A Comparison of MRI Quantitative Susceptibility Mapping and TRUST-Based Measures of Brain Venous Oxygen Saturation in Sickle Cell Anaemia.

In recent years, interest has grown in the potential for magnetic resonance imaging (MRI) measures of venous oxygen saturation (Yv) to improve neurological risk prediction. T2-relaxation-under-spin-tagging (TRUST) is an MRI technique which has revealed changes in Yv in patients with sickle cell anemia (SCA). However, prior studies comparing Yv in patients with SCA relative to healthy controls have reported opposing results depending on whether the calibration model, developed to convert blood T2 to Yv, is based on healthy human hemoglobin (HbA), bovine hemoglobin (HbBV) or sickle hemoglobin (HbS). MRI Quantitative Susceptibility Mapping (QSM) is an alternative technique that may hold promise for estimating Yv in SCA as blood magnetic susceptibility is linearly dependent upon Yv, and no significant difference has been found between the magnetic susceptibility of HbA and HbS. Therefore, the aim of this study was to compare estimates of Yv using QSM and TRUST with five published calibration models in healthy controls and patients with SCA. 17 patients with SCA and 13 healthy controls underwent MRI. Susceptibility maps were calculated from a multi-parametric mapping acquisition and Yv was calculated from the mean susceptibility in a region of interest in the superior sagittal sinus. TRUST estimates of T2, within a similar but much smaller region, were converted to Yv using five different calibration models. Correlation and Bland-Altman analyses were performed to compare estimates of Yv between TRUST and QSM methods. For each method, t-tests were also used to explore group-wise differences between patients with SCA and healthy controls. In healthy controls, significant correlations were observed between QSM and TRUST measures of Yv, while in SCA, there were no such correlations. The magnitude and direction of group-wise differences in Yv varied with method. The TRUST-HbBV and QSM methods suggested decreased Yv in SCA relative to healthy controls, while the TRUST-HbS (p < 0.01) and TRUST-HbA models suggested increased Yv in SCA as in previous studies. Further validation of all MRI measures of Yv, relative to ground truth measures such as O15 PET and jugular vein catheterization, is required in SCA before QSM or TRUST methods can be considered for neurological risk prediction.

Individual Watershed Areas in Sickle Cell Anemia: An Arterial Spin Labeling Study.

Previous studies have pointed to a role for regional cerebral hemodynamic stress in neurological complications in patients with sickle cell anemia (SCA), with watershed regions identified as particularly at risk of ischemic tissue injury. Using single- and multi-inflow time (TI) arterial spin labeling sequences (ASL) in 94 patients with SCA and 42 controls, the present study sought to investigate cerebral blood flow (CBF) and bolus arrival times (BAT) across gray matter, white matter with early arrival times, and in individual watershed areas (iWSAs). In iWSAs, associations between hemodynamic parameters, lesion burden, white matter integrity, and general cognitive performance were also explored. In patients, increases in CBF and reductions in BAT were observed in association with reduced arterial oxygen content across gray matter and white matter with early arrival times using both sequences (all p < 0.001, d = -1.55--2.21). Across iWSAs, there was a discrepancy between sequences, with estimates based on the single-TI sequence indicating higher CBF in association with reduced arterial oxygen content in SCA patients, and estimates based on the multi-TI sequence indicating no significant between-group differences or associations with arterial oxygen content. Lesion burden was similar between white matter with early arrival times and iWSAs in both patients and controls, and using both sequences, only trend-level associations between iWSA CBF and iWSA lesion burden were observed in patients. Further, using the multi-TI sequence in patients, increased iWSA CBF was associated with reduced iWSA microstructural tissue integrity and slower processing speed. Taken together, the results highlight the need for researchers to consider BAT when estimating CBF using single-TI sequences. Moreover, the findings demonstrate the feasibility of multi-TI ASL for objective delineation of iWSAs and for detection of regional hemodynamic stress that is associated with reduced microstructural tissue integrity and slower processing speed. This technique may hold promise for future studies and treatment trials.

Venous cerebral blood flow quantification and cognition in patients with sickle cell anemia.

