Tobias Djamsched Faizy

Heterogeneity of Multiple Sclerosis Lesions in Multislice Myelin Water Imaging

Purpose To assess neuroprotection and remyelination in Multiple Sclerosis (MS), we applied a more robust myelin water imaging (MWI) processing technique, including spatial priors into image reconstruction, which allows for lower SNR, less averages and shorter acquisition times. We sought to evaluate this technique in MS-patients and healthy controls (HC). Materials and Methods Seventeen MS-patients and 14 age-matched HCs received a 3T Magnetic Resonance Imaging (MRI) examination including MWI (8 slices, 12 minutes acquisition time), T2w and T1mprage pre and post gadolinium (GD) administration. Black holes (BH), contrast enhancing lesions (CEL) and T2 lesions were marked and registered to MWI. Additionally, regions of interest (ROI) were defined in the frontal, parietal and occipital normal appearing white matter (NAWM)/white matter (WM), the corticospinal tract (CST), the splenium (SCC) and genu (GCC) of the corpus callosum in patients and HCs. Mean values of myelin water fraction (MWF) were determined for each ROI. Results Significant differences (p≤0.05) of the MWF were found in all three different MS-lesion types (BH, CEL, T2 lesions), compared to the WM of HCs. The mean MWF values among the different lesion types were significantly differing from each other. Comparing MS-patients vs. HCs, we found a significant (p≤0.05) difference of the MWF in all measured ROIs except of GCC and SCC. The mean reduction of MWF in the NAWM of MS-patients compared to HCs was 37%. No age, sex, disability score and disease duration dependency was found for the NAWM MWF. Conclusion MWF measures were in line with previous studies and lesions were clearly visible in MWI. MWI allows for quantitative assessment of NAWM and lesions in MS, which could be used as an additional sensitive imaging endpoint for larger MS studies. Measurements of the MWF also differ between patients and healthy controls.

Magnetic Particle Imaging for High Temporal Resolution Assessment of Aneurysm Hemodynamics

Purpose The purpose of this work was to demonstrate the capability of magnetic particle imaging (MPI) to assess the hemodynamics in a realistic 3D aneurysm model obtained by additive manufacturing. MPI was compared with magnetic resonance imaging (MRI) and dynamic digital subtraction angiography (DSA). Materials and Methods The aneurysm model was of saccular morphology (7 mm dome height, 5 mm cross-section, 3–4 mm neck, 3.5 mm parent artery diameter) and connected to a peristaltic pump delivering a physiological flow (250 mL/min) and pulsation rate (70/min). High-resolution (4 h long) 4D phase contrast flow quantification (4D pc-fq) MRI was used to directly assess the hemodynamics of the model. Dynamic MPI, MRI, and DSA were performed with contrast agent injections (3 mL volume in 3 s) through a proximally placed catheter. Results and Discussion 4D pc-fq measurements showed distinct pulsatile flow velocities (20–80 cm/s) as well as lower flow velocities and a vortex inside the aneurysm. All three dynamic methods (MPI, MRI, and DSA) also showed a clear pulsation pattern as well as delayed contrast agent dynamics within the aneurysm, which is most likely caused by the vortex within the aneurysm. Due to the high temporal resolution of MPI and DSA, it was possible to track the contrast agent bolus through the model and to estimate the average flow velocity (about 60 cm/s), which is in accordance with the 4D pc-fq measurements. Conclusions The ionizing radiation free, 4D high resolution MPI method is a very promising tool for imaging and characterization of hemodynamics in human. It carries the possibility of overcoming certain disadvantages of other modalities like considerably lower temporal resolution of dynamic MRI and limited 2D characteristics of DSA. Furthermore, additive manufacturing is the key for translating powerful pre-clinical techniques into the clinic.

T1- Thresholds in Black Holes Increase Clinical-Radiological Correlation in Multiple Sclerosis Patients.

