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1.  Determination of Split Renal Function Using Dynamic CT-Angiography: Preliminary Results 
PLoS ONE  2014;9(3):e91774.
To determine the feasibility of a dynamic CT angiography-protocol with regard to simultaneous assessment of renal anatomy and function.
7 healthy potential kidney donors (58±7 years) underwent a dynamic computed tomography angiography (CTA) using a 128-slice CT-scanner with continuous bi-directional table movement, allowing the coverage of a scan range of 18 cm within 1.75 sec. Twelve scans of the kidneys (n = 14) were acquired every 3.5 seconds with the aim to simultaneously obtain CTA and renal function data. Image quality was assessed quantitatively (HU-measurements) and qualitatively (grade 1–4, 1 = best). The glomerular filtration rate (GFR) was calculated by a modified Patlak method and compared with the split renal function obtained with renal scintigraphy.
Mean maximum attenuation was 464±58 HU, 435±48 HU and 277±29 HU in the aorta, renal arteries, and renal veins, respectively. The abdominal aorta and all renal vessels were depicted excellently (grade 1.0). The image quality score for cortex differentiation was 1.6±0.49, for the renal parenchyma 2.4±0.49. GFR obtained from dynamic CTA correlated well with renal scintigraphy with a correlation coefficient of r = 0.84; P = 0.0002 (n = 14). The average absolute deviation was 1.6 mL/min. The average effective dose was 8.96 mSv.
Comprehensive assessment of renal anatomy and function is feasible using a single dynamic CT angiography examination. The proposed protocol may help to improve management in case of asymmetric kidney function as well as to simplify evaluation of potential living kidney donors.
PMCID: PMC3950217  PMID: 24618919
2.  Non-Contrast-Enhanced MR Angiography at 3 Tesla in Patients with Advanced Peripheral Arterial Occlusive Disease 
PLoS ONE  2014;9(3):e91078.
The aim of this study was to assess the diagnostic performance of ECG-gated non-contrast-enhanced quiescent interval single-shot (QISS) magnetic resonance angiography at a magnetic field strength of 3 Tesla in patients with advanced peripheral arterial occlusive disease (PAOD).
Method and Materials
A total of 21 consecutive patients with advanced PAOD (Fontaine stage IIb and higher) referred for peripheral magnetic resonance angiography (MRA) were included. Imaging was performed on a 3 T whole body MR. Image quality and stenosis diameter were evaluated in comparison to contrast-enhanced continuous table and TWIST MRA (CE-MRA) as standard of reference. QISS images were acquired with a thickness of 1.5 mm each (high-resolution QISS, HR-QISS). Two blinded readers rated the image quality and the degree of stenosis for both HR-QISS and CE-MRA in 26 predefined arterial vessel segments on 5-point Likert scales.
With CE-MRA as the reference standard, HR-QISS showed high sensitivity (94.1%), specificity (97.8%), positive (95.1%), and negative predictive value (97.2%) for the detection of significant (≥50%) stenosis. Interreader agreement for stenosis assessment of both HR-QISS and CE-MRA was excellent (κ-values of 0.951 and 0.962, respectively). As compared to CR-MRA, image quality of HR-QISS was significantly lower for the distal aorta, the femoral and iliac arteries (each with p<0.01), while no significant difference was found in the popliteal (p = 0.09) and lower leg arteries (p = 0.78).
Non-enhanced ECG-gated HR-QISS performs very well in subjects with severe PAOD and is a good alternative for patients with a high risk of nephrogenic systemic fibrosis.
PMCID: PMC3946661  PMID: 24608937
3.  Visualization, imaging and new preclinical diagnostics in radiation oncology 
Innovative strategies in cancer radiotherapy are stimulated by the growing knowledge on cellular and molecular tumor biology, tumor pathophysiology, and tumor microenvironment. In terms of tumor diagnostics and therapy monitoring, the reliable delineation of tumor boundaries and the assessment of tumor heterogeneity are increasingly complemented by the non-invasive characterization of functional and molecular processes, moving preclinical and clinical imaging from solely assessing tumor morphology towards the visualization of physiological and pathophysiological processes. Functional and molecular imaging techniques allow for the non-invasive characterization of tissues in vivo, using different modalities, including computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, positron emission tomography (PET) and optical imaging (OI). With novel therapeutic concepts combining optimized radiotherapy with molecularly targeted agents focusing on tumor cell proliferation, angiogenesis, and cell death, the non-invasive assessment of tumor microcirculation and tissue water diffusion, together with strategies for imaging the mechanisms of cellular injury and repair is of particular interest. Characterizing the tumor microenvironment prior to and in response to irradiation will help to optimize the outcome of radiotherapy. These novel concepts of personalized multi-modal cancer therapy require careful pre-treatment stratification as well as a timely and efficient therapy monitoring to maximize patient benefit on an individual basis. Functional and molecular imaging techniques are key in this regard to open novel opportunities for exploring and understanding the underlying mechanisms with the perspective to optimize therapeutic concepts and translate them into a personalized form of radiotherapy in the near future.
PMCID: PMC3903445  PMID: 24387195
Radiation oncology; Molecular imaging; Functional imaging; Preclinical models
4.  Regorafenib Effects on Human Colon Carcinoma Xenografts Monitored by Dynamic Contrast-Enhanced Computed Tomography with Immunohistochemical Validation 
PLoS ONE  2013;8(9):e76009.
