Assessment of protein biomarkers for preoperative differential diagnosis between benign and malignant ovarian tumors.

OBJECTIVE: To estimate the diagnostic value of tumor and immune related proteins in the discrimination between benign and malignant adnexal masses, and between different subgroups of tumors. METHODS: In this exploratory diagnostic study, 254 patients with an adnexal mass scheduled for surgery were consecutively enrolled at the University Hospitals Leuven (128 benign, 42 borderline, 22 stage I, 55 stage II-IV, and 7 secondary metastatic tumors). The quantification of 33 serum proteins was done preoperatively, using multiplex high throughput immunoassays (Luminex) and electrochemiluminescence immuno-assay (ECLIA). We calculated univariable areas under the Receiver Operating Characteristic Curves (AUCs). To discriminate malignant from benign tumors, multivariable ridge logistic regression with backward elimination was performed, using bootstrapping to validate the resulting AUCs. RESULTS: CA125 had the highest univariable AUC to discriminate malignant from benign tumors (0.85, 95% confidence interval 0.79-0.89). Combining CA125 with CA72.4 and HE4 increased the AUC to 0.87. For benign vs borderline tumors, CA125 had the highest univariable AUC (0.74). For borderline vs stage I malignancy, no proteins were promising. For stage I vs II-IV malignancy, CA125, HE4, CA72.4, CA15.3 and LAP had univariable AUCs ≥0.80. CONCLUSIONS: The results confirm the dominant role of CA125 for identifying malignancy, and suggest that other markers (HE4, CA72.4, CA15.3 and LAP) may help to distinguish between stage I and stage II-IV malignancies. However, further research is needed, also to investigate the added value over clinical and ultrasound predictors of malignancy, focusing on the differentiation between subtypes of malignancy.

Multi-center reproducibility of structural, diffusion tensor, and resting state functional magnetic resonance imaging measures.

PURPOSE: The aim of this study is to assess multi-center reproducibility and longitudinal consistency of MRI imaging measurements, as part of a phase III longitudinal multi-center study comparing the neurotoxic effect following prophylactic cranial irradiation with hippocampal avoidance (HA-PCI), in comparison with conventional PCI in patients with small-cell lung cancer. METHODS: Harmonized MRI acquisition protocols from six participating sites and two different vendors were compared using both physical and human phantoms. We assessed variability across sites and time points by evaluating various phantoms and data including hippocampal volume, diffusion metrics, and resting-state fMRI, from two healthy volunteers. RESULTS: We report average coefficients of variation (CV) below 5% for intrascanner, intravendor, and intervendor reproducibility for both structural and diffusion imaging metrics, except for diffusion metrics obtained from tractography with average CVs ranging up to 7.8%. Additionally, resting-state fMRI showed stable temporal SNR and reliable generation of subjects DMN across vendors and time points. CONCLUSION: These findings indicate that the presented multi-site MRI acquisition protocol can be used in a longitudinal study design and that pooling of the acquired data as part of the phase III longitudinal HA-PCI project is possible with careful monitoring of the results of the half-yearly QA assessment to follow-up on potential scanner-related longitudinal changes in image quality.

Cyclic movement frequency is associated with muscle typology in athletes.

There is a continuing research interest in the muscle fiber type composition (MFTC) of athletes. Recently, muscle carnosine quantification by proton magnetic resonance spectroscopy (1 H-MRS) was developed as a new non-invasive method to estimate MFTC. This cross-sectional study aims to better understand estimated MFTC in relation to (a) different disciplines within one sport; (b) cyclic sport exercise characteristics; (c) within-athlete variability; and (d) athlete level. A total of 111 elite athletes (74 runners, 7 triathletes, 11 swimmers, 14 cyclists and 5 kayakers) and 188 controls were recruited to measure muscle carnosine in gastrocnemius and deltoid muscle by 1 H-MRS. Within sport disciplines, athletes were divided into subgroups (sprint-, intermediate-, and endurance-type). The controls were used as reference population to allow expression of the athletes' data as Z-scores. Within different sports, endurance-type athletes systematically showed the lowest Z-score compared to sprint-type athletes, with intermediate-type athletes always situated in between. Across the different sports disciplines, carnosine content showed the strongest significant correlation with cyclic movement frequency (R = 0.86, P = 0.001). Both within and between different cyclic sports, estimated MFTC was divergent between sprint- and endurance-type athletes. Cyclic movement frequency, rather than exercise duration came out as the most determining factor for the optimal estimated MFTC in elite athletes.

