Quantifying multiple sclerosis pathology in post mortem spinal cord using MRI.

Multiple sclerosis (MS) is a common inflammatory, demyelinating and degenerative disease of the central nervous system. The majority of people with MS present with symptoms due to spinal cord damage, and in more advanced MS a clinical syndrome resembling that of progressive myelopathy is not uncommon. Significant efforts have been undertaken to predict MS-related disability based on short-term observations, for example, the spinal cord cross-sectional area measured using MRI. The histo-pathological correlates of spinal cord MRI changes in MS are incompletely understood, however a surge of interest in tissue microstructure has recently led to new approaches to improve the precision with which MRI indices relate to underlying tissue features, such as myelin content, neurite density and orientation, among others. Quantitative MRI techniques including T1 and T2, magnetisation transfer (MT) and a number of diffusion-derived indices have all been successfully applied to post mortem MS spinal cord. Combining advanced quantification of histological features with quantitative - particularly diffusion-based - MRI techniques provide a new platform for high-quality MR/pathology data generation. To more accurately quantify grey matter pathology in the MS spinal cord, a key driver of physical disability in advanced MS, remains an important challenge of microstructural imaging.

FLAIR* to visualize veins in white matter lesions: A new tool for the diagnosis of multiple sclerosis?

OBJECTIVE: To explore the potential of a post-processing technique combining FLAIR and T2* (FLAIR*) to distinguish between lesions caused by multiple sclerosis (MS) from cerebral small vessel disease (SVD) in a clinical setting. METHODS: FLAIR and T2* head datasets acquired at 3T of 25 people with relapsing MS (pwRMS) and ten with pwSVD were used. After post-processing, FLAIR* maps were used to determine the proportion of white matter lesions (WML) showing the 'vein in lesion' sign (VIL), a characteristic histopathological feature of MS plaques. Sensitivity and specificity of MS diagnosis were examined on the basis of >45% VIL+ and >60% VIL+ WML, and compared with current dissemination in space (DIS) MRI criteria. RESULTS: All pwRMS had >45% VIL+ WML (range 58-100%) whilst in pwSVD the proportion of VIL+ WML was significantly lower (0-64%; mean 32±20%). Sensitivity based on >45% VIL+ was 100% and specificity 80% whilst with >60% VIL+ as the criterion, sensitivity was 96% and specificity 90%. DIS criteria had 96% sensitivity and 40% specificity. CONCLUSION: FLAIR* enables VIL+ WML detection in a clinical setting, facilitating differentiation of MS from SVD based on brain MRI. KEY POINTS: • FLAIR* in a clinical setting allows visualization of veins in white matter lesions. • Significant proportions of MS lesions demonstrate a vein in lesion on MRI. • Microangiopathic lesions demonstrate a lower proportion of intralesional veins than MS lesions. • Intralesional vein-based criteria may complement current MRI criteria for MS diagnosis.

Use of an internal reference in semi-quantitative dynamic contrast-enhanced MRI (DCE MRI) of indeterminate adnexal masses.

OBJECTIVE: Semi-quantitative dynamic contrast-enhanced MRI (DCE MRI) has proven useful in discriminating benign from borderline/malignant adnexal lesions. Our aim was to assess if the use of a lesion-to-internal-reference ratio improved the performance in characterizing adnexal masses and which internal reference was suitable. METHODS: Semi-quantitative DCE MRI images of 71 indeterminate adnexal lesions were retrospectively reviewed. A region of interest was manually drawn onto the enhancing solid component, psoas muscle and normal outer myometrium. The DCE parameters were evaluated, and the lesion-to-internal-reference ratios were calculated. RESULTS: When the wash in rate of the lesion was higher than that of the myometrium, 97% specificity and 12% sensitivity for borderline/malignancy was reached. When the maximum relative enhancement and maximum absolute enhancement (SImax) of the lesion was less than those of the psoas, 100% specificity for benignity was achieved. The highest area under the curve (AUC) (0.807) was achieved using a SImax lesion-myometrium ratio. A slightly lower AUC (0.799) was achieved using a SImax lesion-psoas ratio, but the psoas muscle was more frequently measurable in the same slice as the lesion ROI. Although the AUC was higher, when using ratios instead of individual DCE values, this was not significantly different. CONCLUSION: DCE MRI has added diagnostic value in the assessment of adnexal lesions, and the use of internal references enables high specificity for malignancy and benignity. Lesion-internal-reference ratios have no added diagnostic value over DCE values alone. ADVANCES IN KNOWLEDGE: Both psoas muscle and myometrium are suitable internal references in the DCE assessment of adnexal lesions enabling high specificity for malignancy and benignity.