To investigate dynamic contrast-enhanced computed tomography for monitoring the effects of regorafenib on experimental colon carcinomas in rats by quantitative assessments of tumor microcirculation parameters with immunohistochemical validation.
Materials and Methods
Colon carcinoma xenografts (HT-29) implanted subcutaneously in female athymic rats (n = 15) were imaged at baseline and after a one-week treatment with regorafenib by dynamic contrast-enhanced computed tomography (128-slice dual-source computed tomography). The therapy group (n = 7) received regorafenib daily (10 mg/kg bodyweight). Quantitative parameters of tumor microcirculation (plasma flow, mL/100 mL/min), endothelial permeability (PS, mL/100 mL/min), and tumor vascularity (plasma volume, %) were calculated using a 2-compartment uptake model. Dynamic contrast-enhanced computed tomography parameters were validated with immunohistochemical assessments of tumor microvascular density (CD-31), tumor cell apoptosis (TUNEL), and proliferation (Ki-67).
Regorafenib suppressed tumor vascularity (15.7±5.3 to 5.5±3.5%; p<0.05) and tumor perfusion (12.8±2.3 to 8.8±2.9 mL/100 mL/min; p = 0.063). Significantly lower microvascular density was observed in the therapy group (CD-31; 48±10 vs. 113±25, p<0.05). In regorafenib-treated tumors, significantly more apoptotic cells (TUNEL; 11844±2927 vs. 5097±3463, p<0.05) were observed. Dynamic contrast-enhanced computed tomography tumor perfusion and tumor vascularity correlated significantly (p<0.05) with microvascular density (CD-31; r = 0.84 and 0.66) and inversely with apoptosis (TUNEL; r = −0.66 and −0.71).
Regorafenib significantly suppressed tumor vascularity (plasma volume) quantified by dynamic contrast-enhanced computed tomography in experimental colon carcinomas in rats with good-to-moderate correlations to an immunohistochemical gold standard. Tumor response biomarkers assessed by dynamic contrast-enhanced computed tomography may be a promising future approach to a more personalized and targeted cancer therapy.
PMCID: PMC3786893  PMID: 24098755
5.  Translation of Atherosclerotic Plaque Phase-Contrast CT Imaging from Synchrotron Radiation to a Conventional Lab-Based X-Ray Source 
PLoS ONE  2013;8(9):e73513.
Phase-contrast imaging is a novel X-ray based technique that provides enhanced soft tissue contrast. The aim of this study was to evaluate the feasibility of visualizing human carotid arteries by grating-based phase-contrast tomography (PC-CT) at two different experimental set-ups: (i) applying synchrotron radiation and (ii) using a conventional X-ray tube.
Materials and Methods
Five ex-vivo carotid artery specimens were examined with PC-CT either at the European Synchrotron Radiation Facility using a monochromatic X-ray beam (2 specimens; 23 keV; pixel size 5.4 µm), or at a laboratory set-up on a conventional X-ray tube (3 specimens; 35-40 kVp; 70 mA; pixel size 100 µm). Tomographic images were reconstructed and compared to histopathology. Two independent readers determined vessel dimensions and one reader determined signal-to-noise ratios (SNR) between PC-CT and absorption images.
In total, 51 sections were included in the analysis. Images from both set-ups provided sufficient contrast to differentiate individual vessel layers. All PCI-based measurements strongly predicted but significantly overestimated lumen, intima and vessel wall area for both the synchrotron and the laboratory-based measurements as compared with histology (all p<0.001 with slope >0.53 per mm2, 95%-CI: 0.35 to 0.70). Although synchrotron-based images were characterized by higher SNRs than laboratory-based images; both PC-CT set-ups had superior SNRs compared to corresponding conventional absorption-based images (p<0.001). Inter-reader reproducibility was excellent (ICCs >0.98 and >0.84 for synchrotron and for laboratory-based measurements; respectively).
Experimental PC-CT of carotid specimens is feasible with both synchrotron and conventional X-ray sources, producing high-resolution images suitable for vessel characterization and atherosclerosis research.
PMCID: PMC3767700  PMID: 24039969
6.  Convergent Findings of Altered Functional and Structural Brain Connectivity in Individuals with High Functioning Autism: A Multimodal MRI Study 
PLoS ONE  2013;8(6):e67329.
Brain tissue changes in autism spectrum disorders seem to be rather subtle and widespread than anatomically distinct. Therefore a multimodal, whole brain imaging technique appears to be an appropriate approach to investigate whether alterations in white and gray matter integrity relate to consistent changes in functional resting state connectivity in individuals with high functioning autism (HFA). We applied diffusion tensor imaging (DTI), voxel-based morphometry (VBM) and resting state functional connectivity magnetic resonance imaging (fcMRI) to assess differences in brain structure and function between 12 individuals with HFA (mean age 35.5, SD 11.4, 9 male) and 12 healthy controls (mean age 33.3, SD 9.0, 8 male). Psychological measures of empathy and emotionality were obtained and correlated with the most significant DTI, VBM and fcMRI findings. We found three regions of convergent structural and functional differences between HFA participants and controls. The right temporo-parietal junction area and the left frontal lobe showed decreased fractional anisotropy (FA) values along with decreased functional connectivity and a trend towards decreased gray matter volume. The bilateral superior temporal gyrus displayed significantly decreased functional connectivity that was accompanied by the strongest trend of gray matter volume decrease in the temporal lobe of HFA individuals. FA decrease in the right temporo-parietal region was correlated with psychological measurements of decreased emotionality. In conclusion, our results indicate common sites of structural and functional alterations in higher order association cortex areas and may therefore provide multimodal imaging support to the long-standing hypothesis of autism as a disorder of impaired higher-order multisensory integration.