Comparison of unsupervised classification methods for brain tumor segmentation using multi-parametric MRI.

Tumor segmentation is a particularly challenging task in high-grade gliomas (HGGs), as they are among the most heterogeneous tumors in oncology. An accurate delineation of the lesion and its main subcomponents contributes to optimal treatment planning, prognosis and follow-up. Conventional MRI (cMRI) is the imaging modality of choice for manual segmentation, and is also considered in the vast majority of automated segmentation studies. Advanced MRI modalities such as perfusion-weighted imaging (PWI), diffusion-weighted imaging (DWI) and magnetic resonance spectroscopic imaging (MRSI) have already shown their added value in tumor tissue characterization, hence there have been recent suggestions of combining different MRI modalities into a multi-parametric MRI (MP-MRI) approach for brain tumor segmentation. In this paper, we compare the performance of several unsupervised classification methods for HGG segmentation based on MP-MRI data including cMRI, DWI, MRSI and PWI. Two independent MP-MRI datasets with a different acquisition protocol were available from different hospitals. We demonstrate that a hierarchical non-negative matrix factorization variant which was previously introduced for MP-MRI tumor segmentation gives the best performance in terms of mean Dice-scores for the pathologic tissue classes on both datasets.

A neuroradiologist's guide to arterial spin labeling MRI in clinical practice.

Arterial spin labeling (ASL) is a non-invasive MRI technique to measure cerebral blood flow (CBF). This review provides a practical guide and overview of the clinical applications of ASL of the brain, as well its potential pitfalls. The technical and physiological background is also addressed. At present, main areas of interest are cerebrovascular disease, dementia and neuro-oncology. In cerebrovascular disease, ASL is of particular interest owing to its quantitative nature and its capability to determine cerebral arterial territories. In acute stroke, the source of the collateral blood supply in the penumbra may be visualised. In chronic cerebrovascular disease, the extent and severity of compromised cerebral perfusion can be visualised, which may be used to guide therapeutic or preventative intervention. ASL has potential for the detection and follow-up of arteriovenous malformations. In the workup of dementia patients, ASL is proposed as a diagnostic alternative to PET. It can easily be added to the routinely performed structural MRI examination. In patients with established Alzheimer's disease and frontotemporal dementia, hypoperfusion patterns are seen that are similar to hypometabolism patterns seen with PET. Studies on ASL in brain tumour imaging indicate a high correlation between areas of increased CBF as measured with ASL and increased cerebral blood volume as measured with dynamic susceptibility contrast-enhanced perfusion imaging. Major advantages of ASL for brain tumour imaging are the fact that CBF measurements are not influenced by breakdown of the blood-brain barrier, as well as its quantitative nature, facilitating multicentre and longitudinal studies.

Muscle carnosine loading by beta-alanine supplementation is more pronounced in trained vs. untrained muscles.

Carnosine occurs in high concentrations in human skeletal muscle and assists working capacity during high-intensity exercise. Chronic beta-alanine (BA) supplementation has consistently been shown to augment muscle carnosine concentration, but the effect of training on the carnosine loading efficiency is poorly understood. The aim of the present study was to compare muscle carnosine loading between trained and untrained arm and leg muscles. In a first study (n = 17), reliability of carnosine quantification by proton magnetic resonance spectroscopy ((1)H-MRS) was evaluated in deltoid and triceps brachii muscles. In a second study, participants (n = 35; 10 nonathletes, 10 cyclists, 10 swimmers, and 5 kayakers) were supplemented with 6.4 g/day of slow-release BA for 23 days. Carnosine content was evaluated in soleus, gastrocnemius medialis, and deltoid muscles by (1)H-MRS. All the results are reported as arbitrary units. In the nonathletes, BA supplementation increased carnosine content by 47% in the arm and 33% in the leg muscles (not significant). In kayakers, the increase was more pronounced in arm (deltoid) vs. leg (soleus + gastrocnemius) muscles (0.089 vs. 0.049), whereas the reverse pattern was observed in cyclists (0.065 vs. 0.084). Swimmers had significantly higher increase in carnosine in both deltoid (0.107 vs. 0.065) and gastrocnemius muscle (0.082 vs. 0.051) compared with nonathletes. We showed that 1) carnosine content can be reliably measured by (1)H-MRS in deltoid muscle, 2) carnosine loading is equally effective in arm vs. leg muscles of nonathletes, and 3) carnosine loading is more pronounced in trained vs. untrained muscles.

