Myeloid cell iron uptake pathways and paramagnetic rim formation in multiple sclerosis.

In multiple sclerosis (MS), sustained inflammatory activity can be visualized by iron-sensitive magnetic resonance imaging (MRI) at the edges of chronic lesions. These paramagnetic rim lesions (PRLs) are associated with clinical worsening, although the cell type-specific and molecular pathways of iron uptake and metabolism are not well known. We studied two postmortem cohorts: an exploratory formalin-fixed paraffin-embedded (FFPE) tissue cohort of 18 controls and 24 MS cases and a confirmatory snap-frozen cohort of 6 controls and 14 MS cases. Besides myelin and non-heme iron imaging, the haptoglobin-hemoglobin scavenger receptor CD163, the iron-metabolizing markers HMOX1 and HAMP as well as immune-related markers P2RY12, CD68, C1QA and IL10 were visualized in myeloid cell (MC) subtypes at RNA and protein levels across different MS lesion areas. In addition, we studied PRLs in vivo in a cohort of 98 people with MS (pwMS) via iron-sensitive 3 T MRI and haptoglobin genotyping by PCR. CSF samples were available from 38 pwMS for soluble CD163 (sCD163) protein level measurements by ELISA. In postmortem tissues, we observed that iron uptake was linked to rim-associated C1QA-expressing MC subtypes, characterized by upregulation of CD163, HMOX1, HAMP and, conversely, downregulation of P2RY12. We found that pwMS with [Formula: see text] 4 PRLs had higher sCD163 levels in the CSF than pwMS with [Formula: see text] 3 PRLs with sCD163 correlating with the number of PRLs. The number of PRLs was associated with clinical worsening but not with age, sex or haptoglobin genotype of pwMS. However, pwMS with Hp2-1/Hp2-2 haplotypes had higher clinical disability scores than pwMS with Hp1-1. In summary, we observed upregulation of the CD163-HMOX1-HAMP axis in MC subtypes at chronic active lesion rims, suggesting haptoglobin-bound hemoglobin but not transferrin-bound iron as a critical source for MC-associated iron uptake in MS. The correlation of CSF-associated sCD163 with PRL counts in MS highlights the relevance of CD163-mediated iron uptake via haptoglobin-bound hemoglobin. Also, while Hp haplotypes had no noticeable influence on PRL counts, pwMS carriers of a Hp2 allele might have a higher risk to experience clinical worsening.

Spinal cord lesions and brain grey matter atrophy independently predict clinical worsening in definite multiple sclerosis: a 5-year, multicentre study.

OBJECTIVES: To evaluate the combined contribution of brain and cervical cord damage in predicting 5-year clinical worsening in a multicentre cohort of definite multiple sclerosis (MS) patients. METHODS: Baseline 3.0T brain and cervical cord T2-weighted and three-dimensional T1-weighted MRI was acquired in 367 patients with MS (326 relapse-onset and 41 progressive-onset) and 179 healthy controls. Expanded Disability Status Scale (EDSS) score was obtained at baseline and after a median follow-up of 5.1 years (IQR=4.8-5.2). At follow-up, patients were classified as clinically stable/worsened according to EDSS changes. Generalised linear mixed models identified predictors of clinical worsening, evolution to secondary progressive (SP) MS and reaching EDSS=3.0, 4.0 and 6.0 milestones at 5 years. RESULTS: At follow-up, 120/367 (33%) patients with MS worsened clinically; 36/256 (14%) patients with relapsing-remitting evolved to SPMS. Baseline predictors of EDSS worsening were progressive-onset versus relapse-onset MS (standardised beta (ß)=0.97), higher EDSS (ß=0.41), higher cord lesion number (ß=0.41), lower normalised cortical volume (ß=-0.15) and lower cord area (ß=-0.28) (C-index=0.81). Older age (ß=0.86), higher EDSS (ß=1.40) and cord lesion number (ß=0.87) independently predicted SPMS conversion (C-index=0.91). Predictors of reaching EDSS=3.0 after 5 years were higher baseline EDSS (ß=1.49), cord lesion number (ß=1.02) and lower normalised cortical volume (ß=-0.56) (C-index=0.88). Baseline age (ß=0.30), higher EDSS (ß=2.03), higher cord lesion number (ß=0.66) and lower cord area (ß=-0.41) predicted EDSS=4.0 (C-index=0.92). Finally, higher baseline EDSS (ß=1.87) and cord lesion number (ß=0.54) predicted EDSS=6.0 (C-index=0.91). CONCLUSIONS: Spinal cord damage and, to a lesser extent, cortical volume loss helped predicting worse 5-year clinical outcomes in MS.

