Lacunar Stroke Lesion Extent and Location and White Matter Hyperintensities Evolution 1 Year Post-lacunar Stroke.

Lacunar strokes are a common type of ischemic stroke. They are associated with long-term disability, but the factors affecting the dynamic of the infarcted lesion and the brain imaging features associated with them, reflective of small vessel disease (SVD) severity, are still largely unknown. We investigated whether the distribution, volume and 1-year evolution of white matter hyperintensities (WMH), one of these SVD features, relate to the extent and location of these infarcts, accounting for vascular risk factors. We used imaging and clinical data from all patients [n = 118, mean age 64.9 (SD 11.75) years old] who presented to a regional hospital with a lacunar stroke syndrome within the years 2010 and 2013 and consented to participate in a study of stroke mechanisms. All patients had a brain MRI scan at presentation, and 88 had another scan 12 months after. Acute lesions (i.e., recent small subcortical infarcts, RSSI) were identified in 79 patients and lacunes in 77. Number of lacunes was associated with baseline WMH volume (B = 0.370, SE = 0.0939, P = 0.000174). RSSI volume was not associated with baseline WMH volume (B = 3.250, SE = 2.117, P = 0.129), but predicted WMH volume change (B = 2.944, SE = 0.913, P = 0.00184). RSSI location was associated with the spatial distribution of WMH and the pattern of 1-year WMH evolution. Patients with the RSSI in the centrum semiovale (n = 33) had significantly higher baseline volumes of WMH, recent and old infarcts, than patients with the RSSI located elsewhere [median 33.69, IQR (14.37 50.87) ml, 0.001 ≤ P ≤ 0.044]. But patients with the RSSI in the internal/external capsule/lentiform nucleus experienced higher increase of WMH volume after a year [n = 21, median (IQR) from 18 (11.70 31.54) ml to 27.41 (15.84 40.45) ml]. Voxel-wise analyses of WMH distribution in patients grouped per RSSI location revealed group differences increased in the presence of vascular risk factors, especially hypertension and recent or current smoking habit. In our sample of patients presenting to the clinic with lacunar strokes, lacunar strokes extent influenced WMH volume fate; and RSSI location and WMH spatial distribution and dynamics were intertwined, with differential patterns emerging in the presence of vascular risk factors. These results, if confirmed in wider samples, open potential avenues in stroke rehabilitation to be explored further.

The effect of hyperglycemia on neurovascular coupling and cerebrovascular patterning in zebrafish.

Neurovascular coupling (through which local cerebral blood flow changes in response to neural activation are mediated) is impaired in many diseases including diabetes. Current preclinical rodent models of neurovascular coupling rely on invasive surgery and instrumentation, but transgenic zebrafish coupled with advances in imaging techniques allow non-invasive quantification of cerebrovascular anatomy, neural activation, and cerebral vessel haemodynamics. We therefore established a novel non-invasive, non-anaesthetised zebrafish larval model of neurovascular coupling, in which visual stimulus evokes neuronal activation in the optic tectum that is associated with a specific increase in red blood cell speed in tectal blood vessels. We applied this model to the examination of the effect of glucose exposure on cerebrovascular patterning and neurovascular coupling. We found that chronic exposure of zebrafish to glucose impaired tectal blood vessel patterning and neurovascular coupling. The nitric oxide donor sodium nitroprusside rescued all these adverse effects of glucose exposure on cerebrovascular patterning and function. Our results establish the first non-mammalian model of neurovascular coupling, offering the potential to perform more rapid genetic modifications and high-throughput screening than is currently possible using rodents. Furthermore, using this zebrafish model, we reveal a potential strategy to ameliorate the effects of hyperglycemia on cerebrovascular function.

Neurologic Deficits in Patients With Newly Diagnosed Celiac Disease Are Frequent and Linked With Autoimmunity to Transglutaminase 6.