Multifocal intraparietal activation during discrimination of action intention in observed tool grasping.

The way we grasp an object varies depending on how we want to use that object, and this knowledge can be used to predict the object-related behavior of others. In this study, we assessed the neural correlates that determine the action intention of another person based on observed prehensile movements. Fourteen right-handed volunteers watched video clips of a person performing right-handed transitive grasping gestures that were either aimed at displacing or using a tool-object. Clips showing the grasping and displacement of neutral shapes served as a control condition. By discrimination of the actor's intention, three roughly symmetrical foci were activated in the anterior, middle, and caudal segments of the intraparietal sulci, and in the fusiform gyri and parts of the lateral occipital complex. Anterior intraparietal activation has been associated with the representation of object goals (object specific), and the present findings extend its involvement to functional goals (use-specific). Activation in the middle intraparietal region during intention discrimination was very similar to the activation elicited in a saccadic localizer task, suggesting a relation with spatial attention and eye movements. The caudal intraparietal region has been related with visuospatial guidance of reaching, and its activation during action intention discrimination indicates that the visuospatial properties of the observed reaching movement contribute to understanding of actions. As these parietal regions are strongly linked with motor behavior, our results appear to support the motor simulation hypothesis for action understanding with the preferential recruitment of the mirror-neuron system. This could at least be the case when no contextual information other than the visual properties of the movement is provided to discriminate the intention of an observed hand action.

MRI analysis of muscle/fat index of the superficial and deep neck muscles in an asymptomatic cohort.

All muscles of the neck have a role in motion and postural control of the cervical region. The aim of this study was to investigate the difference in muscle/fat index between (1) cervical flexors and extensors and (2) deep and superficial neck muscles. Twenty-six healthy subjects participated in the study. Magnetic resonance imaging (MRI) was used to quantify muscle fat indices in different cervical flexor and extensor muscles at the C4-C5 level. Overall, the ventral muscles had a significantly lower fat content compared with the dorsal muscles (P < or = 0.001). For the cervical extensors, significant differences between the muscle/fat index of the deep and superficial muscles were found (P < or = 0.001). For the cervical flexors, there were no significant differences between the different muscles. The higher fat content in the dorsal muscles can be explained by a discrepancy in function between the spine extensors and flexors, reflected in a different muscle fiber distribution. The rather small differences between superficial and deep neck muscles are in line with recent findings that have demonstrated that both muscles groups exhibit phasic activity during isometric muscles contractions and the presumption that there is no difference in fiber type distribution between superficial and deep neck muscles.

Microglial imaging with positron emission tomography and atrophy measurements with magnetic resonance imaging in multiple sclerosis: a correlative study.

OBJECTIVE: The objectives of the present study were to assess brain atrophy in multiple sclerosis (MS) patients during different disease stages and to investigate by PET and [11C]PK11195, a marker of microglial activation, the relationship between inflammation, atrophy and clinically relevant measures. METHODS: Eight healthy subjects and 22 MS patients were included. Semiquantitative [11C]PK11195 uptake values, with normalization on cortical grey matter, were measured for magnetic resonance imaging T2- and T1-lesions and normal appearing white matter (NAWM). As atrophy index we used the ratio of the amount of white and grey matter divided by the ventricular size, using an optimized a priori based segmentation algorithm (SPM99). RESULTS: Atrophy was significantly greater in MS patients compared to age-matched controls. A significant correlation was found between brain atrophy and both disease duration and disability, as measured with the Expanded Disability Status Scale. For NAWM, [11C]PK11195 uptake increased with the amount of atrophy, while T2-lesional [11C]PK11195 uptake values decreased according to increasing brain atrophy. CONCLUSIONS: The present study suggests that brain atrophy, correlating with disease duration and disability, is directly related to NAWM and T2-lesional inflammation as measured by microglial activation.

Comparison between 1 T MRI and non-MRI based volumetry in inoculated tumours in mice.

Tumour volume is an important therapeutic endpoint for mouse tumour models in the evaluation of new chemotherapeutic drugs and in pre-clinical evaluation of new radioimmunotherapy pharmaceuticals. In this study, two 1 T MRI-based methods both using T1-T2 hybrid weighting, a manual method (determination of the area per slice) and a semi-automated method (using thresholding), are compared with two classical methods, the abovementioned calliper method and volumetry by water displacement after dissection of the tumour. Interoperator and intraoperator differences for both MRI-based methods were good (no differences p<0.05 using a repeated measures analysis of variance (ANOVA) test). Correlation between the different methods was excellent. No significant differences were obtained (p<0.05), except for the semi-automated method, because it automatically excludes necrotic regions from the tumour. Therefore, we conclude that both manual and semi-automated tumour volumetry in subcutaneous tumour bearing athymic mice by low-field MRI are accurate and reliable methods. The semi-automated method is especially useful for larger tumour volumes, since it accounts for necrotic areas within the tumour.