Cerebrospinal fluid-related tissue damage in multiple sclerosis patients with iron rim lesions.

BACKGROUND: In multiple sclerosis (MS), iron rim lesions (IRLs) are associated with pronounced tissue damage, higher disease severity and have been suggested as an imaging marker of chronic active inflammation behind the blood-brain barrier indicating progression. Furthermore, chronic intrathecal compartmentalized inflammation has been suggested to be a mediator of a cerebrospinal fluid (CSF)-related tissue damage. OBJECTIVE: To investigate CSF markers of intrathecal inflammation in patients with at least one IRL compared to patients without IRLs and to investigate tissue damage in lesions and normal-appearing white matter (NAWM) with proximity to CSF spaces. METHODS: A total of 102 patients (51 with at least 1 IRL and 51 age-/sex-matched patients without IRL) scanned with the same 3T magnetic resonance imaging (MRI) and having CSF analysis data were included. RESULTS: Patients with at least one IRL had higher disability scores, higher lesion volumes, lower brain volumes and a higher intrathecal immunoglobulin G (IgG) synthesis. Apparent diffusion coefficient (ADC) values in IRLs were higher compared to non-IRLs. We observed a negative linear correlation of ADC values in all tissue classes and distance to CSF, which was stronger in patients with high IgG quotients. CONCLUSION: IRLs are associated with higher intrathecal IgG synthesis. CSF-mediated intrathecal smouldering inflammation could explain a CSF-related gradient of tissue damage.

The neuroradiology of progressive multifocal leukoencephalopathy: a clinical trial perspective.

Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the CNS caused by the JC virus, which infects white and grey matter cells and leads to irreversible demyelination and neuroaxonal damage. Brain MRI, in addition to the clinical presentation and demonstration of JC virus DNA either in the CSF or by histopathology, is an important tool in the detection of PML. In clinical practice, standard MRI pulse sequences are utilized for screening, diagnosis and monitoring of PML, but validated imaging-based outcome measures for use in prospective, interventional clinical trials for PML have yet to be established. We review the existing literature regarding the use of MRI and PET in PML and discuss the implications of PML histopathology for neuroradiology. MRI not only demonstrates the localization and extent of PML lesions, but also mirrors the tissue destruction, ongoing viral spread, and resulting inflammation. Finally, we explore the potential for imaging measures to serve as an outcome in PML clinical trials and provide recommendations for current and future imaging outcome measure development in this area.

Impact of disease-modifying therapies on evolving tissue damage in iron rim multiple sclerosis lesions.

We investigated the impact of disease-modifying therapies (DMTs) on the evolving tissue damage in iron rim multiple sclerosis lesions using a novel post-processing magnetic resonance imaging (MRI) approach, the T1/T2 ratio. In this study, on baseline and 1-year follow-up, T1/T2 ratios of iron rim lesions (IRLs) in patients starting DMT (dimethyl fumarate, fingolimod, ocrelizumab) did not statistically differ compared to patients without DMT. At the second follow-up, T1/T2 ratios were significantly lower in IRLs in patients without DMT (p = 0.002), suggesting that DMTs have a beneficial delayed effect on lesion evolution and tissue matrix damage in IRLs.

Characterizing 1-year development of cervical cord atrophy across different MS phenotypes: A voxel-wise, multicentre analysis.