BACKGROUND Magnetic Resonance Imaging (MRI) is an established tool in diagnosing and evaluating disease activity in Multiple Sclerosis (MS). While clinical-radiological correlations are limited in general, hypointense T1 lesions (also known as Black Holes (BH)) have shown some promising results. The definition of BHs is very heterogeneous and depends on subjective visual evaluation. OBJECTIVE We aimed to improve clinical-radiological correlations by defining BHs using T1 relaxation time (T1-RT) thresholds to achieve best possible correlation between BH lesion volume and clinical disability. METHOD 40 patients with mainly relapsing-remitting MS underwent MRI including 3-dimensional fluid attenuated inversion recovery (FLAIR), magnetization-prepared rapid gradient echo (MPRAGE) before and after Gadolinium (GD) injection and double inversion-contrast magnetization-prepared rapid gradient echo (MP2RAGE) sequences. BHs (BHvis) were marked by two raters on native T1-weighted (T1w)-MPRAGE, contrast-enhancing lesions (CE lesions) on T1w-MPRAGE after GD and FLAIR lesions (total-FLAIR lesions) were detected separately. BHvis and total-FLAIR lesion maps were registered to MP2RAGE images, and the mean T1-RT were calculated for all lesion ROIs. Mean T1 values of the cortex (CTX) were calculated for each patient. Subsequently, Spearman rank correlations between clinical scores (Expanded Disability Status Scale and Multiple Sclerosis Functional Composite) and lesion volume were determined for different T1-RT thresholds. RESULTS Significant differences in T1-RT were obtained between all different lesion types with highest T1 values in visually marked BHs (BHvis: 1453.3±213.4 ms, total-FLAIR lesions: 1394.33±187.38 ms, CTX: 1305.6±35.8 ms; p<0.05). Significant correlations between BHvis/total-FLAIR lesion volume and clinical disability were obtained for a wide range of T1-RT thresholds. The highest correlation for BHvis and total-FLAIR lesion masks were found at T1-RT>1500 ms (Expanded Disability Status Scale vs. lesion volume: rBHvis = 0.442 and rtotal-FLAIR = 0.497, p<0.05; Multiple Sclerosis Functional Composite vs. lesion volume: rBHvis = -0.53 and rtotal-FLAIR = -0.627, p<0.05). CONCLUSION Clinical-radiological correlations in MS patients are increased by application of T1-RT thresholds. With the short acquisition time of the MP2RAGE sequences, quantitative T1 maps could be easily established in clinical studies.

A standardised frankincense extract reduces disease activity in relapsing-remitting multiple sclerosis (the SABA phase IIa trial)

Objective To investigate whether oral administration of a standardised frankincense extract (SFE) is safe and reduces disease activity in patients with relapsing-remitting multiple sclerosis (RRMS). Methods We performed an investigator-initiated, bicentric phase IIa, open-label, baseline-to-treatment pilot study with an oral SFE in patients with RRMS (NCT01450124). After a 4-month baseline observation phase, patients were treated for 8 months with an option to extend treatment for up to 36 months. The primary outcome measures were the number and volume of contrast-enhancing lesions (CEL) measured in MRI during the 4-month treatment period compared with the 4-month baseline period. Eighty patients were screened at two centres, 38 patients were included in the trial, 28 completed the 8-month treatment period and 18 of these participated in the extension period. Results The SFE significantly reduced the median number of monthly CELs from 1.00 (IQR 0.75–3.38) to 0.50 (IQR 0.00–1.13; difference −0.625, 95% CI −1.25 to −0.50; P<0.0001) at months 5–8. We observed significantly less brain atrophy as assessed by parenchymal brain volume change (P=0.0081). Adverse events were generally mild (57.7%) or moderate (38.6%) and comprised mainly gastrointestinal symptoms and minor infections. Mechanistic studies showed a significant increase in regulatory CD4+ T cell markers and a significant decrease in interleukin-17A-producing CD8+ T cells indicating a distinct mechanism of action of the study drug. Interpretation The oral SFE was safe, tolerated well and exhibited beneficial effects on RRMS disease activity warranting further investigation in a controlled phase IIb or III trial. Clinical trial registration NCT01450124; Results.

Reliability of cortical lesion detection on double inversion recovery MRI applying the MAGNIMS-Criteria in multiple sclerosis patients within a 16-months period