Diffusion-weighted and multiphase contrast-enhanced MRI as surrogate markers of response to neoadjuvant sunitinib in metastatic renal cell carcinoma.

BACKGROUND: Current imaging criteria for categorising disease response in metastatic renal cell carcinoma (mRCC) correlate poorly with overall survival (OS) in patients on anti-angiogenic therapies. We prospectively assess diffusion-weighted and multiphase contrast-enhanced (MCE) MR imaging (MRI) as markers of outcome. METHODS: Treatment-naive mRCC patients on a phase II trial using sunitinib completed an MRI substudy. Whole-tumour apparent diffusion coefficient (ADC) maps and histograms were generated, and mean ADC and AUC(low) (proportion of the tumour with ADC values lying below the 25th percentile of the ADC histogram) recorded. On MCE-MRI, regions of interest were drawn around the most avidly enhancing components to analyse enhancement parameters. Baseline (n=26) and treatment-related changes in surviving patients (n=20) were correlated with OS. Imaged metastases were also analysed. RESULTS: Forty-seven per cent of the patients showed significant changes in whole-tumour mean ADC following therapy, but there was no correlation with outcome. Patients with a high baseline AUC(low) and greater-than-median AUC(low) increase had reduced OS (HR=3.67 (95% confidence interval (CI)=1.23-10.9), P=0.012 and HR=3.72 (95% CI=0.98-14.21), P=0.038, respectively). There was no correlation between MCE-MRI parameters and OS. Twenty-eight metastases were analysed and showed positive correlation with primary tumour mean ADC for individual patients (r=0.607; P<0.001). CONCLUSION: Primary RCC ADC histogram analysis shows dynamic changes with sunitinib. Patients in whom the tumour ADC histogram demonstrated high baseline AUC(low) or a greater-than-median increase in AUC(low) with treatment had reduced OS.

Patient-specific respiratory models using dynamic 3D MRI: preliminary volunteer results.

Organ and tumour motion has a significant impact on the planning and delivery of radiotherapy treatment. At present imaging modality such as four-dimensional computer tomography (4DCT) cannot be used to measure the variability of motion between different respiratory cycles. To create reliable motion models, one needs to acquire volumetric data sets of the lungs with sufficient sampling of the breathing cycle. In this paper we investigate the use of highly parallel MRI to acquire such data. A 32 channel coil in conjunction with a balanced SSFP sequence and a SENSE factor of 6 were used to acquire volumetric data sets in five healthy volunteers. The acquisition was repeated for seven series of different breathing patterns. The data acquired was of sufficient spatial resolution (5 × 5 × 5 mm(3)) and image quality to carry out automated non-rigid registration. The acquisition rate (c.a. 2 volumes per second) allowed for a meaningful sampling of the different respiratory curves that were automatically obtained from the skin surface motion. This acquisition technique should provide images of high enough quality to create statistical respiratory models.

Towards clinical assessment of velopharyngeal closure using MRI: evaluation of real-time MRI sequences at 1.5 and 3 T.

OBJECTIVE: The objective of this study was to demonstrate soft palate MRI at 1.5 and 3 T with high temporal resolution on clinical scanners. METHODS: Six volunteers were imaged while speaking, using both four real-time steady-state free-precession (SSFP) sequences at 3 T and four balanced SSFP (bSSFP) at 1.5 T. Temporal resolution was 9-20 frames s(-1) (fps), spatial resolution 1.6 × 1.6 × 10.0-2.7 × 2.7 × 10.0 mm(3). Simultaneous audio was recorded. Signal-to-noise ratio (SNR), palate thickness and image quality score (1-4, non-diagnostic-excellent) were evaluated. RESULTS: SNR was higher at 3 T than 1.5 T in the relaxed palate (nasal breathing position) and reduced in the elevated palate at 3 T, but not 1.5 T. Image quality was not significantly different between field strengths or sequences (p=NS). At 3 T, 40% acquisitions scored 2 and 56% scored 3. Most 1.5 T acquisitions scored 1 (19%) or 4 (46%). Image quality was more dependent on subject or field than sequence. SNR in static images was highest with 1.9 × 1.9 × 10.0 mm(3) resolution (10 fps) and measured palate thickness was similar (p=NS) to that at the highest resolution (1.6 × 1.6 × 10.0 mm(3)). SNR in intensity-time plots through the soft palate was highest with 2.7 × 2.7 × 10.0 mm(3) resolution (20 fps). CONCLUSIONS: At 3 T, SSFP images are of a reliable quality, but 1.5 T bSSFP images are often better. For geometric measurements, temporal should be traded for spatial resolution (1.9 × 1.9 × 10.0 mm(3), 10 fps). For assessment of motion, temporal should be prioritised over spatial resolution (2.7 × 2.7 × 10.0 mm(3), 20 fps). Advances in knowledge Diagnostic quality real-time soft palate MRI is possible using clinical scanners and optimised protocols have been developed. 3 T SSFP imaging is reliable, but 1.5 T bSSFP often produces better images.