PMCID: PMC3688993  PMID: 23825652
7.  Comparison of symptomatic and asymptomatic atherosclerotic carotid plaques using parallel imaging and 3 T black-blood in vivo CMR 
To determine if black-blood 3 T cardiovascular magnetic resonance (bb-CMR) can depict differences between symptomatic and asymptomatic carotid atherosclerotic plaques in acute ischemic stroke patients.
In this prospective monocentric observational study 34 patients (24 males; 70 ±9.3 years) with symptomatic carotid disease defined as ischemic brain lesions in one internal carotid artery territory on diffusion weighted images underwent a carotid bb-CMR at 3 T with fat-saturated pre- and post-contrast T1w-, PDw-, T2w- and TOF images using surface coils and Parallel Imaging techniques (PAT factor = 2) within 10 days after symptom onset. All patients underwent extensive clinical workup (lab, brain MR, duplex sonography, 24-hour ECG, transesophageal echocardiography) to exclude other causes of ischemic stroke. Prevalence of American Heart Association lesion type VI (AHA-LT6), status of the fibrous cap, presence of hemorrhage/thrombus and area measurements of calcification, necrotic core and hemorrhage were determined in both carotid arteries in consensus by two reviewers who were blinded to clinical information. McNemar and Wilcoxon's signed rank tests were use for statistical comparison. A p-value <0.05 was considered statistically significant.
Symptomatic plaques showed a higher prevalence of AHA-LT6 (67.7% vs. 11.8%; p < 0.001; odds ratio = 12.5), ruptured fibrous caps (44.1% vs. 2.9%; p < 0.001; odds ratio = 15.0), juxtaluminal thrombus (26.5 vs. 0%; p < 0.01; odds ratio = 7.3) and intraplaque hemorrhage (58.6% vs. 11.8%; p = 0.01; odds ratio = 3.8). Necrotic core and hemorrhage areas were greater in symptomatic plaques (14.1 mm2 vs. 5.5 mm2 and 13.6 mm2 vs. 5.3 mm2; p < 0.01, respectively).
3 T bb-CMR is able to differentiate between symptomatic and asymptomatic carotid plaques, demonstrating the potential of bb-CMR to differentiate between stable and vulnerable lesions and ultimately to identify patients with low versus high risk for cardiovascular complications. Best predictors of the symptomatic side were a ruptured fibrous cap, AHA-LT 6, juxtaluminal hemorrhage/thrombus, and intraplaque hemorrhage.
PMCID: PMC3693990  PMID: 23705576
Plaque imaging; Cardiovascular MR; Ischemic stroke; Vulnerable plaque; Atherosclerosis
8.  Diagnosing and Mapping Pulmonary Emphysema on X-Ray Projection Images: Incremental Value of Grating-Based X-Ray Dark-Field Imaging 
PLoS ONE  2013;8(3):e59526.
To assess whether grating-based X-ray dark-field imaging can increase the sensitivity of X-ray projection images in the diagnosis of pulmonary emphysema and allow for a more accurate assessment of emphysema distribution.
Materials and Methods
Lungs from three mice with pulmonary emphysema and three healthy mice were imaged ex vivo using a laser-driven compact synchrotron X-ray source. Median signal intensities of transmission (T), dark-field (V) and a combined parameter (normalized scatter) were compared between emphysema and control group. To determine the diagnostic value of each parameter in differentiating between healthy and emphysematous lung tissue, a receiver-operating-characteristic (ROC) curve analysis was performed both on a per-pixel and a per-individual basis. Parametric maps of emphysema distribution were generated using transmission, dark-field and normalized scatter signal and correlated with histopathology.
Transmission values relative to water were higher for emphysematous lungs than for control lungs (1.11 vs. 1.06, p<0.001). There was no difference in median dark-field signal intensities between both groups (0.66 vs. 0.66). Median normalized scatter was significantly lower in the emphysematous lungs compared to controls (4.9 vs. 10.8, p<0.001), and was the best parameter for differentiation of healthy vs. emphysematous lung tissue. In a per-pixel analysis, the area under the ROC curve (AUC) for the normalized scatter value was significantly higher than for transmission (0.86 vs. 0.78, p<0.001) and dark-field value (0.86 vs. 0.52, p<0.001) alone. Normalized scatter showed very high sensitivity for a wide range of specificity values (94% sensitivity at 75% specificity). Using the normalized scatter signal to display the regional distribution of emphysema provides color-coded parametric maps, which show the best correlation with histopathology.
In a murine model, the complementary information provided by X-ray transmission and dark-field images adds incremental diagnostic value in detecting pulmonary emphysema and visualizing its regional distribution as compared to conventional X-ray projections.
