Ultrahigh field MRI in clinical neuroimmunology: a potential contribution to improved diagnostics and personalised disease management

Conventional magnetic resonance imaging (MRI) at 1.5 Tesla (T) is limited by modest spatial resolution and signal-to-noise ratio (SNR), impeding the identification and classification of inflammatory central nervous system changes in current clinical practice. Gaining from enhanced susceptibility effects and improved SNR, ultrahigh field MRI at 7 T depicts inflammatory brain lesions in great detail. This review summarises recent reports on 7 T MRI in neuroinflammatory diseases and addresses the question as to whether ultrahigh field MRI may eventually improve clinical decision-making and personalised disease management

Progressive multifocal leukoencephalopathy in a multiple Sclerosis patient diagnosed after switching from natalizumab to fingolimod

Background: Natalizumab- (NTZ-) associated progressive multifocal leukoencephalopathy (PML) is a severe and often disabling infectious central nervous system disease that can become evident in multiple sclerosis (MS) patients after NTZ discontinuation. Recently, novel diagnostic biomarkers for the assessment of PML risk in NTZ treated MS patients such as the anti-JC virus antibody index have been reported, and the clinical relevance of milky-way lesions detectable by MRI has been discussed. Case Presentation and Conclusion: We report a MS patient in whom PML was highly suspected solely based on MRI findings after switching from NTZ to fingolimod despite repeatedly negative (ultrasensitive) polymerase chain reaction (PCR) testing for JC virus DNA in cerebrospinal fluid. The PML diagnosis was histopathologically confirmed by brain biopsy. The occurrence of an immune reconstitution inflammatory syndrome (IRIS) during fingolimod therapy, elevated measures of JCV antibody indices, and the relevance of milky-way-like lesions detectable by (7 T) MRI are discussed

Quantitative 7T MRI does not detect occult brain damage in neuromyelitis optica

Objective: To investigate and compare occult damages in aquaporin-4 (AQP4)-rich periependymal regions in patients with neuromyelitis optica spectrum disorder (NMOSD) vs healthy controls (HCs) and patients with multiple sclerosis (MS) applying quantitative T1 mapping at 7 Tesla (T) in a cross-sectional study. Methods: Eleven patients with NMOSD (median Expanded Disability Status Scale [EDSS] score 3.5, disease duration 9.3 years, age 43.7 years, and 11 female) seropositive for anti-AQP4 antibodies, 7 patients with MS (median EDSS score 1.5, disease duration 3.6, age 30.2 years, and 4 female), and 10 HCs underwent 7T MRI. The imaging protocol included T2*-weighted (w) imaging and an MP2RAGE sequence yielding 3D T1w images and quantitative T1 maps. We semiautomatically marked the lesion-free periependymal area around the cerebral aqueduct and the lateral, third, and fourth ventricles to finally measure and compare the T1 relaxation time within these areas. Results: We did not observe any differences in the T1 relaxation time between patients with NMOSD and HCs (all > 0.05). Contrarily, the T1 relaxation time was longer in patients with MS vs patients with NMOSD (lateral ventricle = 0.056, third ventricle = 0.173, fourth ventricle = 0.016, and cerebral aqueduct = 0.048) and vs HCs (third ventricle = 0.027, fourth ventricle = 0.013, lateral ventricle = 0.043, and cerebral aqueduct = 0.005). Conclusion: Unlike in MS, we did not observe subtle T1 changes in lesion-free periependymal regions in NMOSD, which supports the hypothesis of a rather focal than diffuse brain pathology in NMOSD

7T MRI in natalizumab-associated PML and ongoing MS disease activity: a case study

OBJECTIVE: To assess the ability of ultra-high-field MRI to distinguish early progressive multifocal leukoencephalopathy (PML) from multiple sclerosis (MS) lesions in a rare case of simultaneous presentation of natalizumab-associated PML and ongoing MS activity. METHODS: Advanced neuroimaging including 1.5T, 3T, and 7T MRI with a spatial resolution of up to 0.08 mm(3) was performed. RESULTS: 7T MRI differentiated between PML-related and MS-related brain damage in vivo. Ring-enhancing MS plaques displayed a central vein, whereas confluent PML lesions were preceded by punctate or milky way-like T2 lesions. CONCLUSIONS: Given the importance of early diagnosis of treatment-associated PML, future systematic studies are warranted to assess the value of highly resolving MRI in differentiating between early PML- and MS-induced brain parenchymal lesions

MRI phase changes in multiple sclerosis vs neuromyelitis optica lesions at 7T

OBJECTIVE: To characterize paramagnetic MRI phase signal abnormalities in neuromyelitis optica spectrum disorder (NMOSD) vs multiple sclerosis (MS) lesions in a cross-sectional study. METHODS: Ten patients with NMOSD and 10 patients with relapsing-remitting MS underwent 7-tesla brain MRI including supratentorial T2*-weighted imaging and supratentorial susceptibility weighted imaging. Next, we analyzed intra- and perilesional paramagnetic phase changes on susceptibility weighted imaging filtered magnetic resonance phase images. RESULTS: We frequently observed paramagnetic rim-like (75 of 232 lesions, 32%) or nodular (32 of 232 lesions, 14%) phase changes in MS lesions, but only rarely in NMOSD lesions (rim-like phase changes: 2 of 112 lesions, 2%, p < 0.001; nodular phase changes: 2 of 112 lesions, 2%, p < 0.001). CONCLUSIONS: Rim-like or nodular paramagnetic MRI phase changes are characteristic for MS lesions and not frequently detectable in NMOSD. Future prospective studies should ask whether these imaging findings can be used as a biomarker to distinguish between NMOSD- and MS-related brain lesions