Does egocentric mental rotation elicit sex differences?

Mental rotation tests traditionally show a male performance advantage. Some neuroimaging studies have reported sex-specific cortical activation patterns during mental rotation. However, these experiments used abstract stimuli and some studies did not systematically exclude performance as a confounding variable. The mental rotation of hands and hand-related objects, compared to abstract objects, is known to evoke an egocentric motor strategy. In this study, we used fMRI to explore potential gender-specific cortical activation patterns for the mental rotation of hands and tools in a sample with an adequate and equal performance for men and women. We found a common neural substrate for men and women comprising superior parietal lobe, dorsolateral premotor cortex, and extrastriate occipital areas, compatible with an egocentric motor strategy for the mental rotation of hands and tools. Sex differences were modest and limited to the mental rotation of hands. Women recruited more left ventral premotor cortex, which could imply that women rely more on imitation or use more perceptual comparisons. Men, on the other hand, drafted more the lingual gyrus, possibly referring to more extensive semantic or early visual processing. We conclude that men and women use a very similar motor strategy during egocentric mental rotation with a potential gender-specific accent.

MRI language dominance assessment in epilepsy patients at 1.0 T: region of interest analysis and comparison with intracarotid amytal testing.

The primary goal of this study was to test the reliability of presurgical language lateralization in epilepsy patients with functional magnetic resonance imaging (fMRI) with a 1.0-T MR scanner using a simple word generation paradigm and conventional equipment. In addition, hemispherical fMRI language lateralization analysis and region of interest (ROI) analysis in the frontal and temporo-parietal regions were compared with the intracarotid amytal test (IAT). Twenty epilepsy patients under presurgical evaluation were prospectively examined by both fMRI and IAT. The fMRI experiment consisted of a word chain task (WCT) using the conventional headphone set and a sparse sequence. In 17 of the 20 patients, data were available for comparison between the two procedures. Fifteen of these 17 patients were categorized as left hemispheric dominant, and 2 patients demonstrated bilateral language representation by both fMRI and IAT. The highest reliability for lateralization was obtained using frontal ROI analysis. Hemispherical analysis was less powerful and reliable in all cases but one, while temporo-parietal ROI analysis was unreliable as a stand-alone analysis when compared with IAT. The effect of statistical threshold on language lateralization prompted for the use of t-value-dependent lateralization index plots. This study illustrates that fMRI-determined language lateralization can be performed reliably in a clinical MR setting operating at a low field strength of 1 T without expensive stimulus presentation systems.

Validation and application of polymer gel dosimetry for the dose verification of an intensity-modulated arc therapy (IMAT) treatment.

Polymer gel dosimetry was used to assess an intensity-modulated arc therapy (IMAT) treatment for whole abdominopelvic radiotherapy. Prior to the actual dosimetry experiment, a uniformity study on an unirradiated anthropomorphic phantom was carried out. A correction was performed to minimize deviations in the R2 maps due to radiofrequency non-uniformities. In addition, compensation strategies were implemented to limit R2 deviations caused by temperature drift during scanning. Inter- and intra-slice R2 deviations in the phantom were thereby significantly reduced. This was verified in an investigative study where the same phantom was irradiated with two rectangular superimposed beams: structural deviations between gel measurements and computational results remained below 3% outside high dose gradient regions; the spatial shift in those regions was within 2.5 mm. When comparing gel measurements with computational results for the IMAT treatment, dose deviations were noted in the liver and right kidney, but the dose-volume constraints were met. Root-mean-square differences between both dose distributions were within 5% with spatial deviations not more than 2.5 mm. Dose fluctuations due to gantry angle discretization in the dose computation algorithm were particularly noticeable in the low-dose region.

Usefulness of language and memory testing during intracarotid amobarbital testing: observations from an fMRI study.