In vitro and in vivo repeatability of abdominal diffusion-weighted MRI.

OBJECTIVE: To study the in vitro and in vivo (abdomen) variability of apparent diffusion coefficient (ADC) measurements at 1.5 T using a free-breathing multislice diffusion-weighted (DW) MRI sequence. METHODS: DW MRI images were obtained using a multislice spin-echo echo-planar imaging sequence with b-values=0, 100, 200, 500, 750 and 1000 s mm(-2). A flood-field phantom was imaged at regular intervals over 100 days, and 10 times on the same day on 2 occasions. 10 healthy volunteers were imaged on two separate occasions. Mono-exponential ADC maps were fitted excluding b=0. Paired analysis was carried out on the liver, spleen, kidney and gallbladder using multiple regions of interest (ROIs) and volumes of interest (VOIs). RESULTS: The in vitro coefficient of variation was 1.3% over 100 days, and 0.5% and 1.0% for both the daily experiments. In vivo, there was no statistical difference in the group mean ADC value between visits for any organ. Using ROIs, the coefficient of reproducibility was 20.0% for the kidney, 21.0% for the gallbladder, 24.7% for the liver and 28.0% for the spleen. For VOIs, values fall to 7.7%, 6.4%, 8.6% and 9.6%, respectively. CONCLUSION: Good in vitro repeatability of ADC measurements provided a sound basis for in vivo measurement. In vivo variability is higher and when considering single measurements in the abdomen as a whole, only changes in ADC value greater than 23.1% would be statistically significant using a two-dimensional ROI. This value is substantially lower (7.9%) if large three-dimensional VOIs are considered.

Finite element analysis animated simulation of velopharyngeal closure.

OBJECTIVE: To use finite element analysis animated simulations to investigate factors affecting velopharyngeal closure. DESIGN: A coronal section multicomponent finite element analysis model of a human soft palate was created in Simulia Abaqus 6.5-1 from high resolution MRI images of a single adult female subject, interpreted by reference to published anatomic dissections. Tissues were assigned hyperelastic property coefficients for neo-Hookean behavior, with gravity at 9.8 ms(-2) in the y-axis. Vector forces based on estimations in previous publications were applied throughout levator veli palatini and palatopharyngeus muscles, using a nonlinear analysis algorithm, to produce animated simulations of velopharyngeal space closure. Variation of levator veli palatini angle from 60° to 49°, the contribution of palatopharyngeus muscle, and the effect of submucous cleft were investigated for their effects on velopharyngeal closure. RESULTS: The animated simulations showed anthropomorphic behavior and supported the previously suggested effects of the levator veli palatini angle, with reduced effectiveness of velopharyngeal closure as levator veli palatini angle decreases. Palatopharyngeus action reduced the efficiency of closure for a levator veli palatini angle of 60°, and a submucous cleft reduced this for both our normal subject and for a levator veli palatini angle of 60°, but both palatopharyngeus action and a submucous cleft enhanced closure for a levator veli palatini angle of 49°. CONCLUSIONS: This study advances soft palate finite element analysis to a real-subject-based multicomponent hyperelastic model that demonstrates anthropomorphic behavior. Animated simulations using the model demonstrate the possible effects of levator veli palatini angle, a submucous cleft, and the contribution of the palatopharyngeus.

Diffusion-weighted imaging in the assessment of tumour grade in endometrial cancer.