Prior studies have described high venous signal qualitatively using arterial spin labelling (ASL) in patients with sickle cell anemia (SCA), consistent with arteriovenous shunting. We aimed to quantify the effect and explored cross-sectional associations with arterial oxygen content (CaO2), disease-modifying treatments, silent cerebral infarction (SCI), and cognitive performance. 94 patients with SCA and 42 controls underwent cognitive assessment and MRI with single- and multi- inflow time (TI) ASL sequences. Cerebral blood flow (CBF) and bolus arrival time (BAT) were examined across gray and white matter and high-signal regions of the sagittal sinus. Across gray and white matter, increases in CBF and reductions in BAT were observed in association with reduced CaO2 in patients, irrespective of sequence. Across high-signal sagittal sinus regions, CBF was also increased in association with reduced CaO2 using both sequences. However, BAT was increased rather than reduced in patients across these regions, with no association with CaO2. Using the multiTI sequence in patients, increases in CBF across white matter and high-signal sagittal sinus regions were associated with poorer cognitive performance. These novel findings highlight the utility of multiTI ASL in illuminating, and identifying objectively quantifiable and functionally significant markers of, regional hemodynamic stress in patients with SCA.

High-resolution microscopic diffusion anisotropy imaging in the human hippocampus at 3T.

PURPOSE: Several neurological conditions are associated with microstructural changes in the hippocampus that can be observed using DWI. Imaging studies often use protocols with whole-brain coverage, imposing limits on image resolution and worsening partial-volume effects. Also, conventional single-diffusion-encoding methods confound microscopic diffusion anisotropy with size variance of microscopic diffusion environments. This study addresses these issues by implementing a multidimensional diffusion-encoding protocol for microstructural imaging of the hippocampus at high resolution. METHODS: The hippocampus of 8 healthy volunteers was imaged at 1.5-mm isotropic resolution with a multidimensional diffusion-encoding sequence developed in house. Microscopic fractional anisotropy (µFA) and normalized size variance (CMD ) were estimated using q-space trajectory imaging, and their values were compared with DTI metrics. The overall scan time was 1 hour. The reproducibility of the protocol was confirmed with scan-rescan experiments, and a shorter protocol (14 minutes) was defined for situations with time constraints. RESULTS: Mean µFA (0.47) was greater than mean FA (0.20), indicating orientation dispersion in hippocampal tissue microstructure. Mean CMD was 0.17. The reproducibility of q-space trajectory imaging metrics was comparable to DTI, and microstructural metrics in the healthy hippocampus are reported. CONCLUSION: This work shows the feasibility of high-resolution microscopic anisotropy imaging in the human hippocampus at 3 T and provides reference values for microstructural metrics in a healthy hippocampus.

Tractographic and Microstructural Analysis of the Dentato-Rubro-Thalamo-Cortical Tracts in Children Using Diffusion MRI.

The dentato-rubro-thalamo-cortical tract (DRTC) is the main outflow pathway of the cerebellum, contributing to a finely balanced corticocerebellar loop involved in cognitive and sensorimotor functions. Damage to the DRTC has been implicated in cerebellar mutism syndrome seen in up to 25% of children after cerebellar tumor resection. Multi-shell diffusion MRI (dMRI) combined with quantitative constrained spherical deconvolution tractography and multi-compartment spherical mean technique modeling was used to explore the frontocerebellar connections and microstructural signature of the DRTC in 30 healthy children. The highest density of DRTC connections were to the precentral (M1) and superior frontal gyri (F1), and from cerebellar lobules I-IV and IX. The first evidence of a topographic organization of anterograde projections to the frontal cortex at the level of the superior cerebellar peduncle (SCP) is demonstrated, with streamlines terminating in F1 lying dorsomedially in the SCP compared to those terminating in M1. The orientation dispersion entropy of DRTC regions appears to exhibit greater contrast than that shown by fractional anisotropy. Analysis of a separate reproducibility cohort demonstrates good consistency in the dMRI metrics described. These novel anatomical insights into this well-studied pathway may prove to be of clinical relevance in the surgical resection of cerebellar tumors.

Comparison Between Diffusion-Weighted MRI and 123 I-mIBG Uptake in Primary High-Risk Neuroblastoma.