BACKGROUND: Spatio-temporal evolution of cord atrophy in multiple sclerosis (MS) has not been investigated yet. OBJECTIVE: To evaluate voxel-wise distribution and 1-year changes of cervical cord atrophy in a multicentre MS cohort. METHODS: Baseline and 1-year 3D T1-weighted cervical cord scans and clinical evaluations of 54 healthy controls (HC) and 113 MS patients (14 clinically isolated syndromes (CIS), 77 relapsing-remitting (RR), 22 progressive (P)) were used to investigate voxel-wise cord volume loss in patients versus HC, 1-year volume changes and clinical correlations (SPM12). RESULTS: MS patients exhibited baseline cord atrophy versus HC at anterior and posterior/lateral C1/C2 and C4-C6 (p < 0.05, corrected). While CIS patients showed baseline volume increase at C4 versus HC (p < 0.001, uncorrected), RRMS exhibited posterior/lateral C1/C2 atrophy versus CIS, and PMS showed widespread cord atrophy versus RRMS (p < 0.05, corrected). At 1 year, 13 patients had clinically worsened. Cord atrophy progressed in MS, driven by RRMS, at posterior/lateral C2 and C3-C6 (p < 0.05, corrected). CIS patients showed no volume changes, while PMS showed circumscribed atrophy progression. Baseline cord atrophy at posterior/lateral C1/C2 and C3-C6 correlated with concomitant and 1-year disability (r = -0.40/-0.62, p < 0.05, corrected). CONCLUSIONS: Voxel-wise analysis characterized spinal cord neurodegeneration over 1 year across MS phenotypes and helped to explain baseline and 1-year disability.

Association of iron rim lesions with brain and cervical cord volume in relapsing multiple sclerosis.

OBJECTIVES: In multiple sclerosis (MS), iron rim lesions (IRLs) are indicators of chronic low-grade inflammation and ongoing tissue destruction. The aim of this study was to assess the relationship of IRLs with clinical measures and magnetic resonance imaging (MRI) markers, in particular brain and cervical cord volume. METHODS: Clinical and MRI parameters from 102 relapsing MS patients (no relapses for at least 6 months, no contrast-enhancing lesions) were included; follow-up data obtained after 12 months was available in 49 patients. IRLs were identified on susceptibility-weighted images (SWIs). In addition to standard brain and spinal cord MRI parameters, normalised cross-sectional area (nCSA) of the upper cervical cord was calculated. RESULTS: Thirty-eight patients had at least one IRL on SWI MRI. At baseline, patients with IRLs had higher EDSS scores, higher lesion loads (brain and spinal cord), and lower cortical grey matter volumes and a lower nCSA. At follow-up, brain atrophy rates were higher in patients with IRLs. IRLs correlated spatially with T1-hypointense lesions. CONCLUSIONS: Relapsing MS patients with IRLs showed more aggressive MRI disease characteristics in both the cross-sectional and longitudinal analyses. KEY POINTS: • Multiple sclerosis patients with iron rim lesions had higher EDSS scores, higher brain and spinal cord lesion loads, lower cortical grey matter volumes, and a lower normalised cross-sectional area of the upper cervical spinal cord. • Iron rim lesions are a new lesion descriptor obtained from susceptibility-weighted MRI. Our data suggests that further exploration of this lesion characteristic in regard to a poorer prognosis in multiple sclerosis patients is warranted.