OBJECTIVE: Endometrial cancer is the most common gynaecological malignancy in developed countries. Histological grade and subtype are important prognostic factors obtained by pipelle biopsy. However, pipelle biopsy "samples" tissue and a high-grade component that requires more aggressive treatment may be missed. The purpose of the study was to assess the use of diffusion-weighted MRI (DW-MRI) in the assessment of tumour grade in endometrial lesions. METHOD: 42 endometrial lesions including 23 endometrial cancers and 19 benign lesions were evaluated with DW-MRI (1.5T with multiple b-values between 0 and 750 s mm(-2)). Visual evaluation and the calculation of mean and minimum apparent diffusion coefficient (ADC) value were performed and correlated with histology. RESULTS: The mean and minimum ADC values for each histological grade were 1.02 ± 0.29×10(-3) mm(2) s(-1) and 0.74 ± 0.24×10(-3) mm(2) s(-1) (grade 1), 0.88 ± 0.39×10(-3) mm(2) s(-1) and 0.64 ± 0.36×10(-3) mm(2) s(-1) (grade 2), and 0.94 ± 0.32×10(-3) mm(2) s(-1) and 0.72 ± 0.36×10(-3) mm(2) s(-1) (grade 3), respectively. There was no statistically significant difference between tumour grades. However, the mean ADC value for endometrial carcinoma was 0.97 ± 0.31, which was significantly lower (p<0.0001) than that of benign endometrial pathology (1.50 ± 0.14). Applying a cut-off mean ADC value of less than 1.28 × 10(-3) mm(2) s(-1)we obtained a sensitivity, specificity, positive predictive value and negative predictive value for malignancy of 87%, 100%, 100% and 85.7%, respectively. CONCLUSION: Tumour mean and minimum ADC values are not useful in differentiating histological tumour grade in endometrial carcinoma. However, mean ADC measurement can provide useful information in differentiating benign from malignant endometrial lesions. This information could be clinically relevant in those patients where pre-operative endometrial sampling is not possible.

Effects of phantom volume and shape on the accuracy of MRI BANG gel dosimetry using BANG3.

Complex radiotherapy techniques call for three-dimensional dosimetric methods with high spatial resolution. Radiation-sensitive polymer gel systems (e.g. commercially available BANG(TM) gel), read using MRI T2 mapping, offer a promising solution. A series of calibration test tubes is traditionally used to calculate the dose delivered to a larger, differently shaped volume of gel. In this work, we investigated the implicit assumption that the sensitivity of the gel is independent of shape and size. Phantoms of different shapes and volumes, and 20 glass test-tubes, were filled with BANG3 gel. T2 mapping of gels was performed pre- and post-irradiation using a 32 echo Carr-Purcell-Meiboom-Gill sequence and single exponential fitting. Gel irradiation was performed with a 6 MV Varian 6EX linear accelerator. The T2 values of both non-irradiated and irradiated gels varied with container volume. For containers of the same shape receiving the same radiation dose, larger volumes exhibited a lower T2 value than did smaller volumes. Containers of the same volume but different shape also showed a smaller variation in response to radiation. The greatest difference in T2 values at the same dose was seen between test-tubes and larger volumes. This would imply that if test-tubes alone are used to calibrate larger volumes, then up to a 35% error could be introduced into radiotherapy plan verification. This can be reduced to <10% error if the gel volume is normalized with an external measurement device. Consequently, the traditional test-tube calibration method would be unacceptable for clinical plan verification.

MRI-based measurements of respiratory motion variability and assessment of imaging strategies for radiotherapy planning.

Respiratory organ motion has a significant impact on the planning and delivery of radiotherapy (RT) treatment for lung cancer. Currently widespread techniques, such as 4D-computed tomography (4DCT), cannot be used to measure variability of this motion from one cycle to the next. In this paper, we describe the use of fast magnetic resonance imaging (MRI) techniques to investigate the intra- and inter-cycle reproducibility of respiratory motion and also to estimate the level of errors that may be introduced into treatment delivery by using various breath-hold imaging strategies during lung RT planning. A reference model of respiratory motion is formed to enable comparison of different breathing cycles at any arbitrary position in the respiratory cycle. This is constructed by using free-breathing images from the inhale phase of a single breathing cycle, then co-registering the images, and thereby tracking landmarks. This reference model is then compared to alternative models constructed from images acquired during the exhale phase of the same cycle and the inhale phase of a subsequent cycle, to assess intra- and inter-cycle variability ('hysteresis' and 'reproducibility') of organ motion. The reference model is also compared to a series of models formed from breath-hold data at exhale and inhale. Evaluation of these models is carried out on data from ten healthy volunteers and five lung cancer patients. Free-breathing models show good levels of intra- and inter-cycle reproducibility across the tidal breathing range. Mean intra-cycle errors in the position of organ surface landmarks of 1.5(1.4)-3.5(3.3) mm for volunteers and 2.8(1.8)-5.2(5.2) mm for patients. Equivalent measures of inter-cycle variability across this range are 1.7(1.0)-3.9(3.3) mm for volunteers and 2.8(1.8)-3.3(2.2) mm for patients. As expected, models based on breath-hold sequences do not represent normal tidal motion as well as those based on free-breathing data, with mean errors of 4.4(2.2)-7.7(3.9) mm for volunteers and 10.1(6.1)-12.5(6.3) mm for patients. Errors are generally larger still when using a single breath-hold image at either exhale or inhale to represent the lung. This indicates that account should be taken of intra- and inter-cycle respiratory motion variability and that breath-hold-based methods of obtaining data for RT planning may potentially introduce large errors. This approach to analysis of motion and variability has potential to inform decisions about treatment margins and optimize RT planning.