BACKGROUND: High-risk neuroblastoma (HR-NB) has a variable response to preoperative chemotherapy. It is not possible to differentiate viable vs. nonviable residual tumor before surgery. PURPOSE: To explore the association between apparent diffusion coefficient (ADC) values from diffusion-weighted magnetic resonance imaging (DW-MRI), 123 I-meta-iodobenzyl-guanidine (123 I-mIBG) uptake, and histology before and after chemotherapy. STUDY TYPE: Retrospective. SUBJECTS: Forty patients with HR-NB. FIELD STRENGTH/SEQUENCE: 1.5T axial DW-MRI (b = 0,1000 s/mm2 ) and T2 -weighted sequences. 123 I-mIBG scintigraphy planar imaging (all patients), with additional 123 I-mIBG single-photon emission computed tomography / computerized tomography (SPECT/CT) imaging (15 patients). ASSESSMENT: ADC maps and 123 I-mIBG SPECT/CT images were coregistered to the T2 -weighted images. 123 I-mIBG uptake was normalized with a tumor-to-liver count ratio (TLCR). Regions of interest (ROIs) for primary tumor volume and different intratumor subregions were drawn. The lower quartile ADC value (ADC25prc ) was used over the entire tumor volume and the overall level of 123 I-mIBG uptake was graded into avidity groups. STATISTICAL TESTS: Analysis of variance (ANOVA) and linear regression were used to compare ADC and MIBG values before and after treatment. Threshold values to classify tumors as viable/necrotic were obtained using ROC analysis of ADC and TLCR values. RESULTS: No significant difference in whole-tumor ADC25prc values were found between different 123 I-mIBG avidity groups pre- (P = 0.31) or postchemotherapy (P = 0.35). In the "intratumor" analysis, 5/15 patients (prechemotherapy) and 0/14 patients (postchemotherapy) showed a significant correlation between ADC and TLCR values (P < 0.05). Increased tumor shrinkage was associated with lower pretreatment tumor ADC25prc values (P < 0.001); no association was found with pretreatment 123 I-mIBG avidity (P = 0.17). Completely nonviable tumors had significantly lower postchemotherapy ADC25prc values than tumors with >10% viable tumor (P < 0.05). Both pre- and posttreatment TLCR values were significantly higher in patients with >50% viable tumor than those with 10-50% viable tumor (P < 0.05). DATA CONCLUSION: 123 I-mIBG avidity and ADC values are complementary noninvasive biomarkers of therapeutic response in HR-NB. LEVEL OF EVIDENCE: 4. TECHNICAL EFFICACY STAGE: 3.

Neurosurgical applications of tractography in the UK.

INTRODUCTION: Tractography derived from diffusion MRI can provide important insights into human brain microstructure in vivo. Neurosurgeons were quick to adopt the technique at the turn of the century, but it remains plagued by technical fallibilities. This study aims to describe how tractography is deployed clinically in a modern-day, public healthcare system, serving as a snapshot from the 'shop floor' of British neurosurgical practice. METHODS: An 11-question survey was circulated to the mailing lists of the Society of British Neurological Surgeons and British Neurosurgical Trainees' Association, including questions on frequency, indication, tracts reconstructed, specific details of techniques used and personnel by whom it was performed, and a free-text section on the limitations of tractography. RESULTS: 58 survey responses were received, covering all 40 neurosurgical units in the UK and Ireland. Overall, responses were received from neurosurgeons at 36 units (90.0%) stating tractography was in use at that unit. 74.1% of the responses were from Consultants. The most common indication for tractography was in tumour resection. It was most commonly performed by neuroradiologists or imaging scientists. 75.9% of respondents stated that the model used to process tractography was the diffusion tensor (DTI). Many respondents were unaware of which algorithm (74.1%) or software tools (65.6%) were used by the operator to produce tractography visualisations. The corticospinal tract was the most commonly reconstructed tract. The most commonly cited limitations of the technique were perceived inaccuracy and brain shift. CONCLUSIONS: In this UK-based survey of practising neurosurgeons, we show that 90% of neurosurgical units in the UK and Ireland use tractography regularly; that predominantly DTI-based reconstructions are used; that tumour resection remains the most frequent use of the technique; and that large tracts such as the corticospinal tract are most frequently identified. Many neurosurgeons remain unfamiliar with the underlying methods used to produce tractography visualisations.