TSPO PET imaging of natalizumab-associated progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a severe infection of the CNS caused by the polyomavirus JC that can occur in multiple sclerosis patients treated with natalizumab. Clinical management of patients with natalizumab-associated PML is challenging not least because current imaging tools for the early detection, longitudinal monitoring and differential diagnosis of PML lesions are limited. Here we evaluate whether translocator protein (TSPO) PET imaging can be applied to monitor the inflammatory activity of PML lesions over time and differentiate them from multiple sclerosis lesions. For this monocentre pilot study we followed eight patients with natalizumab-associated PML with PET imaging using the TSPO radioligand 18F-GE-180 combined with frequent 3 T MRI. In addition we compared TSPO PET signals in PML lesions with the signal pattern of multiple sclerosis lesions from 17 independent multiple sclerosis patients. We evaluated the standardized uptake value ratio as well as the morphometry of the TSPO uptake for putative PML and multiple sclerosis lesions areas compared to a radiologically unaffected pseudo-reference region in the cerebrum. Furthermore, TSPO expression in situ was immunohistochemically verified by determining the density and cellular identity of TSPO-expressing cells in brain sections from four patients with early natalizumab-associated PML as well as five patients with other forms of PML and six patients with inflammatory demyelinating CNS lesions (clinically isolated syndrome/multiple sclerosis). Histological analysis revealed a reticular accumulation of TSPO expressing phagocytes in PML lesions, while such phagocytes showed a more homogeneous distribution in putative multiple sclerosis lesions. TSPO PET imaging showed an enhanced tracer uptake in natalizumab-associated PML lesions that was present from the early to the chronic stages (up to 52 months after PML diagnosis). While gadolinium enhancement on MRI rapidly declined to baseline levels, TSPO tracer uptake followed a slow one phase decay curve. A TSPO-based 3D diagnostic matrix taking into account the uptake levels as well as the shape and texture of the TSPO signal differentiated >96% of PML and multiple sclerosis lesions. Indeed, treatment with rituximab after natalizumab-associated PML in three patients did not affect tracer uptake in the assigned PML lesions but reverted tracer uptake to baseline in the assigned active multiple sclerosis lesions. Taken together our study suggests that TSPO PET imaging can reveal CNS inflammation in natalizumab-associated PML. TSPO PET may facilitate longitudinal monitoring of disease activity and help to distinguish recurrent multiple sclerosis activity from PML progression.

Accelerated white matter lesion analysis based on simultaneous T1 and T2∗ quantification using magnetic resonance fingerprinting and deep learning.

PURPOSE: To develop an accelerated postprocessing pipeline for reproducible and efficient assessment of white matter lesions using quantitative magnetic resonance fingerprinting (MRF) and deep learning. METHODS: MRF using echo-planar imaging (EPI) scans with varying repetition and echo times were acquired for whole brain quantification of T1 and T2∗ in 50 subjects with multiple sclerosis (MS) and 10 healthy volunteers along 2 centers. MRF T1 and T2∗ parametric maps were distortion corrected and denoised. A CNN was trained to reconstruct the T1 and T2∗ parametric maps, and the WM and GM probability maps. RESULTS: Deep learning-based postprocessing reduced reconstruction and image processing times from hours to a few seconds while maintaining high accuracy, reliability, and precision. Mean absolute error performed the best for T1 (deviations 5.6%) and the logarithmic hyperbolic cosinus loss the best for T2∗ (deviations 6.0%). CONCLUSIONS: MRF is a fast and robust tool for quantitative T1 and T2∗ mapping. Its long reconstruction and several postprocessing steps can be facilitated and accelerated using deep learning.

Characterization of chronic active multiple sclerosis lesions with sodium (23 Na) magnetic resonance imaging-preliminary observations.

BACKGROUND AND PURPOSE: There has been an increasing interest in chronic active multiple sclerosis (MS) lesions as a new magnetic resonance imaging (MRI) marker of disease progression. Chronic active lesions are characterized by progressive tissue matrix damage, axonal loss and chronic inflammation. Sodium (23 Na) MRI provides a biochemical marker of cell integrity and tissue viability in a quantitative manner. The aim of this study was to investigate with 23 Na MRI tissue abnormalities in chronic active lesions as indicators of tissue destruction. METHODS: To identify chronic active lesions, two 3D magnetization-prepared rapid acquisition gradient-echo datasets obtained 12 months apart were processed using the voxel-guided morphometry algorithm. Cross-sectional 23 Na MRI was performed during the 12-month follow-up period. Total sodium concentration was calculated in chronic active lesions compared to shrinking, chronic stable and acute contrast-enhancing lesions. RESULTS: Overall, 70 MS lesions (21 chronic active, 10 shrinking, 29 chronic stable lesions, 10 acute contrast-enhancing lesions) in 12 patients were included. Total sodium concentration in chronic active lesions (49.57 ± 8.47 mM) was significantly higher than in shrinking (42.16 ± 3.9 mM; p = 0.03) and chronic stable lesions (39.92 ± 4.82 mM; p < 0.001). Chronic active lesions showed similar sodium values compared to acute contrast-enhancing lesions (48.06 ± 6.65 mM; p = 0.97). No differences between shrinking and chronic stable lesions were observed (p = 0.89). CONCLUSION: High sodium values in chronic active MS lesions may be an indicator of ongoing inflammation and tissue damage.