BACKGROUND: Several procedures for testing language lateralization and memory function exist during the intracarotid amobarbital test (IAT). The use of functional magnetic resonance imaging (fMRI) gives the opportunity to assess the validity of some of these procedures, or at least to inspect the neuronal correlates. A comprehensive fMRI protocol was tested, aimed at addressing aspects of lateralization of language, as well as testing memory in relation to activation of mesiotemporal regions. Here we report observations with possible consequences for the current IAT procedures. MATERIALS AND METHODS: The protocol consisted of three language tasks (overt naming, semantic decision and silent word generation) and two memory tasks (encoding and retrieving visual scenes). The paradigms used a block-related procedure in nine right-handed normal volunteers. During the procedure dynamic weighted full brain images were acquired which are sensitive to the blood oxygenation activation effect. RESULTS: Encoding showed symmetrical bilateral activation in the mesiotemporal regions, specifically the hippocampus, parahippocampal gyrus and fusiform gyrus. With a retrieval task activation of the mesiotemporal areas was restricted to the posterior hippocampal area. Overt object naming showed results, similar to encoding tasks with bilateral activation of hippocampal areas. Silent word generation showed much stronger ability to lateralize than the other two language-related tasks and especially object naming. CONCLUSION: Activation revealed by fMRI activation shows that IAT procedures, using active semantic language processing or comprehensive procedures with multiple language tasks have the highest guarantee for individual activation lateralization. Simple object naming does not guarantee a lateralized language fMRI activation pattern. Of the different memory procedures during IAT, the procedures (Interview and the Montreal) demanding encoding processing will be related to larger areas of bilateral hippocampal activation than procedures (Seattle) exclusively requiring retrieval. Moreover, tasks using recognition of previously presented language items (naming objects) are equally effective for assessing hippocampal activation compared with presenting separate memory items.

PET visualization of microglia in multiple sclerosis patients using [11C]PK11195.

Activated microglia are involved in the immune response of multiple sclerosis (MS). The peripheral benzodiazepine receptor (PBR) is expressed on microglia and up-regulated after neuronal injury. [11C]PK11195 is a positron emission tomography (PET) radioligand for the PBR. The objective of the present study was to investigate [11C]PK11195 imaging in MS patients and its additional value over magnetic resonance imaging (MRI) concerning the immuno-pathophysiological process. Seven healthy and 22 MS subjects were included. Semiquantitative [11C]PK11195 uptake values were assessed with normalization on cortical grey matter. Uptake in Gadolinium-lesions was significantly increased compared with normal white matter. Uptake in T2-lesions was generally decreased, suggesting a PBR down-regulation. However, uptake values increased whenever a clinical or MR-relapse was present, suggestive for a dynamic process with a transient PBR up-regulation. During disease progression, an increase of normal-appearing white matter (NAWM) uptake was found, propagating NAWM as the possible real burden of disease. In conclusion, [11C]PK11195 and PET are able to demonstrate inflammatory processes with microglial involvement in MS.

A pure sensorimotor stroke due to cervical vertebral artery occlusion.

We reviewed the case history of a 45 year-old women, who presented a pure right sensorimotor stroke, due to a left paramedial medullary infarct as result of a left cervical vertebral artery occlusion. The unusual location of the infarct could be explained by the combination of an anatomical variant of the left branch of the anterior spinal artery and the presence of a deep cervical artery, issued from the costo-cervical trunck. This collateral circulation allowed that the lateral and upper medulla was not infarcted.

Developing a comprehensive presurgical functional MRI protocol for patients with intractable temporal lobe epilepsy: a pilot study.

Our aim was to put together and test a comprehensive functional MRI (fMRI) protocol which could compete with the intracarotid amytal (IAT) or Wada test for the localisation of language and memory function in patients with intractable temporal lobe epilepsy. The protocol was designed to be performed in under 1 h on a standard 1.5 tesla imager. We used five paradigms to test nine healthy right-handed subjects: complex scene-encoding, picture-naming, reading, word-generation and semantic-decision tasks. The combination of these tasks generated two activation maps related to memory in the mesial temporal lobes, and three language-related maps of activation in a major part of the known language network. The functional maps from the encoding and naming tasks showed typical and symmetrical posterior mesial temporal lobe activation related to memory in all subjects. Only four of nine subjects also showed symmetrical anterior hippocampal activation. Language lateralisation was best with the word generation and reading paradigms and proved possible in all subjects. The reading paradigm enables localisation of language function in the left anterior temporal pole and middle temporal gyrus, areas typically resected during epilepsy surgery. The combined results of this comprehensive f MRI protocol are adequate for a comparative study with the IAT in patients with epilepsy being assessed for surgery.