Purpose In patients with multiple sclerosis (MS), Double Inversion Recovery (DIR) magnetic resonance imaging (MRI) can be used to identify cortical lesions (CL). We sought to evaluate the reliability of CL detection on DIR longitudinally at multiple subsequent time-points applying the MAGNIMs scoring criteria for CLs. Methods 26 MS patients received a 3T-MRI (Siemens, Skyra) with DIR at 12 time-points (TP) within a 16 months period. Scans were assessed in random order by two different raters. Both raters separately marked all CLs on each scan and total lesion numbers were obtained for each scan-TP and patient. After a retrospective re-evaluation, the number of consensus CLs (conL) was defined as the total number of CLs, which both raters finally agreed on. CLs volumes, relative signal intensities and CLs localizations were determined. Both ratings (conL vs. non-consensus scoring) were compared for further analysis. Results A total number of n = 334 CLs were identified by both raters in 26 MS patients with a first agreement of both raters on 160 out of 334 of the CLs found (κ = 0.48). After the retrospective re-evaluation, consensus agreement increased to 233 out of 334 CL (κ = 0.69). 93.8% of conL were visible in at least 2 consecutive TP. 74.7% of the conL were visible in all 12 consecutive TP. ConL had greater mean lesion volumes and higher mean signal intensities compared to lesions that were only detected by one of the raters (p<0.05). A higher number of CLs in the frontal, parietal, temporal and occipital lobe were identified by both raters than the number of those only identified by one of the raters (p<0.05). Conclusions After a first assessment, slightly less than a half of the CL were considered as reliably detectable on longitudinal DIR images. A retrospective re-evaluation notably increased the consensus agreement. However, this finding is narrowed, considering the fact that retrospective evaluation steps might not be practicable in clinical routine. Lesions that were not reliably identifiable by both raters seem to be characterized by lower signal intensity and smaller size, or located in distinct anatomical brain regions.

Using 3D spatial correlations to improve the noise robustness of multi component analysis of 3D multi echo quantitative T2 relaxometry data

Purpose We present a computationally feasible and iterative multi‐voxel spatially regularized algorithm for myelin water fraction (MWF) reconstruction. This method utilizes 3D spatial correlations present in anatomical/pathological tissues and underlying B1+‐inhomogeneity or flip angle inhomogeneity to enhance the noise robustness of the reconstruction while intrinsically accounting for stimulated echo contributions using T2‐distribution data alone. Methods Simulated data and in vivo data acquired using 3D non‐selective multi‐echo spin echo (3DNS‐MESE) were used to compare the reconstruction quality of the proposed approach against those of the popular algorithm (the method by Prasloski et al.) and our previously proposed 2D multi‐slice spatial regularization spatial regularization approach. We also investigated whether the inter‐sequence correlations and agreements improved as a result of the proposed approach. MWF‐quantifications from two sequences, 3DNS‐MESE vs 3DNS‐gradient and spin echo (3DNS‐GRASE), were compared for both reconstruction approaches to assess correlations and agreements between inter‐sequence MWF‐value pairs. MWF values from whole‐brain data of six volunteers and two multiple sclerosis patients are being reported as well. Results In comparison with competing approaches such as Prasloskis method or our previously proposed 2D multi‐slice spatial regularization method, the proposed method showed better agreements with simulated truths using regression analyses and Bland‐Altman analyses. For 3DNS‐MESE data, MWF‐maps reconstructed using the proposed algorithm provided better depictions of white matter structures in subcortical areas adjoining gray matter which agreed more closely with corresponding contrasts on T2‐weighted images than MWF‐maps reconstructed with the method by Prasloski et al. We also achieved a higher level of correlations and agreements between inter‐sequence (3DNS‐MESE vs 3DNS‐GRASE) MWF‐value pairs. Conclusion The proposed algorithm provides more noise‐robust fits to T2‐decay data and improves MWF‐quantifications in white matter structures especially in the sub‐cortical white matter and major white matter tract regions. HighlightsAn accurate determination of T2 distribution in short T2 pool regime is not feasible, given the shortest achievable echo time is ˜ 7–10 ms.The voxel wise estimation of myelin water fraction value depends on three scalar values rather than entire T2 distributions (refer to appendix F).The proposed method utilizes 3D spatial correlations present in in‐vivo tissues and underlying effective B1+‐inhomogeneity map and iteratively refines both maps to enhance the noise robustness of the reconstruction.Using measured B1+‐map to correct for stimulated echo contributions would be suboptimal for reasons mentioned in the discussion section.