Comparison of models of diffusion in Wilms' tumours and normal contralateral renal tissue.

OBJECTIVE: ADC (Apparent Diffusion Coefficient) derived from Diffusion-Weighted Imaging (DWI) has shown promise as a non-invasive quantitative imaging biomarker in Wilms' tumours. However, many non-Gaussian models could be applied to DWI. This study aimed to compare the suitability of four diffusion models (mono exponential, IVIM [Intravoxel Incoherent Motion], stretched exponential, and kurtosis) in Wilms' tumours and the unaffected contralateral kidneys. MATERIALS AND METHODS: DWI data were retrospectively reviewed (110 Wilms' tumours and 75 normal kidney datasets). The goodness of fit for each model was measured voxel-wise using Akaike Information Criteria (AIC). Mean AIC was calculated for each tumour volume (or contralateral normal kidney tissue). One-way ANOVAs with Greenhouse-Geisser correction and post hoc tests using the Bonferroni correction evaluated significant differences between AIC values; the lowest AIC indicating the optimum model. RESULTS: IVIM and stretched exponential provided the best fits to the Wilms' tumour DWI data. IVIM provided the best fit for the normal kidney data. Mono exponential was the least appropriate fitting method for both Wilms' tumour and normal kidney data. DISCUSSION: The diffusion weighted signal in Wilms' tumours and normal kidney tissue does not exhibit a mono-exponential decay and is better described by non-Gaussian models of diffusion.

Quantitative MRI demonstrates abnormalities of the third ventricle subventricular zone in neurofibromatosis type-1 and sporadic paediatric optic pathway glioma.

BACKGROUND: The subventricular zone of the third ventricle (TVZ) is a germinal stem cell niche, identified as the possible location of optic pathway glioma (OPG) cell origin. Paediatric OPGs are predominantly diagnosed as low-grade astrocytomas, which are either sporadic or are associated with neurofibromatosis type-1 (NF1). These tumours often cause a significant impairment to visual acuity (VA). Infiltrative/invasive tumour activity is associated with increased apparent diffusion coefficient (ADC) and cerebral blood flow (CBF). This study aimed to determine whether TVZ imaging features differed between sporadic-OPG, NF1-OPG and controls, and whether the ADC and CBF profile at the germinal stem cell niche (the TVZ) correlated with the primary outcome of VA. METHODS: ADC and CBF MRI data were acquired from 30 paediatric OPG patients (median age 6 years; range 8 months-17 years), along with VA measurements, during clinical surveillance of their tumour. Values for mean ADC and maximum CBF were measured at the TVZ, and normalized to normal-appearing grey matter. These values were compared between the two OPG groups and the healthy control subjects, and multivariate linear regression was used to test the linear association between these values and patient's VA. RESULTS: In the TVZ, normalized mean ADC was higher in NF1-associated OPG patients (N = 15), compared to both sporadic OPG patients (N = 15; p = 0.010) and healthy controls (N = 14; p < 0.001). In the same region, normalized maximum CBF was higher in sporadic OPG patients compared to both NF1-OPG patients (p = 0.016) and healthy controls (p < 0.001). In sporadic OPG patients only, normalized mean ADC in the TVZ was significantly correlated with visual acuity (R2 = 0.41, p = 0.019). No significant correlations were found between TVZ CBF and ADC values and visual acuity in the NF1-associated OPG patients. CONCLUSION: Quantitative MRI detects TVZ abnormalities in both sporadic and NF1-OPG patients, and identifies TVZ features that differentiate the two. TVZ features may be useful MRI markers of interest in future predictive studies involving sporadic OPG.

Combined Denoising and Suppression of Transient Artifacts in Arterial Spin Labeling MRI Using Deep Learning.