Using combined x-ray and MR imaging for prostate I-125 post-implant dosimetry: phantom validation and preliminary patient work.

Post-implantation dosimetry is an important element of permanent prostate brachytherapy. This process relies on accurate localization of implanted seeds relative to the surrounding organs. Localization is commonly achieved using CT images, which provide suboptimal prostate delineation. On MR images, conversely, prostate visualization is excellent but seed localization is imprecise due to distortion and susceptibility artefacts. This paper presents a method based on fused MR and x-ray images acquired consecutively in a combined x-ray and MRI interventional suite. The method does not rely on any explicit registration step but on a combination of system calibration and tracking. A purpose-built phantom was imaged using MRI and x-rays, and the images were successfully registered. The same protocol was applied to three patients where combining soft tissue information from MRI with stereoscopic seed identification from x-ray imaging facilitated post-implant dosimetry. This technique has the potential to improve on dosimetry using either CT or MR alone.

Evaluation of the dosimetric performance of BANG3 polymer gel.

New radiotherapy techniques call for three-dimensional dosimetric methods with high spatial resolution. Radiation sensitive gels read out using MRI T(2) mapping provide an extremely promising option, and commercially available BANG polymer gels provide a convenient route into gel dosimetry. Gel dosimetry is dependent on the ability to calibrate gel response against radiation dose. This in turn is dependent on the reproducibility of response both between gels irradiated to the same dose and for a single gel sample over time. This study aims to evaluate the performance of a commercially available BANG gel. Our experimental arrangement gave excellent precision of radiation delivery (<0.2%) and reproducibility of T(2) measurement (<0.5%). Seven groups of 10 test tubes containing BANG3 gel were irradiated in 0.5 Gy steps between 0 and 3 Gy. A further four groups of four samples were irradiated in 2 Gy steps between 4 and 10 Gy. The gel samples were identical and derived from the same manufacturing batch. MR imaging was carried out four days after irradiation and then at weekly intervals for four weeks. Short-term variation in gel response can readily be corrected using reference samples. Longer term systematic drift of the gel calibration curve was observed relative to reference samples prepared in-house for quality assurance purposes. This implies that read-out of the calibration gels and dosimetry phantom must be performed at the same time after irradiation, or errors of up to 25% may be incurred. Precision of gel response did not change significantly over time. The observation of significantly different T(2) values both prior to irradiation and following irradiation to the same dose (variation up to 15%) illustrates the current difficulties associated with BANG3 gel calibration and constrains the practical utility of these commercially available gels for clinical radiation dosimetry.

Three- and four-dimensional reconstruction of intra-cardiac anatomy from two-dimensional magnetic resonance images.

The present study was designed to evaluate the feasibility and clinical usefulness of three-dimensional (3D) reconstruction of intra-cardiac anatomy from a series of two-dimensional (2D) MR images using commercially available software. Sixteen patients (eight with structurally normal hearts but due to have catheter radio-frequency ablation of atrial tachyarrhythmias and eight with atrial septal defects (ASD) due for trans-catheter closure) and two volunteers were imaged at 1T. For each patient, a series of ECG-triggered images (5 mm thick slices, 2-3 mm apart) were acquired during breath holding. Depending on image quality, T1- or T2-weighted spin-echo images or gradient-echo cine images were used. The 3D reconstruction was performed off-line: the blood pools within cardiac chambers and great vessels were semi-automatically segmented, their outer surface was extracted using a marching cube algorithm and rendered. Intra- and inter-observer variability, effect of breath-hold position and differences between pulse sequences were assessed by imaging a volunteer. The 3D reconstructions were assessed by three cardiologists and compared with the 2D MR images and with 2D and 3D trans-esophagal and intra-cardiac echocardiography obtained during interventions. In every case, an anatomically detailed 3D volume was obtained. In the two patients where a 3 mm interval between slices was used, the resolution was not as good but it was still possible to visualize all the major anatomical structures. Spin-echo images lead to reconstructions more detailed than those obtained from gradient-echo images. However, gradient-echo images are easier to segment due to their greater contrast. Furthermore, because images were acquired at least at ten points in the cardiac cycles for every slice it was possible to reconstruct a cine loop and, for example, to visualize the evolution of the size and margins of the ASD during the cardiac cycle. 3D reconstruction proved to be an effective way to assess the relationship between the different parts of the cardiac anatomy. The technique was useful in planning interventions in these patients.