeutic action of DBS is still unclear. Stimulation-induced side effects are not uncommon and require electrical "dose" adjustments. Quantitative methods are needed to fully characterize the electric field in the deep brain region that surrounds the electrodes in order to help with adjustments and maximize the efficacy of the device. Herein we report a magnetic resonance imaging (MRI)-based head model proposed for analysis of fields generated by deep brain stimulation (DBS). The model was derived from multimodal image data at 0.5mm isotropic spatial resolution and distinguishes 142 anatomical structures, including the basal ganglia and 38 nuclei of the thalamus. Six bipolar electrode configurations (1-2, 1-3, 1-4, 2-3, 2-4, 3-4) were modeled in order to assess the effects of the inter-electrode distance of the electric field. Increasing the distance between the electrodes results in an attenuated stimulation, with up to 25% reduction in electric field amplitude delivered (2-3 vs. 1-4). The map of the deep brain structures provided a highly precise anatomical detail which is useful for the quantitative assessment of current spread around the electrode and a better evaluation of the stimulation setting for the treatment optimization.
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http://dx.doi.org/10.1109/EMBC.2014.6945059DOI Listing
November 2015