Neuromyelitis optica does not impact periventricular venous density versus healthy controls: a 7.0 Tesla MRI clinical study

Objective: To quantify the periventricular venous density in neuromyelitis optica spectrum disease (NMOSD) in comparison to that in patients with multiple sclerosis (MS) and healthy control subjects. Materials and methods: Sixteen patients with NMOSD, 16 patients with MS and 16 healthy control subjects underwent 7.0-Tesla (7T) MRI. The imaging protocol included T2*-weighted (T2*w) fast low angle-shot (FLASH) and fluid-attenuated inversion recovery (FLAIR) sequences. The periventricular venous area (PVA) was manually determined by a blinded investigator in order to estimate the periventricular venous density in a region of interest-based approach. Results: No significant differences in periventricular venous density indicated by PVA were detectable in NMOSD versus healthy controls (p = 0.226). In contrast, PVA was significantly reduced in MS patients compared to healthy controls (p = 0.013). Conclusion: Unlike patients with MS, those suffering from NMOSD did not show reduced venous visibility. This finding may underscore primary and secondary pathophysiological differences between these two distinct diseases of the central nervous system

Ultrahochfeld-MRT im Kontext neurologischer Erkrankungen [Ultrahigh field MRI in context of neurological diseases]

Ultrahigh field magnetic resonance imaging (UHF-MRI) has recently gained substantial scientific interest. At field strengths of 7 Tesla (T) and higher UHF-MRI provides unprecedented spatial resolution due to an increased signal-to-noise ratio (SNR). The UHF-MRI method has been successfully applied in various neurological disorders. In neuroinflammatory diseases UHF-MRI has already provided a detailed insight into individual pathological disease processes and elucidated differential diagnoses of several disease entities, e.g. multiple sclerosis (MS), neuromyelitis optica (NMO) and Susac's syndrome. The excellent depiction of normal blood vessels, vessel abnormalities and infarct morphology by UHF-MRI can be utilized in vascular diseases. Detailed imaging of the hippocampus in Alzheimer's disease and the substantia nigra in Parkinson's disease as well as sensitivity to iron depositions could be valuable in neurodegenerative diseases. Current UHF-MRI studies still suffer from small sample sizes, selection bias or propensity to image artefacts. In addition, the increasing clinical relevance of 3T-MRI has not been sufficiently appreciated in previous studies. Although UHF-MRI is only available at a small number of medical research centers it could provide a high-end diagnostic tool for healthcare optimization in the foreseeable future. The potential of UHF-MRI still has to be carefully validated by profound prospective research to define its place in future medicine

Photochemistry of Furyl- and Thienyldiazomethanes: Spectroscopic Characterization of Triplet 3-Thienylcarbene

Photolysis (λ \u3e 543 nm) of 3-thienyldiazomethane (1), matrix isolated in Ar or N2 at 10 K, yields triplet 3-thienylcarbene (13) and α-thial-methylenecyclopropene (9). Carbene 13 was characterized by IR, UV/vis, and EPR spectroscopy. The conformational isomers of 3-thienylcarbene (s-E and s-Z) exhibit an unusually large difference in zero-field splitting parameters in the triplet EPR spectrum (|D/hc| = 0.508 cm–1, |E/hc| = 0.0554 cm–1; |D/hc| = 0.579 cm–1, |E/hc| = 0.0315 cm–1). Natural Bond Orbital (NBO) calculations reveal substantially differing spin densities in the 3-thienyl ring at the positions adjacent to the carbene center, which is one factor contributing to the large difference in D values. NBO calculations also reveal a stabilizing interaction between the sp orbital of the carbene carbon in the s-Z rotamer of 13 and the antibonding σ orbital between sulfur and the neighboring carbon—an interaction that is not observed in the s-E rotamer of 13. In contrast to the EPR spectra, the electronic absorption spectra of the rotamers of triplet 3-thienylcarbene (13) are indistinguishable under our experimental conditions. The carbene exhibits a weak electronic absorption in the visible spectrum (λmax = 467 nm) that is characteristic of triplet arylcarbenes. Although studies of 2-thienyldiazomethane (2), 3-furyldiazomethane (3), or 2-furyldiazomethane (4) provided further insight into the photochemical interconversions among C5H4S or C5H4O isomers, these studies did not lead to the spectroscopic detection of the corresponding triplet carbenes (2-thienylcarbene (11), 3-furylcarbene (23), or 2-furylcarbene (22), respectively)

Outer-Sphere Contributions to the Electronic Structure of Type Zero Copper Proteins

Bioinorganic canon states that active-site thiolate coordination promotes rapid electron transfer (ET) to and from type 1 copper proteins. In recent work, we have found that copper ET sites in proteins also can be constructed without thiolate ligation (called “type zero” sites). Here we report multifrequency electron paramagnetic resonance (EPR), magnetic circular dichroism (MCD), and nuclear magnetic resonance (NMR) spectroscopic data together with density functional theory (DFT) and spectroscopy-oriented configuration interaction (SORCI) calculations for type zero Pseudomonas aeruginosa azurin variants. Wild-type (type 1) and type zero copper centers experience virtually identical ligand fields. Moreover, O-donor covalency is enhanced in type zero centers relative that in the C112D (type 2) protein. At the same time, N-donor covalency is reduced in a similar fashion to type 1 centers. QM/MM and SORCI calculations show that the electronic structures of type zero and type 2 are intimately linked to the orientation and coordination mode of the carboxylate ligand, which in turn is influenced by outer-sphere hydrogen bonding