Lesion probability mapping in MS patients using a regression network on MR fingerprinting.

BACKGROUND: To develop a regression neural network for the reconstruction of lesion probability maps on Magnetic Resonance Fingerprinting using echo-planar imaging (MRF-EPI) in addition to [Formula: see text], [Formula: see text], NAWM, and GM- probability maps. METHODS: We performed MRF-EPI measurements in 42 patients with multiple sclerosis and 6 healthy volunteers along two sites. A U-net was trained to reconstruct the denoised and distortion corrected [Formula: see text] and [Formula: see text] maps, and to additionally generate NAWM-, GM-, and WM lesion probability maps. RESULTS: WM lesions were predicted with a dice coefficient of [Formula: see text] and a lesion detection rate of [Formula: see text] for a threshold of 33%. The network jointly enabled accurate [Formula: see text] and [Formula: see text] times with relative deviations of 5.2% and 5.1% and average dice coefficients of [Formula: see text] and [Formula: see text] for NAWM and GM after binarizing with a threshold of 80%. CONCLUSION: DL is a promising tool for the prediction of lesion probability maps in a fraction of time. These might be of clinical interest for the WM lesion analysis in MS patients.

[Multiple sclerosis treatment consensus group (MSTCG): position paper on disease-modifying treatment of multiple sclerosis 2021 (white paper)]. / Multiple Sklerose Therapie Konsensus Gruppe (MSTKG): Positionspapier zur verlaufsmodifizierenden Therapie der Multiplen Sklerose 2021 (White Paper).

Multiple sclerosis is a complex, autoimmune-mediated disease of the central nervous system characterized by inflammatory demyelination and axonal/neuronal damage. The approval of various disease-modifying therapies and our increased understanding of disease mechanisms and evolution in recent years have significantly changed the prognosis and course of the disease. This update of the Multiple Sclerosis Therapy Consensus Group treatment recommendation focuses on the most important recommendations for disease-modifying therapies of multiple sclerosis in 2021. Our recommendations are based on current scientific evidence and apply to those medications approved in wide parts of Europe, particularly German-speaking countries (Germany, Austria, Switzerland).

Longitudinal spinal cord atrophy in multiple sclerosis using the generalized boundary shift integral.

OBJECTIVE: Spinal cord atrophy is a clinically relevant feature of multiple sclerosis (MS), but longitudinal assessments on magnetic resonance imaging using segmentation-based methods suffer from measurement variability, especially in multicenter studies. We compared the generalized boundary shift integral (GBSI), a registration-based method, with a standard segmentation-based method. METHODS: Baseline and 1-year spinal cord 3-dimensional T1-weighted images (1mm isotropic) were obtained from 282 patients (52 clinically isolated syndrome [CIS], 196 relapsing-remitting MS [RRMS], 34 progressive MS [PMS]), and 82 controls from 8 MAGNIMS (Magnetic Resonance Imaging in Multiple Sclerosis) sites on multimanufacturer and multi-field-strength scans. Spinal Cord Toolbox was used for C2-5 segmentation and cross-sectional area (CSA) calculation. After cord straightening and registration, GBSI measured atrophy based on the probabilistic boundary-shift region of interest. CSA and GBSI percentage annual volume change was calculated. RESULTS: GBSI provided similar rates of atrophy, but reduced measurement variability compared to CSA in all MS subtypes (CIS: -0.95 ± 2.11% vs -1.19 ± 3.67%; RRMS: -1.74 ± 2.57% vs -1.74 ± 4.02%; PMS: -2.29 ± 2.40% vs -1.29 ± 3.20%) and healthy controls (0.02 ± 2.39% vs -0.56 ± 3.77%). GBSI performed better than CSA in differentiating healthy controls from CIS (area under the curve [AUC] = 0.66 vs 0.53; p = 0.03), RRMS (AUC = 0.73 vs 0.59; p < 0.001), PMS (AUC = 0.77 vs 0.53; p < 0.001), and patients with disability progression from patients without progression (AUC = 0.59 vs 0.50; p = 0.04). Sample size to detect 60% treatment effect on spinal cord atrophy over 1 year was lower for GBSI than CSA (CIS: 106 vs 830; RRMS: 95 vs 335; PMS: 44 vs 215; power = 80%; alpha = 5%). INTERPRETATION: The registration-based method (GBSI) allowed better separation between MS patients and healthy controls and improved statistical power, when compared with a conventional segmentation-based method (CSA), although it is still far from perfect. ANN NEUROL 2019 ANN NEUROL 2019;86:704-713.