BACKGROUND & AIMS: Celiac disease is an autoimmune disorder induced by ingestion of gluten that affects 1% of the population and is characterized by gastrointestinal symptoms, weight loss, and anemia. We evaluated the presence of neurologic deficits and investigated whether the presence of antibodies to Transglutaminase 6 (TG6) increases the risk of neurologic defects in patients with a new diagnosis of celiac disease. METHODS: We performed a prospective cohort study at a secondary-care gastroenterology center of 100 consecutive patients who received a new diagnosis of celiac disease based on gastroscopy and duodenal biopsy. We collected data on neurologic history, and patients were evaluated in a clinical examination along with magnetic resonance imaging of the brain, magnetic resonance (MR) spectroscopy of the cerebellum, and measurements of antibodies against TG6 in serum samples. The first 52 patients recruited underwent repeat MR spectroscopy at 1 year after a gluten-free diet (GFD). The primary aim was to establish if detection of antibodies against TG6 can be used to identify patients with celiac disease and neurologic dysfunction. RESULTS: Gait instability was reported in 24% of the patients, persisting sensory symptoms in 12%, and frequent headaches in 42%. Gait ataxia was found in 29% of patients, nystagmus in 11%, and distal sensory loss in 10%. Sixty percent of patients had abnormal results from magnetic resonance imaging, 47% had abnormal results from MR spectroscopy of the cerebellum, and 25% had brain white matter lesions beyond that expected for their age group. Antibodies against TG6 were detected in serum samples from 40% of patients-these patients had significant atrophy of subcortical brain regions compared with patients without TG6 autoantibodies. In patients with abnormal results from MR spectroscopy of the cerebellum, those on the GFD had improvements detected in the repeat MR spectroscopy 1 year later. CONCLUSIONS: In a prospective cohort study of patients with a new diagnosis of celiac disease at a gastroenterology clinic, neurologic deficits were common and 40% had circulating antibodies against TG6. We observed a significant reduction in volume of specific brain regions in patients with TG6 autoantibodies, providing evidence for a link between autoimmunity to TG6 and brain atrophy in patients with celiac disease. There is a need for early diagnosis, increased awareness of the neurologic manifestations among clinicians, and reinforcement of adherence to a strict GFD by patients to avoid permanent neurologic disability.

Metric to quantify white matter damage on brain magnetic resonance images.

PURPOSE: Quantitative assessment of white matter hyperintensities (WMH) on structural Magnetic Resonance Imaging (MRI) is challenging. It is important to harmonise results from different software tools considering not only the volume but also the signal intensity. Here we propose and evaluate a metric of white matter (WM) damage that addresses this need. METHODS: We obtained WMH and normal-appearing white matter (NAWM) volumes from brain structural MRI from community dwelling older individuals and stroke patients enrolled in three different studies, using two automatic methods followed by manual editing by two to four observers blind to each other. We calculated the average intensity values on brain structural fluid-attenuation inversion recovery (FLAIR) MRI for the NAWM and WMH. The white matter damage metric is calculated as the proportion of WMH in brain tissue weighted by the relative image contrast of the WMH-to-NAWM. The new metric was evaluated using tissue microstructure parameters and visual ratings of small vessel disease burden and WMH: Fazekas score for WMH burden and Prins scale for WMH change. RESULTS: The correlation between the WM damage metric and the visual rating scores (Spearman ρ > =0.74, p < 0.0001) was slightly stronger than between the latter and WMH volumes (Spearman ρ > =0.72, p < 0.0001). The repeatability of the WM damage metric was better than WM volume (average median difference between measurements 3.26% (IQR 2.76%) and 5.88% (IQR 5.32%) respectively). The follow-up WM damage was highly related to total Prins score even when adjusted for baseline WM damage (ANCOVA, p < 0.0001), which was not always the case for WMH volume, as total Prins was highly associated with the change in the intense WMH volume (p = 0.0079, increase of 4.42 ml per unit change in total Prins, 95%CI [1.17 7.67]), but not with the change in less-intense, subtle WMH, which determined the volumetric change. CONCLUSION: The new metric is practical and simple to calculate. It is robust to variations in image processing methods and scanning protocols, and sensitive to subtle and severe white matter damage.

Sample size considerations for trials using cerebral white matter hyperintensity progression as an intermediate outcome at 1 year after mild stroke: results of a prospective cohort study.