BACKGROUND: Arterial spin labeling (ASL) is a useful tool for measuring cerebral blood flow (CBF). However, due to the low signal-to-noise ratio (SNR) of the technique, multiple repetitions are required, which results in prolonged scan times and increased susceptibility to artifacts. PURPOSE: To develop a deep-learning-based algorithm for simultaneous denoising and suppression of transient artifacts in ASL images. STUDY TYPE: Retrospective. SUBJECTS: 131 pediatric neuro-oncology patients for model training and 11 healthy adult subjects for model evaluation. FIELD STRENGTH/SEQUENCE: 3T / pseudo-continuous and pulsed ASL with 3D gradient-and-spin-echo readout. ASSESSMENT: A denoising autoencoder (DAE) model was designed with stacked encoding/decoding convolutional layers. Reference standard images were generated by averaging 10 pairwise ASL subtraction images. The model was trained to produce perfusion images of a similar quality using a single subtraction image. Performance was compared against Gaussian and non-local means (NLM) filters. Evaluation metrics included SNR, peak SNR (PSNR), and structural similarity index (SSIM) of the CBF images, compared to the reference standard. STATISTICAL TESTS: One-way analysis of variance (ANOVA) tests for group comparisons. RESULTS: The DAE model was the only model to produce a significant increase in SNR compared to the raw images (P < 0.05), providing an average SNR gain of 62%. The DAE model was also effective at suppressing transient artifacts, and was the only model to show a significant improvement in accuracy in the generated CBF images, as assessed using PSNR values (P < 0.05). In addition, using data from multiple inflow time acquisitions, the DAE images produced the best fit to the Buxton kinetic model, offering a 75% reduction in the fitting error compared to the raw images. DATA CONCLUSION: Deep-learning-based algorithms provide superior accuracy when denoising ASL images, due to their ability to simultaneously increase SNR and suppress artifactual signals in raw ASL images. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 1.

Vascular Instability and Neurological Morbidity in Sickle Cell Disease: An Integrative Framework.

It is well-established that patients with sickle cell disease (SCD) are at substantial risk of neurological complications, including overt and silent stroke, microstructural injury, and cognitive difficulties. Yet the underlying mechanisms remain poorly understood, partly because findings have largely been considered in isolation. Here, we review mechanistic pathways for which there is accumulating evidence and propose an integrative systems-biology framework for understanding neurological risk. Drawing upon work from other vascular beds in SCD, as well as the wider stroke literature, we propose that macro-circulatory hyper-perfusion, regions of relative micro-circulatory hypo-perfusion, and an exhaustion of cerebral reserve mechanisms, together lead to a state of cerebral vascular instability. We suggest that in this state, tissue oxygen supply is fragile and easily perturbed by changes in clinical condition, with the potential for stroke and/or microstructural injury if metabolic demand exceeds tissue oxygenation. This framework brings together recent developments in the field, highlights outstanding questions, and offers a first step toward a linking pathophysiological explanation of neurological risk that may help inform future screening and treatment strategies.

Arterial spin labelling and diffusion-weighted imaging in paediatric brain tumours.

BACKGROUND: Diffusion- and perfusion-weighted MRI are valuable tools for measuring the cellular and vascular properties of brain tumours. This has been well studied in adult patients, however, the biological features of childhood brain tumours are unique, and paediatric-focused studies are less common. We aimed to assess the diagnostic utility of apparent diffusion coefficient (ADC) values derived from diffusion-weighted imaging (DWI) and cerebral blood flow (CBF) values derived from arterial spin labelling (ASL) in paediatric brain tumours. METHODS: We performed a meta-analysis of published studies reporting ADC and ASL-derived CBF values in paediatric brain tumours. Data were combined using a random effects model in order to define typical parameter ranges for different histological tumour subtypes and WHO grades. New data were also acquired in a 'validation cohort' at our institution, in which ADC and CBF values in treatment naïve paediatric brain tumour patients were measured, in order to test the validity of the findings from the literature in an un-seen cohort. ADC and CBF quantification was performed by two radiologists via manual placement of tumour regions of interest (ROIs), in addition to an automated approach to tumour ROI placement. RESULTS: A total of 14 studies met the inclusion criteria for the meta-analysis, constituting data acquired in 542 paediatric patients. Parameters of interest were based on measurements from ROIs placed within the tumour, including mean and minimum ADC values (ADCROI-mean, ADCROI-min) and the maximum CBF value normalised to grey matter (nCBFROI-max). After combination of the literature data, a number of histological tumour subtype groups showed significant differences in ADC values, which were confirmed, where possible, in our validation cohort of 32 patients. In both the meta-analysis and our cohort, diffuse midline glioma was found to be an outlier among high-grade tumour subtypes, with ADC and CBF values more similar to the low-grade tumours. After grouping patients by WHO grade, significant differences in grade groups were found in ADCROI-mean, ADCROI-min, and nCBFROI-max, in both the meta-analysis and our validation cohort. After excluding diffuse midline glioma, optimum thresholds (derived from ROC analysis) for separating low/high-grade tumours were 0.95 × 10-3 mm2/s (ADCROI-mean), 0.82 × 10-3 mm2/s (ADCROI-min) and 1.45 (nCBFROI-max). These thresholds were able to identify low/high-grade tumours with 96%, 83%, and 83% accuracy respectively in our validation cohort, and agreed well with the results from the meta-analysis. Diagnostic power was improved by combining ADC and CBF measurements from the same tumour, after which 100% of tumours in our cohort were correctly classified as either low- or high-grade (excluding diffuse midline glioma). CONCLUSION: ADC and CBF values are useful for differentiating certain histological subtypes, and separating low- and high-grade paediatric brain tumours. The threshold values presented here are in agreement with previously published studies, as well as a new patient cohort. If ADC and CBF values acquired in the same tumour are combined, the diagnostic accuracy is optimised.