PMCID: PMC3608711  PMID: 23555692
9.  Micro-RNAs as Potential New Molecular Biomarkers in Oncology: Have They Reached Relevance for the Clinical Imaging Sciences? 
Theranostics  2013;3(12):943-952.
Minimally invasive biomarkers for early cancer detection and monitoring of personalized therapies are of high importance to further improve prognosis in oncological disease. MicroRNAs (miRNAs) are small regulatory RNAs in humans and play a key role in carcinogenesis. In recent years they have emerged as promising biomarkers in oncology. miRNA profiling has demonstrated its capacity for sub-classifying tumors and monitoring of therapeutic effects. Different expression profiles of miRNAs in cancer and the stability of circulating miRNAs potentially provide a clinically accessible molecular monitoring tool of malignant tissues and its response to therapies. Clinical imaging including the modalities PET/CT and MRI is well established for characterizing tumor tissue and sub-classifying morphological, metabolic or vascular treatment response in cancer. Sophisticated clinical imaging biomarkers for cancer detection and monitoring should now been correlatively applied to further validate the potential of miRNAs as oncologic biomarkers for the clinic.
PMCID: PMC3881096  PMID: 24396505
MicroRNA; Treatment Monitoring; Personalized Therapy; Cancer Imaging; Biomarker
10.  Characteristics of carotid atherosclerotic plaques of chronic lipid apheresis patients as assessed by In Vivo High-Resolution CMR - a comparative analysis 
Components of carotid atherosclerotic plaques can reliably be identified and quantified using high resolution in vivo 3-Tesla CMR. It is suspected that lipid apheresis therapy in addition to lowering serum lipid levels also has an influence on development and progression of atherosclerotic plaques. The purpose of this study was to evaluate the influence of chronic lipid apheresis (LA) on the composition of atherosclerotic carotid plaques.
32 arteries of 16 patients during chronic LA-therapy with carotid plaques and stenosis of 1–80% were matched according to degree of stenosis with 32 patients, who had recently suffered an ischemic stroke. Of these patients only the asymptomatic carotid artery was analyzed. All patients underwent black-blood 3 T CMR of the carotids using parallel imaging and dedicated surface coils. Cardiovascular risk factors were recorded. Morphology and composition of carotid plaques were evaluated. For statistical evaluation Fisher’s Exact and unpaired t-test were used. A p-value <0.05 was considered statistically significant.
Patients in the LA-group were younger (63.5 vs. 73.9. years, p<0.05), had a higher prevalence of hypercholesterolemia and of established coronary heart disease in patients and in first-degree relatives (p<0.05, respectively). LA-patients had smaller maximum wall areas (49.7 vs. 59.6mm2, p<0.05), showed lower prevalence of lipid cores (28.1% vs. 56.3%, p<0.05) and the lipid content was smaller than in the control group (5.0 vs. 11.6%, p<0.05). Minimum lumen areas and maximum total vessel areas did not differ significantly between both groups.
Results of this study suggest that, despite a severer risk profile for cardiovascular complications in LA-patients, chronic LA is associated with significantly lower lipid content in carotid plaques compared to plaques of patients without LA with similar degrees of stenosis, which is characteristic of clinically stable plaques.
PMCID: PMC3524023  PMID: 23194143
Atherosclerosis; Lipid apheresis; Cardiovascular MR; Plaque imaging; Stroke; Cardiovascular disease
11.  Numerical comparison of X-ray differential phase contrast and attenuation contrast 
Biomedical Optics Express  2012;3(6):1141-1148.
We present a numerical tool to compare directly the contrast-to-noise-ratio (CNR) of the attenuation- and differential phase-contrast signals available from grating-based X-ray imaging for single radiographs. The attenuation projection is differentiated to bring it into a modality comparable to the differential phase projection using a Gaussian derivative filter. A Relative Contrast Gain (RCG) is then defined as the ratio of the CNR of image values in a region of interest (ROI) in the differential phase projection to the CNR of image values in the same ROI in the differential attenuation projection. We apply the method on experimental data of human breast tissue acquired using a grating interferometer to compare the two contrast modes for two regions of interest differing in the type of tissue. Our results indicate that the proposed method can be used as a local estimate of the spatial distribution of the ratio δ/β, i.e., real and imaginary part of the complex refractive index, across a sample.
PMCID: PMC3370957  PMID: 22741063
(110.7440) X-ray imaging; (100.2960) Image analysis; (100.2000) Digital image processing
12.  Anisotropy of transcallosal motor fibers indicates functional impairment in children with periventricular leukomalacia 
In children with bilateral spastic cerebral palsy (CP), periventricular leukomalacia (PVL) is commonly identified on magnetic resonance imaging. We characterized this white matter condition by examining callosal microstructure, interhemispheric inhibitory competence (IIC), and mirror movements.
We examined 7 children (age range 11y 9mo–17y 9mo, median age 15y 10mo, 4 females) with bilateral spastic CP/PVL (Gross Motor Function Classification System level I or II, Manual Ability Classification System level I) and 12 age-matched controls (age range 11y 7mo–17y 1mo, median age 15y 6mo, 7 females). Fractional anisotropy of the transcallosal motor fibers (TCMF) and the corticospinal tract (CST) of both sides were calculated. The parameters of IIC (transcranial magnetic stimulation) and mirror movements were measured using standardized clinical examination and a computer-based hand motor test.