Assessment of lesions on magnetic resonance imaging in multiple sclerosis: practical guidelines.

MRI has improved the diagnostic work-up of multiple sclerosis, but inappropriate image interpretation and application of MRI diagnostic criteria contribute to misdiagnosis. Some diseases, now recognized as conditions distinct from multiple sclerosis, may satisfy the MRI criteria for multiple sclerosis (e.g. neuromyelitis optica spectrum disorders, Susac syndrome), thus making the diagnosis of multiple sclerosis more challenging, especially if biomarker testing (such as serum anti-AQP4 antibodies) is not informative. Improvements in MRI technology contribute and promise to better define the typical features of multiple sclerosis lesions (e.g. juxtacortical and periventricular location, cortical involvement). Greater understanding of some key aspects of multiple sclerosis pathobiology has allowed the identification of characteristics more specific to multiple sclerosis (e.g. central vein sign, subpial demyelination and lesional rims), which are not included in the current multiple sclerosis diagnostic criteria. In this review, we provide the clinicians and researchers with a practical guide to enhance the proper recognition of multiple sclerosis lesions, including a thorough definition and illustration of typical MRI features, as well as a discussion of red flags suggestive of alternative diagnoses. We also discuss the possible place of emerging qualitative features of lesions which may become important in the near future.

Arterial Spin Labeling Cerebral Perfusion Magnetic Resonance Imaging in Migraine Aura: An Observational Study.

BACKGROUND: Changes in cerebral perfusion during migraine with aura (MA) have been assessed mainly using dynamic susceptibility contrast (DSC) magnetic resonance perfusion imaging. A contrast agent-free method to assess these changes would be desirable. We assessed changes in cerebral perfusion during MA using arterial spin labeling (ASL) perfusion magnetic resonance imaging. METHODS: We investigated 4 patients with a standardized protocol including ASL perfusion imaging during MA (n = 2) or early headache phase (n = 2) and asymptomatic follow-up. Semiquantitative evaluation was done using a region of interest (ROI) within hypoperfused or hyperperfused areas and corresponding ROIs in the contralateral hemisphere. Relative ratios of mean perfusion in the corresponding ROIs were calculated. DSC imaging was done at initial time points and compared visually with ASL findings. RESULTS: In all patients, regional perfusion changes were detected in the acute phase. These abnormalities did not respect the boundaries of major cerebral vascular territories but overlapped onto adjoining regions. During MA, adjacent hypoperfused and hyperperfused areas were found, whereas during headache, regional hyperperfusion only was observed. Perfusion abnormalities normalized on follow-up. CONCLUSIONS: ASL perfusion imaging is a contrast agent-free method suitable for assessment of reversible perfusion changes during or immediately after MA.

A common brain network links development, aging, and vulnerability to disease.