BACKGROUND: White matter hyperintensities (WMHs) are commonly seen on in brain imaging and are associated with stroke and cognitive decline. Therefore, they may provide a relevant intermediate outcome in clinical trials. WMH can be measured as a volume or visually on the Fazekas scale. We investigated predictors of WMH progression and design of efficient studies using WMH volume and Fazekas score as an intermediate outcome. METHODS: We prospectively recruited 264 patients with mild ischaemic stroke and measured WMH volume, Fazekas score, age and cardiovascular risk factors at baseline and 1 year. We modelled predictors of WMH burden at 1 year and used the results in sample size calculations for hypothetical randomised controlled trials with different analysis plans and lengths of follow-up. RESULTS: Follow-up WMH volume was predicted by baseline WMH: a 0.73-ml (95% CI 0.65-0.80, p < 0.0001) increase per 1-ml baseline volume increment, and a 2.93-ml increase (95% CI 1.76-4.10, p < 0.0001) per point on the Fazekas scale. Using a mean difference of 1 ml in WMH volume between treatment groups, 80% power and 5% alpha, adjusting for all predictors and 2-year follow-up produced the smallest sample size (n = 642). Other study designs produced samples sizes from 2054 to 21,270. Sample size calculations using Fazekas score as an outcome with the same power and alpha, as well as an OR corresponding to a 1-ml difference, were sensitive to assumptions and ranged from 2504 to 18,886. CONCLUSIONS: Baseline WMH volume and Fazekas score predicted follow-up WMH volume. Study size was smallest using volumes and longer-term follow-up, but this must be balanced against resources required to measure volumes versus Fazekas scores, bias due to dropout and scanner drift. Samples sizes based on Fazekas scores may be best estimated with simulation studies.

A qualitative comparison of arterial spin labelling and dynamic susceptibility contrast MRI in 52 children with a range of neurological conditions.

OBJECTIVE: To assess the usefulness of arterial spin labelling (ASL) compared with dynamic susceptibility contrast (DSC) perfusion MRI for typical paediatric neuroimaging applications at 1.5 T. METHODS: 52 children (age: 4 months-17 years) with a variety of neurological disorders were scanned using three-dimensional ASL and echoplanar imaging DSC sequences. All images were reviewed by an experienced neuroradiologist; image quality was recorded as "good", "acceptable" or "poor" and diagnostic value was noted as being "greater", "similar" or "less" for ASL when compared with DSC. RESULTS: ASL cerebral blood flow (CBF) images were judged to be acceptable in 89% of cases, poor in 11% of cases and good in 0% of cases, while DSC CBF images were acceptable in 88% of cases, poor in 12% of cases and good in 0% of cases. ASL images were judged to have better diagnostic value than DSC images in 28% of cases, about the same in 58% of cases and worse in 14% of cases. CONCLUSION: The results of this study suggest that ASL offers a realistic alternative to DSC in the paediatric setting for the majority of cases encountered in this study. However, there are some situations where DSC outperforms ASL; so, care is required to choose the most appropriate technique for the pathology under investigation. A larger study is required to corroborate these preliminary findings. Advances in knowledge: ASL is a relatively new perfusion imaging technique whose use has not been explored extensively in the paediatric setting. This work is a preliminary study to evaluate its usefulness in paediatric neuroimaging.

Tracer kinetic modelling for DCE-MRI quantification of subtle blood-brain barrier permeability.

There is evidence that subtle breakdown of the blood-brain barrier (BBB) is a pathophysiological component of several diseases, including cerebral small vessel disease and some dementias. Dynamic contrast-enhanced MRI (DCE-MRI) combined with tracer kinetic modelling is widely used for assessing permeability and perfusion in brain tumours and body tissues where contrast agents readily accumulate in the extracellular space. However, in diseases where leakage is subtle, the optimal approach for measuring BBB integrity is likely to differ since the magnitude and rate of enhancement caused by leakage are extremely low; several methods have been reported in the literature, yielding a wide range of parameters even in healthy subjects. We hypothesised that the Patlak model is a suitable approach for measuring low-level BBB permeability with low temporal resolution and high spatial resolution and brain coverage, and that normal levels of scanner instability would influence permeability measurements. DCE-MRI was performed in a cohort of mild stroke patients (n=201) with a range of cerebral small vessel disease severity. We fitted these data to a set of nested tracer kinetic models, ranking their performance according to the Akaike information criterion. To assess the influence of scanner drift, we scanned 15 healthy volunteers that underwent a "sham" DCE-MRI procedure without administration of contrast agent. Numerical simulations were performed to investigate model validity and the effect of scanner drift. The Patlak model was found to be most appropriate for fitting low-permeability data, and the simulations showed vp and K(Trans) estimates to be reasonably robust to the model assumptions. However, signal drift (measured at approximately 0.1% per minute and comparable to literature reports in other settings) led to systematic errors in calculated tracer kinetic parameters, particularly at low permeabilities. Our findings justify the growing use of the Patlak model in low-permeability states, which has the potential to provide valuable information regarding BBB integrity in a range of diseases. However, absolute values of the resulting tracer kinetic parameters should be interpreted with extreme caution, and the size and influence of signal drift should be measured where possible.