Fractional anisotropy was lower in children with bilateral spastic CP/PVL regarding the TCMF, but not the left or right CST. Resting motor threshold was elevated in children with bilateral spastic CP/PVL whereas measures of IIC tended to be lower. Mirror movements were markedly elevated in bilateral spastic CP/PVL.
This study provides new information on different aspects of motor function in children with bilateral spastic CP/PVL. Decreased fractional anisotropy of TCMF is consistent with impairment of hand motor function in children with bilateral spastic CP/PVL. The previously overlooked microstructure of the TCMF may serve as a potential indicator for hand motor function in patients with bilateral spastic CP/PVL.
PMCID: PMC3057566  PMID: 21121906
13.  Variation within the Huntington's Disease Gene Influences Normal Brain Structure 
PLoS ONE  2012;7(1):e29809.
Genetics of the variability of normal and diseased brain structure largely remains to be elucidated. Expansions of certain trinucleotide repeats cause neurodegenerative disorders of which Huntington's disease constitutes the most common example. Here, we test the hypothesis that variation within the IT15 gene on chromosome 4, whose expansion causes Huntington's disease, influences normal human brain structure. In 278 normal subjects, we determined CAG repeat length within the IT15 gene on chromosome 4 and analyzed high-resolution T1-weighted magnetic resonance images by the use of voxel-based morphometry. We found an increase of GM with increasing long CAG repeat and its interaction with age within the pallidum, which is involved in Huntington's disease. Our study demonstrates that a certain trinucleotide repeat influences normal brain structure in humans. This result may have important implications for the understanding of both the healthy and diseased brain.
PMCID: PMC3250493  PMID: 22235343
14.  Age determination of vessel wall hematoma in spontaneous cervical artery dissection: A multi-sequence 3T Cardiovascular Magnetic resonance study 
Previously proposed classifications for carotid plaque and cerebral parenchymal hemorrhages are used to estimate the age of hematoma according to its signal intensities on T1w and T2w MR images. Using these classifications, we systematically investigated the value of cardiovascular magnetic resonance (CMR) in determining the age of vessel wall hematoma (VWH) in patients with spontaneous cervical artery dissection (sCAD).
35 consecutive patients (mean age 43.6 ± 9.8 years) with sCAD received a cervical multi-sequence 3T CMR with fat-saturated black-blood T1w-, T2w- and TOF images. Age of sCAD was defined as time between onset of symptoms (stroke, TIA or Horner's syndrome) and the CMR scan. VWH were categorized into hyperacute, acute, early subacute, late subacute and chronic based on their signal intensities on T1w- and T2w images.
The mean age of sCAD was 2.0, 5.8, 15.7 and 58.7 days in patients with acute, early subacute, late subacute and chronic VWH as classified by CMR (p < 0.001 for trend). Agreement was moderate between VWH types in our study and the previously proposed time scheme of signal evolution for cerebral hemorrhage, Cohen's kappa 0.43 (p < 0.001). There was a strong agreement of CMR VWH classification compared to the time scheme which was proposed for carotid intraplaque hematomas with Cohen's kappa of 0.74 (p < 0.001).
Signal intensities of VWH in sCAD vary over time and multi-sequence CMR can help to determine the age of an arterial dissection. Furthermore, findings of this study suggest that the time course of carotid hematomas differs from that of cerebral hematomas.
PMCID: PMC3283525  PMID: 22122756
CMR; internal carotid artery dissection; vertebral artery dissection; hematoma; stroke
15.  Childhood Stress, Serotonin Transporter Gene and Brain Structures in Major Depression 
Neuropsychopharmacology  2010;35(6):1383-1390.
The underlying neurobiology of major depression (MD) is likely to represent an interaction between genetic susceptibility and environmental factors such as stress. We investigated, in a multimodal high-resolution magnetic resonance imaging (MRI) genetic study, whether reduced hippocampal volumes and other brain alterations are associated with the tri-allelic polymorphism of the serotonin transporter and childhood stress in patients with MD and healthy subjects. Patients with MD and healthy participants were investigated using high-resolution MRI and genotyping for serotonin transporter polymorphism in the promoter region of the serotonin transporter gene (SLC6A4, 5-HTTLPR). Region of interest analysis of the hippocampus, whole-brain voxel-based morphometry (VBM), and assessment of childhood stress were carried out. Patients carrying the risk S-allele developed smaller hippocampal volumes when they had a history of emotional neglect compared with patients who only had one risk factor (environmental or genetic). In patients, childhood stress also predicted further hippocampal white matter alterations independently from the genotype. Moreover, the left prefrontal cortex was smaller in patients, whereby childhood stress resulted in larger prefrontal volumes in those subjects carrying the non-risk L-allele, suggesting preventive effects. The findings indicate that subjects with both environmental and genetic risk factors are susceptible to stress-related hippocampal changes. Structural brain changes due to stress represent part of the mechanism by which the illness risk and outcome might be genetically mediated.
