Spinal cord atrophy measured from cerebral T1-weighted MRI: applications in clinical investigations of neuromyelitis optica spectrum disorders

Magnetic resonance imaging (MRI) is used extensively for differential diagnosis and disease monitoring in neuroinflammatory disorders. Neuromyelitis optica spectrum disorders (NMOSD) are autoimmune neuroinflammatory diseases of the central nervous system that affect mainly the optic nerves, and spinal cord (SC). SC MRI shows longitudinally extensive transverse myelitis in the vast majority of NMOSD patients, where chronic inflammation leads to SC lesions and SC atrophy. In vivo imaging biomarkers are lacking for these patients, which could greatly aid in evaluating treatment efficacy or monitoring disease- related changes. The key questions addressed in my dissertation are: 1. Can cerebral T1-weighted MRI be used to measure SC atrophy in NMOSD? 2. Is there a difference in SC affection between aquaporin-4 IgG seropositive (AQP4-IgG+) and myelin oligodendrocyte glycoprotein IgG seropositive (MOG-IgG+) NMOSD patients? 3. Is spinal cord atrophy associated with damage in thalamic subregions of AQP4-IgG+ patients with myelitis? Cervical cord volume, total cord volume, and mean upper cervical cord area (MUCCA) were compared and demonstrated the ability to discriminate between AQP4-IgG+ NMOSD patients and healthy participants. MUCCA, measured from cerebral T1-weighted MRIs, correlated well with cervical cord and total cord volumes, even in patients. SC atrophy measurements using MUCCA were thus shown to accurately reflect damage in the entire SC of AQP4-IgG+ NMOSD patients. The SC lesion prevalence in specific locations and the mean MUCCA between the NMOSD antibody subgroups were similar. However, AQP4-IgG+ patients had more myelitis attacks, SC lesions, and SC atrophy than MOG-IgG+ patients. MUCCA associated with clinical attacks and disability in both NMOSD subgroups combined. Damage to the ventral posterior nucleus of the thalamus in AQP4-IgG+ patients with myelitis attacks were tested for association with MUCCA. This assessment of mutual damage/atrophy was negative. In summary, these studies proved that SC atrophy can be assessed using MUCCA, increases in NMOSD patients with more myelitis attacks, and that MUCCA is a valuable in vivo imaging parameter in NMOSD. These findings will be crucial in future clinical studies that monitor or evaluate treatment efficacy of patients with neuromyelitis optica spectrum disorders.Die Magnetresonanztomographie (MRT) ist eine wichtige Methode für die Differentialdiagnose und das Monitoring neuroinflammatorischer Erkrankungen. Bei Neuromyelitis optica Spektrum-Erkrankungen (NMOSD) handelt es sich um eine Gruppe autoimmuner, inflammatorischer Erkrankungen des zentralen Nervensystems, die vor allem die Sehnerven und das Rückenmark betreffen. Mittels spinaler MRT kann bei einer überwiegenden Mehrheit der NMOSD Patienten eine longitudinale extensive transverse Myelitis nachgewiesen werden. Zur Beobachtung krankheitsbedingter Veränderungen in diesen Patienten und zur Therapieevaluation fehlen in-vivo bildgebende Biomarker. Die vorliegende Dissertation behandelt drei zentrale Fragen anhand von Studien: 1. Eignen sich zerebrale T1-gewichtete MRT Aufnahmen, um die Rückenmarkatrophie bei NMOSD Patienten zu quantifizieren? 2. Gibt es Unterschiede zwischen Aquaporin-IgG-seropositiven (AQP4-IgG+) und Myelin-Oligodendrozyten-Glykoprotein (MOG-IgG+) NMOSD Patienten im Hinblick auf die Myelonaffektion? 3. Besteht bei AQP4-IgG+ Patienten mit Myelitis ein Zusammenhang zwischen Atrophie im Rückenmark und Schäden in Teilregionen des Thalamus? Sowohl das Zervikalmarksvolumen, das gesamte Rückenmarksvolumen als auch die mittlere Querschnittsfläche des oberen Zervikalmarks (“mean upper cervical cord area”, MUCCA) zeigten signifikante Unterschiede zwischen AQP4-IgG+ NMOSD Patienten und gesunden Probanden. MUCCA, gemessen mittels zerebralen T1-gewichteten MRTs, korreliert gut mit den zuvor genannten Volumina, auch in NMOSD-Patienten. Die Quantifizierung von Rückenmarkatrophie mittels MUCCA ist daher geeignet, um Schäden im gesamten Rückenmark in AQP4-IgG+ NMOSD Patienten erfassen. Die Prävalenz von SC-Läsionen an bestimmten Lokationen und den MUCCA-Mittelwerten zwischen den NMOSD-Antikörper-Patientengruppen waren ähnlich. Im Vergleich zu MOG-IgG+ Patienten erleiden AQP4-IgG+ Patienten häufig mehr Myelitisschübe, Rückenmarksläsionen, und Rückenmarksatrophie. MUCCA korreliert mit der Anzahl der Krankheitsschübe und Behinderung für beide NMOSD Patientengruppen zusammen betrachtet. Eine Betrachtung der Schäden im Nucleus ventralis posterior des Thalamus in AQP4-IgG+ Patienten mit Myelitisschüben ergab keine Korrelationen mit MUCCA. Zusammenfassend konnte daher gezeigt werden, dass Rückenmarksatrophie mittels MUCCA gemessen werden kann, in NMOSD Patienten mit Myelitis die Atrophie zunimmt, und dass MUCCA einen wertvollen in-vivo bildgebenden Biomarker darstellt. Diese Ergebnisse werden in der Durchführung zukünftiger klinischer Studien zur Beobachtung und Evaluierung von Therapien bei Patienten mit NMOSD eine wichtige Rolle spielen