Diffuse intrinsic pontine glioma: is MRI surveillance improved by region of interest volumetry?

BACKGROUND: Paediatric diffuse intrinsic pontine glioma (DIPG) is noteworthy for its fibrillary infiltration through neuroparenchyma and its resultant irregular shape. Conventional volumetry methods aim to approximate such irregular tumours to a regular ellipse, which could be less accurate when assessing treatment response on surveillance MRI. Region-of-interest (ROI) volumetry methods, using manually traced tumour profiles on contiguous imaging slices and subsequent computer-aided calculations, may prove more reliable. OBJECTIVE: To evaluate whether the reliability of MRI surveillance of DIPGs can be improved by the use of ROI-based volumetry. MATERIALS AND METHODS: We investigated the use of ROI- and ellipsoid-based methods of volumetry for paediatric DIPGs in a retrospective review of 22 MRI examinations. We assessed the inter- and intraobserver variability of the two methods when performed by four observers. RESULTS: ROI- and ellipsoid-based methods strongly correlated for all four observers. The ROI-based volumes showed slightly better agreement both between and within observers than the ellipsoid-based volumes (inter-[intra-]observer agreement 89.8% [92.3%] and 83.1% [88.2%], respectively). Bland-Altman plots show tighter limits of agreement for the ROI-based method. CONCLUSION: Both methods are reproducible and transferrable among observers. ROI-based volumetry appears to perform better with greater intra- and interobserver agreement for complex-shaped DIPG.

Use of dynamic contrast-enhanced MRI to measure subtle blood-brain barrier abnormalities.

There is growing interest in investigating the role of subtle changes in blood-brain barrier (BBB) function in common neurological disorders and the possible use of imaging techniques to assess these abnormalities. Some studies have used dynamic contrast-enhanced MR imaging (DCE-MRI) and these have demonstrated much smaller signal changes than obtained from more traditional applications of the technique, such as in intracranial tumors and multiple sclerosis. In this work, preliminary results are presented from a DCE-MRI study of patients with mild stroke classified according to the extent of visible underlying white matter abnormalities. These data are used to estimate typical signal enhancement profiles in different tissue types and by degrees of white matter abnormality. The effect of scanner noise, drift and different intrinsic tissue properties on signal enhancement data is also investigated and the likely implications for interpreting the enhancement profiles are discussed. No significant differences in average signal enhancement or contrast agent concentration were observed between patients with different degrees of white matter abnormality, although there was a trend towards greater signal enhancement with more abnormal white matter. Furthermore, the results suggest that many of the factors considered introduce uncertainty of a similar magnitude to expected effect sizes, making it unclear whether differences in signal enhancement are truly reflective of an underlying BBB abnormality or due to an unrelated effect. As the ultimate aim is to achieve a reliable quantification of BBB function in subtle disorders, this study highlights the factors which may influence signal enhancement and suggests that further work is required to address the challenging problems of quantifying contrast agent concentration in healthy and diseased living human tissue and of establishing a suitable model to enable quantification of relevant physiological parameters. Meanwhile, it is essential that future studies use an appropriate control group to minimize these influences.

Pretreatment tumoural perfusion correlates with an imaging-based response to dexamethasone in patients with glioblastoma multiforme.

Imaging-based markers of treatment response are increasingly being used in studies of brain-tumour therapies, for evaluating novel treatments and further understanding of existing therapies. An ultimate goal of these studies is to identify pre- or early-stage treatment imaging biomarkers that enable prediction of subsequent treatment response. We hypothesised that pretreatment MRI-based measurements of tumoural perfusion may provide a suitable imaging-based biomarker for prediction of subsequent treatment response and evaluated this in a group of nine high-grade glioma patients undergoing dexamethasone treatment. A strong positive correlation was observed between tumoural blood flow (R(2)=0.90, p<0.001) and tumoural blood volume (R(2)=0.76, p=0.002), and subsequent treatment response as measured by alterations in tumour leakage properties. These preliminary results indicate that measurements of tumoural perfusion may provide useful imaging biomarkers for predicting treatment response to dexamethasone and would therefore also be worth evaluating in newer emerging therapies.

Quantitative assessment of intracranial tumor response to dexamethasone using diffusion, perfusion and permeability magnetic resonance imaging.