PMCID: PMC3055341  PMID: 20147891
major depression; childhood stress; 5-HTTLPR; hippocampus; gene–environment; Depression; Unipolar/Bipolar; Serotonin; Imaging; Clinical or Preclinical; Biological Psychiatry; environment-gene interaction; hippocampus; neuroplasticity
17.  Structural MRI correlates for vulnerability and resilience to major depressive disorder 
In major depressive disorder (MDD), it is unclear to what extent structural brain changes are associated with depressive episodes or represent part of the mechanism by which the risk for illness is mediated. The aim of this study was to investigate whether structural abnormalities are related to risk for the development of MDD.
We compared healthy controls with a positive family history for MDD (HC-FHP), healthy controls with no family history of any psychiatric disease (HC-FHN) and patients with MDD. Groups were age- and sex-matched. We analyzed data from high-resolution magnetic resonance imaging using voxel-based morphometry. We performed small volume corrections for our regions of interest (hippocampus, dorsolateral [DLPFC] and dorsomedial prefrontal cortex [DMPFC], anterior cingulate cortex [ACC] and basal ganglia) using a family-wise error correction (p < 0.05) to control for multiple comparisons.
There were 30 participants in the HC-FHP group, 64 in the HC-FHN group and 33 patients with MDD. The HC-FHP group had smaller right hippocampal and DLPFC grey matter volumes compared with the HC-FHN group, and even smaller right hippocampal volumes compared with patients with MDD. In addition, the HC-FHP group exhibited smaller white matter volumes in the DLPFC and left putamen but also greater volumes in 2 areas of the DMPFC compared with the HC-FHN group. Patients with MDD exhibited smaller volumes in the ACC, DMPFC, DLPFC and the basal ganglia compared with healthy controls.
The retrospective identification of family history might result in a bias toward unidentified participants in the control group at risk for MDD, diminishing the effect size.
Volume reductions in the hippocampus and DLPFC might be associated with a greater risk for MDD. The HC-FHP group had smaller hippocampal volumes compared with patients with MDD, which is suggestive for neuroplastic effects of treatment. The HC-FHP group had not yet experienced a depressive episode and therefore might have been resilient and might have had some protective strategies. Whether resilience is associated with the larger white matter volumes in the DMPFC (e.g., owing to compensatory, neuroplastic remodelling mechanisms) needs to be confirmed in future studies.
PMCID: PMC3004971  PMID: 20964952
18.  Usefulness of Age and Gender in the Early Triage of Patients with Acute Chest Pain Having Cardiac Computed Tomographic Angiography 
The American journal of cardiology  2009;104(9):1165-1170.
To identify age- and gender- specific sub-populations of patients with acute chest pain in whom coronary CT angiography (CTA) yields the highest diagnostic benefit. Subjects with acute chest pain and an inconclusive initial evaluation (non-diagnostic electrocardiogram, negative cardiac biomarkers) underwent contrast-enhanced 64-slice CT coronary angiography as part of an observational cohort study. Independent investigators determined the presence of significant coronary stenosis (>50% luminal narrowing) and the occurrence of acute coronary syndrome (ACS) during index hospitalization. We determined diagnostic accuracy and impact on pretest probability of ACS using Bayes' theorem. Among 368 patients (52.7±12 age, 61% males), 8% had ACS. Presence of significant coronary stenosis by CT and the occurrence of ACS increased with age for both men and women (p<0.001). Cardiac CTA was highly sensitive and specific in women younger than 65 years of age (sensitivity: 100% and specificity >87%) and men younger than 55 years of age (sensitivity: 100% in <45 and 80% in 45-54 years old men; specificity: >88.2%). Moreover, in these patients coronary CTA led to restratification from low to high (for a positive CTA) or from low to very low risk (for a negative CTA). In contrast, a negative CTA result did not result in restratification to low risk category in women >65 and men >55 years of age. In conclusion, this analysis provides initial evidence that men <55 and women <65 might benefit more from cardiac CTA than elderly patients. Thus, age and gender may serve as simple criteria to appropriately select patients who may derive the greatest diagnostic benefit from coronary CTA in the setting of acute chest pain.
PMCID: PMC2765413  PMID: 19840556
19.  Metabolic syndrome predicts vascular changes in whole body magnetic resonance imaging in patients with long standing diabetes mellitus 
Although diabetic patients have an increased rate of cardio-vascular events, there is considerable heterogeneity with respect to cardiovascular risk, requiring new approaches to individual cardiovascular risk factor assessment. In this study we used whole body-MR-angiography (WB-MRA) to assess the degree of atherosclerosis in patients with long-standing diabetes and to determine the association between metabolic syndrome (MetS) and atherosclerotic burden.
Long standing (≥10 years) type 1 and type 2 diabetic patients (n = 59; 31 males; 63.3 ± 1.7 years) were examined by WB-MRA. Based on the findings in each vessel, we developed an overall score representing the patient's vascular atherosclerotic burden (MRI-score). The score's association with components of the MetS was assessed.
The median MRI-score was 1.18 [range: 1.00-2.41] and MetS was present in 58% of the cohort (type 2 diabetics: 73%; type 1 diabetics: 26%). Age (p = 0.0002), HDL-cholesterol (p = 0.016), hypertension (p = 0.0008), nephropathy (p = 0.0093), CHD (p = 0.001) and MetS (p = 0.0011) were significantly associated with the score. Adjusted for age and sex, the score was significantly (p = 0.02) higher in diabetics with MetS (1.450 [1.328-1.572]) compared to those without MetS (1.108 [0.966-1.50]). The number of MetS components was associated with a linear increase in the MRI-score (increase in score: 0.09/MetS component; r2 = 0.24, p = 0.038). Finally, using an established risk algorithm, we found a significant association between MRI-score and 10-year risk for CHD, fatal CHD and stroke.