An alternative approach to contrast-enhanced imaging: diffusion-weighted imaging and T1-weighted imaging identifies and quantifies necrosis in Wilms tumour.

OBJECTIVES: Volume of necrosis in Wilms tumour is informative of chemotherapy response. Contrast-enhanced T1-weighted MRI (T1w) provides a measure of necrosis using gadolinium. This study aimed to develop a non-invasive method of identifying non-enhancing (necrotic) tissue in Wilms tumour. METHODS: In this single centre, retrospective study, post-chemotherapy MRI data from 34 Wilms tumour patients were reviewed (March 2012-March 2017). Cases with multiple b value diffusion-weighted imaging (DWI) and T1w imaging pre- and post-gadolinium were included. Fractional T1 enhancement maps were generated from the gadolinium T1w data. Multiple linear regression determined whether fitted parameters from a mono-exponential model (ADC) and bi-exponential model (IVIM - intravoxel incoherent motion) (D, D*, f) could predict fractional T1 enhancement in Wilms tumours, using normalised pre-gadolinium T1w (T1wnorm) signal as an additional predictor. Measured and predicted fractional enhancement values were compared using the Bland-Altman plot. An optimum threshold for separating necrotic and viable tissue using fractional T1 enhancement was established using ROC. RESULTS: ADC and D (diffusion coefficient) provided the strongest predictors of fractional T1 enhancement in tumour tissue (p < 0.001). Using the ADC-T1wnorm model (adjusted R2 = 0.4), little bias (mean difference = - 0.093, 95% confidence interval = [- 0.52, 0.34]) was shown between predicted and measured values of fractional enhancement and analysed via the Bland-Altman plot. The optimal threshold for differentiating viable and necrotic tissue was 33% fractional T1 enhancement (based on measured values, AUC = 0.93; sensitivity = 85%; specificity = 90%). CONCLUSIONS: Combining ADC and T1w imaging predicts enhancement in Wilms tumours and reliably identifies and measures necrotic tissue without gadolinium. KEY POINTS: • Alternative method to identify necrotic tissue in Wilms tumour without using contrast agents but rather using diffusion and T 1 weighted MRI. • A method is presented to visualise and quantify necrotic tissue in Wilms tumour without contrast. • The proposed method has the potential to reduce costs and burden to Wilms tumour patients who undergo longitudinal follow-up imaging as contrast agents are not used.

Quantitative MRI in post-operative paediatric cerebellar mutism syndrome.

Post-operative paediatric cerebellar mutism syndrome (pCMS) occurs in around 25% of children undergoing surgery for cerebellar and fourth ventricular tumours. Reversible mutism is the hallmark of a syndrome which comprises severe motor, cognitive and linguistic deficits. Recent evidence from advanced neuroimaging studies has led to the current theoretical understanding of the condition as a form of diaschisis contingent on damage to efferent cerebellar circuitry. Tractography data derived from diffusion MRI studies have shown disruption of the dentato-rubro-thalamo-cortical tract in patients with pCMS, and perfusion studies have indicated widespread supratentorial regions which may give rise to the florid signs and symptoms of pCMS. Given the difficulties in predicting pCMS from standard structural MRI, this review discusses findings from quantitative MRI modalities which have contributed to our understanding of this debilitating syndrome, and considers the goals and challenges which lie ahead in the field.