Several theories link processes of development and aging in humans. In neuroscience, one model posits for instance that healthy age-related brain degeneration mirrors development, with the areas of the brain thought to develop later also degenerating earlier. However, intrinsic evidence for such a link between healthy aging and development in brain structure remains elusive. Here, we show that a data-driven analysis of brain structural variation across 484 healthy participants (8-85 y) reveals a largely--but not only--transmodal network whose lifespan pattern of age-related change intrinsically supports this model of mirroring development and aging. We further demonstrate that this network of brain regions, which develops relatively late during adolescence and shows accelerated degeneration in old age compared with the rest of the brain, characterizes areas of heightened vulnerability to unhealthy developmental and aging processes, as exemplified by schizophrenia and Alzheimer's disease, respectively. Specifically, this network, while derived solely from healthy subjects, spatially recapitulates the pattern of brain abnormalities observed in both schizophrenia and Alzheimer's disease. This network is further associated in our large-scale healthy population with intellectual ability and episodic memory, whose impairment contributes to key symptoms of schizophrenia and Alzheimer's disease. Taken together, our results suggest that the common spatial pattern of abnormalities observed in these two disorders, which emerge at opposite ends of the life spectrum, might be influenced by the timing of their separate and distinct pathological processes in disrupting healthy cerebral development and aging, respectively.

Prediction of Early Reperfusion From Repeated Arterial Spin Labeling Perfusion Magnetic Resonance Imaging During Intravenous Thrombolysis.

BACKGROUND AND PURPOSE: There are few in vivo data on the pathophysiology of reperfusion during systemic thrombolysis. We monitored the time course of cerebral perfusion changes in patients during thrombolysis with repeated arterial spin labeling perfusion magnetic resonance imaging. METHODS: Ten patients with proximal arterial occlusion within 4.5 hours after symptom onset were prospectively enrolled. All patients received intravenous thrombolysis during the magnetic resonance imaging examination. Repeated arterial spin labeling perfusion images were acquired during the 60-minute therapy and at follow-up after 24 to 72 hours. Clinical data, magnetic resonance imaging features, and cerebral perfusion changes were analyzed. RESULTS: Before thrombolysis, arterial spin labeling hypoperfusion and fluid-attenuation inversion recovery vascular hyperintensity in the territory of the occluded arteries were observed in all patients. In 5 patients, extensive arterial transit artifacts (ATA) developed in the hypoperfused area. The ATA corresponded with fluid-attenuation inversion recovery vascular hyperintensities. All 5 patients who developed extensive ATA in the hypoperfused area had complete reperfusion after thrombolysis, whereas the 5 without extensive ATA showed no or only partial reperfusion (P<0.01). The development of ATA preceded the normalization of tissue perfusion. CONCLUSIONS: The development of ATA during thrombolysis is associated with early reperfusion after thrombolysis. arterial spin labeling assessment during intravenous thrombolysis has the potential to guide subsequent therapeutic strategies in patients with acute stroke.

Heterogeneity of acute multiple sclerosis lesions on sodium (23Na) MRI.

BACKGROUND: Advanced magnetic resonance imaging (MRI) techniques provide a window into pathological processes in multiple sclerosis (MS). Nevertheless, to date only few studies have performed sodium MRI in MS. OBJECTIVES: We analysed total sodium concentration (TSC) in hyperacute, acute and chronic lesions in MS with (23)Na MRI. METHODS: (23)Na MRI and (1)H MRI were performed in 65 MS patients and 10 healthy controls (HC). Mean TSC was quantified in all MS lesions with a diameter of >5 mm and in the normal appearing white and grey matter (NAWM, NAGM). RESULTS: TSC in the NAWM and the NAGM of MS patients was significantly higher compared to HC (WM: 37.51 ± 2.65 mM versus 35.17 ± 3.40 mM; GM: 43.64 ± 2.75 mM versus 40.09 ± 4.64 mM). Acute and chronic MS lesions showed elevated TSC levels of different extent (contrast-enhancing lesions (49.07 ± 6.99 mM), T1 hypointense lesions (45.06 ± 6.26 mM) and remaining T1 isointense lesions (39.88 ± 5.54 mM)). However, non-enhancing hyperacute lesions with a reduced apparent diffusion coefficient showed a TSC comparable to the NAWM (37.22 ± 4.62 mM). CONCLUSIONS: TSC is not only a sensitive marker of the severity of chronic tissue abnormalities in MS but is also highly sensitive to opening of the blood-brain barrier and vasogenic tissue oedema in contrast-enhancing lesions.