There is increasing interest in obtaining quantitative imaging parameters to aid in the assessment of tumor responses to treatment. In this study, the feasibility of performing integrated diffusion, perfusion and permeability magnetic resonance imaging (MRI) for characterizing responses to dexamethasone in intracranial tumors was assessed. Eight patients with glioblastoma, five with meningioma and three with metastatic carcinoma underwent MRI prior to and 48-72 h following dexamethasone administration. The MRI protocol enabled quantification of the volume transfer constant (K(trans)), extracellular space volume fraction (nu(e)), plasma volume fraction (nu(p)), regional cerebral blood flow (rCBF), regional cerebral blood volume (rCBV), longitudinal relaxation time (T(1)) and mean diffusivity (D(av)). All subjects successfully completed the imaging protocol for the presteroid and poststeroid scans. Significant reductions were observed after the treatment for K(trans), nu(e) and nu(p) in enhancing tumor as well as for T(1) and D(av) in the edematous brain in glioblastoma; on the other hand, for meningioma, significant differences were seen only in edematous brain T(1) and D(av). No significant difference was observed for any parameter in metastatic carcinoma, most likely due to the small sample size. In addition, no significant difference was observed for enhancing tumor rCBF and rCBV in any of the tumor types, although the general trend was for rCBV to be reduced and for rCBF to be more variable. The yielded parameters provide a wealth of physiologic information and contribute to the understanding of dexamethasone actions on different types of intracranial tumors.

Visualization and analysis of white matter structural asymmetry in diffusion tensor MRI data.

This work presents a method that permits the characterization, quantification, and 3D visualization of white matter structural information contained within diffusion tensor MR imaging (DT-MRI) data. In this method, regions within the brain are defined as possessing linear, planar, or spherical diffusion. Visualization of this diffusion metric data is realized by generating streamtube and streamsurface models to represent regions of linear and planar diffusion. Quantification of differences in diffusion anisotropy between different regions of interest (ROIs) is then achieved by analyzing 2D barycentric histograms created from the complete distribution of diffusion metric values measured in each region. In four healthy volunteers, there was only a small degree of asymmetry (epsilon) in the number of linear, planar, or spherical diffusion voxels between the right and left hemispheres (epsilon approximately equal to +/- 2%). However, in a patient with a metastatic brain lesion there was marked asymmetry in both linear (epsilon approximately -10%) and planar (epsilon approximately equal to 5%) diffusion between comparable ipsilateral and contralateral regions, with a significant reduction in the number of linear diffusion voxels and an increase in the number of planar diffusion voxels in the tumor-bearing hemisphere. These results demonstrate the potential of this approach to characterize brain structure in both healthy and diseased subjects.

Fusion of contrast-enhanced breast MR and mammographic imaging data.

Increasing use is being made of Gd-DTPA contrast-enhanced magnetic resonance imaging for breast cancer assessment since it provides 3D functional information via pharmacokinetic interaction between contrast agent and tumour vascularity, and because it is applicable to women of all ages as well as patients with post-operative scarring. Contrast-enhanced MRI (CE-MRI) is complementary to conventional X-ray mammography, since it is a relatively low-resolution functional counterpart of a comparatively high-resolution 2D structural representation. However, despite the additional information provided by MRI, mammography is still an extremely important diagnostic imaging modality, particularly for several common conditions such as ductal carcinoma in situ (DCIS) where it has been shown that there is a strong correlation between microcalcification clusters and malignancy. Pathological indicators such as calcifications and fine spiculations are not visible in CE-MRI and therefore there is clinical and diagnostic value in fusing the high-resolution structural information available from mammography with the functional data acquired from MRI imaging. This paper presents a novel data fusion technique whereby medial-lateral oblique (MLO) and cranial-caudal (CC) mammograms (2D data) are registered to 3D contrast-enhanced MRI volumes. We utilise a combination of pharmacokinetic modelling, projection geometry, wavelet-based landmark detection and thin-plate spline non-rigid 'warping' to transform the coordinates of regions of interest (ROIs) from the 2D mammograms to the spatial reference frame of the contrast-enhanced MRI volume. Of key importance is the use of a flexible wavelet-based feature extraction technique that enables feature correspondences to be robustly determined between the very different image characteristics of X-ray mammography and MRI. An evaluation of the fusion framework is demonstrated with a series of clinical cases and a total of 14 patient examples.