CT-perfusion stroke imaging: a threshold free probabilistic approach to predict infarct volume compared to traditional ischemic thresholds

The aim was to evaluate a novel method of threshold-free prediction of brain infarct from computed tomography perfusion (CTP) imaging in comparison to conventional ischemic thresholds. In a multicenter cohort of 161 patients with acute large vessel occlusion who received endovascular therapy, brain infarction was predicted by CTP using (1) optimized parameter cut-off values determined by ROC curve analysis and (2) probabilistic logistic regression threshold-free analysis. Predicted infarct volumes and prediction errors based on four perfusion parameter maps were compared against observed infarcts. In 93 patients with successful recanalization, the mean observed infarct volume was 35.7 ± 61.9 ml (the reference for core infarct not savable by reperfusion). Optimal parameter thresholds predicted mean infarct volumes between 53.2 ± 44.4 and 125.0 ± 95.4 ml whereas threshold-free analysis predicted mean volumes between 35.9 ± 28.5 and 36.1 ± 29.0 ml. In 68 patients with persistent occlusion, the mean observed infarct volume was 113.4 ± 138.3 ml (the reference to define penumbral infarct savable by reperfusion). Predicted mean infarct volumes by parameter thresholds ranged from 91.4 ± 81.5 to 163.8 ± 135.7 ml, by threshold-free analysis from 113.2 ± 89.9 to 113.5 ± 89.0 ml. Threshold-free prediction of infarct volumes had a higher precision and lower patient-specific prediction error than conventional thresholding. Penumbra to core lesion mismatch estimate may therefore benefit from threshold-free CTP analysis.

T1 Recovery Is Predominantly Found in Black Holes and Is Associated with Clinical Improvement in Patients with Multiple Sclerosis

BACKGROUND AND PURPOSE: Quantitative MR imaging parameters help to evaluate disease progression in multiple sclerosis and increase correlation with clinical disability. We therefore hypothesized that T1 values might be a marker for ongoing tissue damage or even remyelination and may help increase clinical correlation. MATERIALS AND METHODS: MR imaging was performed in 17 patients with relapsing-remitting MS at baseline and after 12 months of starting immunotherapy with dimethyl fumarate. On baseline images, lesion segmentation was performed for normal-appearing white matter, T2 hyperintense (FLAIR lesions), T1 hypointense (black holes), and contrast-enhancing lesions, and T1 relaxation times were obtained at baseline and after 12 months. Changes in clinical status were assessed by using the Expanded Disability Status Scale and Symbol Digit Modalities Test at both dates (Expanded Disability Status Scale-difference/Symbol Digit Modalities Test-diff). RESULTS: The highest T1 relaxation time at baseline was measured in black holes (1460.2 ± 209.46 ms) followed by FLAIR lesions (1400.38 ± 189.1 ms), pure FLAIR lesions (1327.5 ± 210.04 ms), contrast-enhancing lesions (1205.59 ± 199.95 ms), and normal-appearing white matter (851.34 ± 30.61 ms). After 12 months, T1 values had decreased significantly in black holes (1369.4 ± 267.81 ms), contrast-enhancing lesions (1079.57 ± 183.36 ms) (both P < .001), and normal-appearing white matter (841.98 ± 36.1 ms, P = .006). With the Jonckheere-Terpstra Test, better clinical scores were associated with decreasing T1 relaxation times in black holes (P < .05). CONCLUSIONS: T1 relaxation time is a useful quantitative MR imaging technique, which helps detect changes in MS lesions with time. We assume that these changes are associated with the degree of myelination within the lesions themselves and are pronounced in black holes. Additionally, decreasing T1 values in black holes were associated with clinical improvement.

Age-Related Measurements of the Myelin Water Fraction derived from 3D multi-echo GRASE reflect Myelin Content of the Cerebral White Matter

Myelin Water Fraction (MWF) measurements derived from quantitative Myelin Water Imaging (MWI) may detect demyelinating changes of the cerebral white matter (WM) microstructure. Here, we investigated age-related alterations of the MWF in normal aging brains of healthy volunteers utilizing two fast and clinically feasible 3D gradient and spin echo (GRASE) MWI sequences with 3 mm and 5 mm isotropic voxel size. In 45 healthy subjects (age range: 18–79 years), distinct regions of interest (ROI) were defined in the cerebral WM including corticospinal tracts. For the 3 mm sequence, significant correlations of the mean MWF with age were found for most ROIs (r < −0.8 for WM ROIs; r = −0.55 for splenium of corpus callosum; r = −0.75 for genu of corpus callosum; p < 0.001 for all ROIs). Similar correlations with age were found for the ROIs of the 5 mm sequence. No significant correlations were found for the corticospinal tract and the occipital WM (p > 0.05). Mean MWF values obtained from the 3 mm and 5 mm sequences were strongly comparable. The applied 3D GRASE MWI sequences were found to be sensitive for age-dependent myelin changes of the cerebral WM microstructure. The reported MWF values might be of substantial use as reference for further investigations in patient studies.