Delineation of the visual pathway in paediatric optic pathway glioma patients using probabilistic tractography, and correlations with visual acuity.

Background: Radiological biomarkers which correlate with visual function are needed to improve the clinical management of optic pathway glioma (OPG) patients. Currently, these are not available using conventional magnetic resonance imaging (MRI) sequences. The aim of this study was to determine whether diffusion MRI could be used to delineate the entire optic pathway in OPG patients, and provide imaging biomarkers within this pathway which correlate with a patient's visual acuity (VA). Methods: Multi-shell diffusion MRI data were acquired in a cohort of paediatric OPG patients, along with VA measurements in each eye. Diffusion MRI data were processed using constrained spherical deconvolution and probabilistic fibre tractography, to delineate the white matter bundles forming the optic pathway in each patient. Median fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were measured in the optic nerves, tracts, and radiations, and correlated against each patient's VA. Results: In the optic nerves, median FA significantly correlated with VA (R2adj = 0.31, p = 0.0082), with lower FA associated with poorer vision. In the optic radiations, both lower FA and higher ADC were significantly associated with poorer vision (R2adj = 0.52, p = 0.00075 and R2adj = 0.50, p = 0.0012 respectively). No significant correlations between VA and either FA or ADC were found in the optic tracts. Conclusions: Multi-shell diffusion MRI provides in vivo delineation of the optic pathway in OPG patients, despite the presence of tumour invasion. This technique provides imaging biomarkers which are sensitive to microstructural damage to the underlying white matter in this pathway, which is not always visible on conventional MRI.

Cerebral perfusion characteristics show differences in younger versus older children with sickle cell anaemia: Results from a multiple-inflow-time arterial spin labelling study.

Sickle cell anaemia (SCA) is associated with chronic anaemia and oxygen desaturation, which elevate cerebral blood flow (CBF) and increase the risk of neurocognitive complications. Arterial spin labelling (ASL) provides a methodology for measuring CBF non-invasively; however, ASL techniques using only a single inflow time are not sufficient to fully characterize abnormal haemodynamic behaviour in SCA. This study investigated haemodynamic parameters from a multi-inflow-time ASL acquisition in younger (8-12 years) and older (13-18 years) children with SCA with and without silent cerebral infarction (SCI+/-) (n = 20 and 19 respectively, 6 and 4 SCI+ respectively) and healthy controls (n = 9 and 7 respectively). Compared with controls, CBF was elevated globally in both groups of patients. In the younger SCA patients, blood oxygen content was negatively correlated with CBF in the middle and posterior cerebral artery territories and significantly positively correlated with bolus arrival time (BAT) in the anterior and middle cerebral artery territories. In older children, SCA patients had significantly shorter BAT than healthy controls and there was a significant negative correlation between CBF and oxygen content only in the territory of the posterior cerebral artery, with a trend for a correlation in the anterior cerebral artery but no relationship for the middle cerebral artery territory. In the younger group, SCI+ patients had significantly higher CBF in the posterior cerebral artery territory (SCI+ mean = 92.78 ml/100 g/min; SCI- mean = 72.71 ml/100 g/min; F = 4.28, p = 0.04), but this no longer reached significance when two children with abnormal transcranial Doppler and one with haemoglobin SC disease were excluded, and there were no significant differences between patients with and without SCI in the older children. With age, there appears to be increasing disparity between patients and controls in terms of the relationship between CBF and oxygen content in the anterior circulation, potentially predicting the risk of acute and chronic compromise of brain tissue.

A general model to calculate the spin-lattice (T1) relaxation time of blood, accounting for haematocrit, oxygen saturation and magnetic field strength.