In this high-risk diabetic population, WB-MRA revealed large heterogeneity in the degree of systemic atherosclerosis. Presence and number of traits of the MetS are associated with the extent of atherosclerotic burden. These results support the perspective that diabetic patients are a heterogeneous population with increased but varying prevalence of atherosclerosis and risk.
PMCID: PMC2936364  PMID: 20804545
20.  High resolution carotid black-blood 3T MR with parallel imaging and dedicated 4-channel surface coils 
Most of the carotid plaque MR studies have been performed using black-blood protocols at 1.5 T without parallel imaging techniques. The purpose of this study was to evaluate a multi-sequence, black-blood MR protocol using parallel imaging and a dedicated 4-channel surface coil for vessel wall imaging of the carotid arteries at 3 T.
Materials and methods
14 healthy volunteers and 14 patients with intimal thickening as proven by duplex ultrasound had their carotid arteries imaged at 3 T using a multi-sequence protocol (time-of-flight MR angiography, pre-contrast T1w-, PDw- and T2w sequences in the volunteers, additional post-contrast T1w- and dynamic contrast enhanced sequences in patients). To assess intrascan reproducibility, 10 volunteers were scanned twice within 2 weeks.
Intrascan reproducibility for quantitative measurements of lumen, wall and outer wall areas was excellent with Intraclass Correlation Coefficients >0.98 and measurement errors of 1.5%, 4.5% and 1.9%, respectively. Patients had larger wall areas than volunteers in both common carotid and internal carotid arteries and smaller lumen areas in internal carotid arteries (p < 0.001). Positive correlations were found between wall area and cardiovascular risk factors such as age, hypertension, coronary heart disease and hypercholesterolemia (Spearman's r = 0.45-0.76, p < 0.05). No significant correlations were found between wall area and body mass index, gender, diabetes or a family history of cardiovascular disease.
The findings of this study indicate that high resolution carotid black-blood 3 T MR with parallel imaging is a fast, reproducible and robust method to assess carotid atherosclerotic plaque in vivo and this method is ready to be used in clinical practice.
PMCID: PMC2773764  PMID: 19860875
21.  Classification of Small Contrast Enhancing Breast Lesions in Dynamic Magnetic Resonance Imaging Using a Combination of Morphological Criteria and Dynamic Analysis Based on Unsupervised Vector-Quantization 
Investigative radiology  2008;43(1):56-64.
To evaluate the diagnostic value of breast magnetic resonance imaging (MRI) in small focal lesions using dynamic analysis based on unsupervised vector quantization in combination with a score for morphologic criteria.
Materials and Methods
We examined 85 mammographically indetermintate lesions (BIRADS 3–4; 47 malignant, mean lesion size 1.2 cm; 38 benign, mean lesion size 1.1 cm). MRI was performed with a dynamic T1-weighted gradient echo sequence (1 precontrast and 5 postcontrast series). Lesions with an initial contrast enhancement ≥50% were selected with semiautomatic segmentation. For conventional dynamic analysis, we calculated the mean initial signal increase and postinitial course of all voxels included in a lesion. Secondly, all voxels within the lesions were assigned to 4 clusters using minimal-free-energy vector quantization. Dynamic and morphologic criteria were summarized in a diagnostic score and evaluated by receiver operating characteristic analysis.
In the present collection of small lesions, morphologic criteria [area under the curve (AUC) = 0.610] were inferior to dynamic criteria in the detection of breast cancer. Dynamic analysis with vector quantization (AUC = 0.760) presented slightly better results compared with standard dynamic analysis (AUC = 0.693). There was no benefit for combined morphologic and dynamic analysis.
In small MR-mammographic lesions, dynamic analysis with vector quantization alone tends to result in a higher diagnostic accuracy compared with combined morphologic and dynamic analysis.
PMCID: PMC2758815  PMID: 18097278
breast cancer; breast MRI; vector quantization
22.  MMP-1 serum levels predict coronary atherosclerosis in humans 
Myocardial infarction results as a consequence of atherosclerotic plaque rupture, with plaque stability largely depending on the lesion forming extracellular matrix components. Lipid enriched non-calcified lesions are considered more instable and rupture prone than calcified lesions. Matrix metalloproteinases (MMPs) are extracellular matrix degrading enzymes with plaque destabilisating characteristics which have been implicated in atherogenesis. We therefore hypothesised MMP-1 and MMP-9 serum levels to be associated with non-calcified lesions as determined by CT-angiography in patients with coronary artery disease.
260 patients with typical or atypical chest pain underwent dual-source multi-slice CT-angiography (0.6-mm collimation, 330-ms gantry rotation time) to exclude coronary artery stenosis. Atherosclerotic plaques were classified as calcified, mixed or non-calcified.