A review on multiple sclerosis prognostic findings from imaging, inflammation, and mental health studies

Magnetic resonance imaging (MRI) of the brain is commonly used to detect where chronic and active lesions are in multiple sclerosis (MS). MRI is also extensively used as a tool to calculate and extrapolate brain health by way of volumetric analysis or advanced imaging techniques. In MS patients, psychiatric symptoms are common comorbidities, with depression being the main one. Even though these symptoms are a major determinant of quality of life in MS, they are often overlooked and undertreated. There has been evidence of bidirectional interactions between the course of MS and comorbid psychiatric symptoms. In order to mitigate disability progression in MS, treating psychiatric comorbidities should be investigated and optimized. New research for the prediction of disease states or phenotypes of disability have advanced, primarily due to new technologies and a better understanding of the aging brain

Regenerated Cellulose Fiber Solar Cell

Wearable electronics and smart textiles are growing fields in the cause to integrate modern communication and computing tools into clothing instead of carrying around smart phones and tablets. Naturally, this also requires power sources to be integrated in textiles. In this paper, a proof-of-concept is presented in form of a photovoltaic cell based on a commercially available viscose fiber. This has been realized using a silver nanowire network around the viscose fiber to establish electrical contact and a photoactive coating using the standard workhorse among organic thin film solar cells, a blend of poly(3-hexylthiophene) (P3HT) and phenyl-C61-butyric acid methyl ester (PCBM). Structure and performance of single fiber devices demonstrate their feasibility and functionality. The applied materials and methods are compatible to solution processing therewith qualifying for potential roll-to-roll large-scale production

Imaging markers of disability in aquaporin-4 immunoglobulin G seropositive neuromyelitis optica: a graph theory study