Many MRI techniques require prior knowledge of the T1-relaxation time of blood (T1bl). An assumed/fixed value is often used; however, T1bl is sensitive to magnetic field (B0), haematocrit (Hct), and oxygen saturation (Y). We aimed to combine data from previous in vitro measurements into a mathematical model, to estimate T1bl as a function of B0, Hct, and Y. The model was shown to predict T1bl from in vivo studies with a good accuracy (± 87 ms). This model allows for improved estimation of T1bl between 1.5-7.0 T while accounting for variations in Hct and Y, leading to improved accuracy of MRI-derived perfusion measurements.

A multi-Gaussian model for apparent diffusion coefficient histogram analysis of Wilms' tumour subtype and response to chemotherapy.

Wilms' tumours (WTs) are large heterogeneous tumours, which typically consist of a mixture of histological cell types, together with regions of chemotherapy-induced regressive change and necrosis. The predominant cell type in a WT is assessed histologically following nephrectomy, and used to assess the tumour subtype and potential risk. The purpose of this study was to develop a mathematical model to identify subregions within WTs with distinct cellular environments in vivo, determined using apparent diffusion coefficient (ADC) values from diffusion-weighted imaging (DWI). We recorded the WT subtype from the histopathology of 32 tumours resected in patients who received DWI prior to surgery after pre-operative chemotherapy had been administered. In 23 of these tumours, DWI data were also available prior to chemotherapy. Histograms of ADC values were analysed using a multi-Gaussian model fitting procedure, which identified 'subpopulations' with distinct cellular environments within the tumour volume. The mean and lower quartile ADC values of the predominant viable tissue subpopulation (ADC(1MEAN), ADC(1LQ)), together with the same parameters from the entire tumour volume (ADC(0MEAN), ADC(0LQ)), were tested as predictors of WT subtype. ADC(1LQ) from the multi-Gaussian model was the most effective parameter for the stratification of WT subtype, with significantly lower values observed in high-risk blastemal-type WTs compared with intermediate-risk stromal, regressive and mixed-type WTs (p < 0.05). No significant difference in ADC(1LQ) was found between blastemal-type and intermediate-risk epithelial-type WTs. The predominant viable tissue subpopulation in every stromal-type WT underwent a positive shift in ADC(1MEAN) after chemotherapy. Our results suggest that our multi-Gaussian model is a useful tool for differentiating distinct cellular regions within WTs, which helps to identify the predominant histological cell type in the tumour in vivo. This shows potential for improving the risk-based stratification of patients at an early stage, and for guiding biopsies to target the most malignant part of the tumour.

Multi-centre reproducibility of diffusion MRI parameters for clinical sequences in the brain.

The purpose of this work was to assess the reproducibility of diffusion imaging, and in particular the apparent diffusion coefficient (ADC), intra-voxel incoherent motion (IVIM) parameters and diffusion tensor imaging (DTI) parameters, across multiple centres using clinically available protocols with limited harmonization between sequences. An ice-water phantom and nine healthy volunteers were scanned across fives centres on eight scanners (four Siemens 1.5T, four Philips 3T). The mean ADC, IVIM parameters (diffusion coefficient D and perfusion fraction f) and DTI parameters (mean diffusivity MD and fractional anisotropy FA), were measured in grey matter, white matter and specific brain sub-regions. A mixed effect model was used to measure the intra- and inter-scanner coefficient of variation (CV) for each of the five parameters. ADC, D, MD and FA had a good intra- and inter-scanner reproducibility in both grey and white matter, with a CV ranging between 1% and 7.4%; mean 2.6%. Other brain regions also showed high levels of reproducibility except for small structures such as the choroid plexus. The IVIM parameter f had a higher intra-scanner CV of 8.4% and inter-scanner CV of 24.8%. No major difference in the inter-scanner CV for ADC, D, MD and FA was observed when analysing the 1.5T and 3T scanners separately. ADC, D, MD and FA all showed good intra-scanner reproducibility, with the inter-scanner reproducibility being comparable or faring slightly worse, suggesting that using data from multiple scanners does not have an adverse effect compared with using data from the same scanner. The IVIM parameter f had a poorer inter-scanner CV when scanners of different field strengths were combined, and the parameter was also affected by the scan acquisition resolution. This study shows that the majority of diffusion MRI derived parameters are robust across 1.5T and 3T scanners and suitable for use in multi-centre clinical studies and trials.