In multivariable regession analysis, MMP-1 serum levels were associated with total plaque burden (OR: 1.37 (CI: 1.02-1.85); p < 0.05) in a model adjusted for age, sex, BMI, classical cardiovascular risk factors, hsCRP, adiponectin, pericardial fat volume and medication. Specification of plaque morphology revealed significant association of MMP-1 serum levels with non-calcified plaques (OR: 1.16 (CI: 1.0-1.34); p = 0.05) and calcified plaques (OR: 1.22 (CI: 1,03-1.45); p < 0.05) while association with mixed plaques was lost in the fully adjusted model. No associations were found between MMP9 serum levels and total plaque burden or plaque morphology.
MMP-1 serum levels are associated with total plaque burden but do not allow a specification of plaque morphology.
PMCID: PMC2754422  PMID: 19751510
23.  Advancing radiology through informed leadership: summary of the proceedings of the Seventh Biannual Symposium of the International Society for Strategic Studies in Radiology (IS3R), 23–25 August 2007 
European Radiology  2009;19(8):1827-1836.
The International Society for Strategic Studies in Radiology (IS3R) brings together thought leaders from academia and industry from around the world to share ideas, points of view and new knowledge. This article summarizes the main concepts presented at the 2007 IS3R symposium, providing a window onto trends shaping the future of radiology. Topics addressed include new opportunities and challenges in the field of interventional radiology; emerging techniques for evaluating and improving quality and safety in radiology; and factors impeding progress in molecular imaging and nanotechnology and possible ways to overcome them. Regulatory hurdles to technical innovation and drug development are also discussed more broadly, along with proposals for addressing regulators’ concerns and streamlining the regulatory process.
PMCID: PMC2705708  PMID: 19277668
Interventional radiology; Molecular imaging; Device approval processes; Drug approval processes; Health-care quality; Radiology; Leadership
24.  Low Adiponectin Levels Are an Independent Predictor of Mixed and Non-Calcified Coronary Atherosclerotic Plaques 
PLoS ONE  2009;4(3):e4733.
Atherosclerosis is the primary cause of coronary artery disease (CAD). There is increasing recognition that lesion composition rather than size determines the acute complications of atherosclerotic disease. Low serum adiponectin levels were reported to be associated with coronary artery disease and future incidence of acute coronary syndrome (ACS). The impact of adiponectin on lesion composition still remains to be determined.
Methodology/Principal Findings
We measured serum adiponectin levels in 303 patients with stable typical or atypical chest pain, who underwent dual-source multi-slice CT-angiography to exclude coronary artery stenosis. Atherosclerotic plaques were classified as calcified, mixed or non-calcified. In bivariate analysis adiponectin levels were inversely correlated with total coronary plaque burden (r = −0.21, p = 0.0004), mixed (r = −0.20, p = 0.0007) and non-calcified plaques (r = −0.18, p = 0.003). No correlation was seen with calcified plaques (r = −0.05, p = 0.39). In a fully adjusted multivariate model adiponectin levels remained predictive of total plaque burden (estimate: −0.036, 95%CI: −0.052 to −0.020, p<0.0001), mixed (estimate: −0.087, 95%CI: −0.132 to −0.042, p = 0.0001) and non-calcified plaques (estimate: −0.076, 95%CI: −0.115 to −0.038, p = 0.0001). Adiponectin levels were not associated with calcified plaques (estimate: −0.021, 95% CI: −0.043 to −0.001, p = 0.06). Since the majority of coronary plaques was calcified, adiponectin levels account for only 3% of the variability in total plaque number. In contrast, adiponectin accounts for approximately 20% of the variability in mixed and non-calcified plaque burden.
Adiponectin levels predict mixed and non-calcified coronary atherosclerotic plaque burden. Low adiponectin levels may contribute to coronary plaque vulnerability and may thus play a role in the pathophysiology of ACS.
PMCID: PMC2649379  PMID: 19266101
25.  Effect of hippocampal and amygdala volumes on clinical outcomes in major depression: a 3-year prospective magnetic resonance imaging study 
According to the stress-toxicity hypothesis of depression, hippocampal volumes may diminish as the disease progresses. We sought to examine the changes in hippocampal and amygdala volumes at baseline and at 3 years after an acute depressive episode, and the impact of reduced hippocampal volumes on the outcome.
In a prospective, longitudinal study, we examined the hippocampus and amygdala of 30 inpatients with major depression from the Department of Psychiatry and Psychotherapy and 30 healthy participants from the community (control group) using high-resolution magnetic resonance images at baseline and after 3 years. Psychopathology was assessed at baseline, weekly during the inpatient phase and then after 1, 2 and 3 years.
During the 3-year follow-up period, neither hippocampal nor amygdala volumes changed significantly among patients or participants in the control group. However, in the subgroup of patients who took antidepressants over the full 3 years, the left hippocampal volumes increased significantly. Patients with small hippocampal volumes and previous depressive episodes had a worse clinical outcome compared with patients with large hippocampal volumes and previous depressive episodes.
Overall, our results suggest that a relatively small hippocampal volume may be a vulnerability factor for a bad treatment response in major depression. Subtle changes in hippocampal volumes may be detectable during continuous antidepressant therapy. Such changes may be the result of neuroplastic processes.
PMCID: PMC2527720  PMID: 18787661
hippocampus; amygdala; magnetic resonance imaging; depressive disorder, major

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