Design of TRUST, a non-interventional, multicenter, 3-year prospective study investigating an integrated patient management approach in patients with relapsing-remitting multiple sclerosis treated with natalizumab.

BACKGROUND: Natalizumab provides rapid and high-efficacy control of multiple sclerosis disease activity with long-term stabilization. However, the benefits of the drug are countered by a risk of developing progressive multifocal leukoencephalopathy in patients infected with the John Cunningham Virus. Close monitoring is required in patients with increased progressive multifocal leukoencephalopathy risk receiving natalizumab in the long-term for an optimal benefit-risk evaluation. Standardized high-quality monitoring procedures may provide a superior basis for individual benefit and risk evaluation and thus improve treatment decisions. The non-interventional study TRUST was designed to capture natalizumab effectiveness under real-life conditions and to examine alternate approaches for clinical assessments, magnetic resonance imaging monitoring and use of biomarkers for progressive multifocal leukoencephalopathy risk stratification. METHODS/DESIGN: TRUST is a non-interventional, multicenter, prospective cohort study conducted at approximately 200 German neurological centers. The study is intended to enroll 1260 relapsing-remitting multiple sclerosis patients with ongoing natalizumab therapy for at least 12 months. Patients will be followed for a period of 3 years, irrespective of treatment changes after study start. Data on clinical, subclinical and patient-centric outcomes will be documented in order to compare the effectiveness of continuous versus discontinued natalizumab treatment. Furthermore, the type and frequency of clinical, magnetic resonance imaging and biomarker assessments, reasons for continuation or discontinuation of therapy and the safety profile of natalizumab will be collected to explore the impact of a systematic patient management approach and its potential impact on patient outcome. Specifically, the role of biomarkers, the use of expert opinions, the impact of high-frequency magnetic resonance imaging assessment for early progressive multifocal leukoencephalopathy detection and the role of additional radiological and clinical expert advice will be explored. DISCUSSION: TRUST was initiated in spring 2014 and enrollment is anticipated to be completed by mid 2016. Annual interim analyses will deliver continuous information and transparency with regard to the patient cohorts and the completeness and quality of data as well as closely monitor any safety signals in the natalizumab-treated cohort. The study's results may provide insights into opportunities to improve the benefit-risk assessment in clinical practice and support treatment decisions.

Acute Stroke Syndromes with Isolated Hypoperfusion on MRI - A Clinical and MRI Study.

BACKGROUND: Acute stroke syndromes with negative diffusion-weighted imaging (DWI) but extensive perfusion deficits are rare and constitute a diagnostic challenge due to different operational definitions of penumbral hypoperfusion in acute stroke patients based on MRI criteria. METHODS: MR profiles of 19 patients presenting with acute stroke syndromes with negative DWI in the presence of an extensive area of hypoperfusion on time-to-peak (TTP) maps of dynamic susceptibility contrast perfusion-weighted imaging (PWI) were analysed. DWI and PWI lesions were quantified and interpreted with regard to the clinical course. RESULTS: Despite the large area of abnormal perfusion on TTP maps, the clinical course was benign (median National Institute of Health Stroke Scale 2 at admission, 0 at discharge). The volume of hypoperfused tissue was significantly smaller on postprocessed TTP maps with a TTP delay of >4 s than on unprocessed TTP maps with manual contrast adjustment. Semiquantitatively assessed TTP lesion volume was associated with the presence of DWI lesions on follow-up. CONCLUSION: TTP maps are highly sensitive to demonstrate even small-scale perfusion abnormalities. The additional information from TTP delay thresholds indicates critically reduced perfusion and appears to be a good prognostic indicator in combination with MR angiography and symptomatology.