Neuromyelitis optica spectrum disorders lack imaging biomarkers associated with disease course and supporting prognosis. This complex and heterogeneous set of disorders affects many regions of the central nervous system, including the spinal cord and visual pathway. Here, we use graph theory-based multimodal network analysis to investigate hypothesis-free mixed networks and associations between clinical disease with neuroimaging markers in 40 aquaporin-4-immunoglobulin G antibody seropositive patients (age = 48.16 ± 14.3 years, female:male = 36:4) and 31 healthy controls (age = 45.92 ± 13.3 years, female:male = 24:7). Magnetic resonance imaging measures included total brain and deep grey matter volumes, cortical thickness and spinal cord atrophy. Optical coherence tomography measures of the retina and clinical measures comprised of clinical attack types and expanded disability status scale were also utilized. For multimodal network analysis, all measures were introduced as nodes and tested for directed connectivity from clinical attack types and disease duration to systematic imaging and clinical disability measures. Analysis of variance, with group interactions, gave weights and significance for each nodal association (hyperedges). Connectivity matrices from 80% and 95% F-distribution networks were analyzed and revealed the number of combined attack types and disease duration as the most connected nodes, directly affecting changes in several regions of the central nervous system. Subsequent multivariable regression models, including interaction effects with clinical parameters, identified associations between decreased nucleus accumbens (β = −0.85, P = 0.021) and caudate nucleus (β = −0.61, P = 0.011) volumes with higher combined attack type count and longer disease duration, respectively. We also confirmed previously reported associations between spinal cord atrophy with increased number of clinical myelitis attacks. Age was the most important factor associated with normalized brain volume, pallidum volume, cortical thickness and the expanded disability status scale score. The identified imaging biomarker candidates warrant further investigation in larger-scale studies. Graph theory-based multimodal networks allow for connectivity and interaction analysis, where this method may be applied in other complex heterogeneous disease investigations with different outcome measures

Clinical and neuroimaging findings in MOGAD–MRI and OCT

Myelin oligodendrocyte glycoprotein antibody-associated disorders (MOGAD) are rare in both children and adults, and have been recently suggested to be an autoimmune neuroinflammatory group of disorders that are different from aquaporin-4 autoantibody-associated neuromyelitis optica spectrum disorder and from classic multiple sclerosis. In-vivo imaging of the MOGAD patient central nervous system has shown some distinguishing features when evaluating magnetic resonance imaging of the brain, spinal cord and optic nerves, as well as retinal imaging using optical coherence tomography. In this review, we discuss key clinical and neuroimaging characteristics of paediatric and adult MOGAD. We describe how these imaging techniques may be used to study this group of disorders and discuss how image analysis methods have led to recent insights for consideration in future studies

Practical recognition tools of immunoglobulin G serum antibodies against the myelin oligodendrocyte glycoprotein‐positive optic neuritis and its clinical implications

Myelin oligodendrocyte glycoprotein (MOG)-associated disease is an autoimmune disease of the central nervous system, associated with the presence of immunoglobulin G serum antibodies against MOG. Recent data have allowed characterization of the clinical spectrum of MOG-associated disease, which is now considered a new disease entity, distinct from multiple sclerosis and neuromyelitis optica spectrum disorders. Optic neuritis is the most common clinical presentation of MOG-associated disease in adults, both at disease onset and during the disease course, and has several distinct clinical and paraclinical features. Immunoglobulin G serum antibodies against MOG-positive optic neuritis is often bilateral and associated with optic disc swelling and a longitudinally extensive abnormal magnetic resonance imaging signal involving the retrobulbar portion of the optic nerve. The visual acuity during the acute attack is severely decreased, and the response to corticosteroids is often rapid and prominent. However, early relapses after steroid cessation are common, and a subset of patients is left with a permanent visual disability. In this review, we discuss the clinical and paraclinical features of immunoglobulin G serum antibodies against MOG-positive optic neuritis in adults, and focus on the distinctive features that can enable its early diagnosis. Therapeutical considerations at the acute stage and for relapse prevention are further deliberated

Retinal Optical Coherence Tomography in Neuromyelitis Optica

Retina; Pérdida visualRetina; Visual lossRetina; Pèrdua visualBackground and Objectives To determine optic nerve and retinal damage in aquaporin-4 antibody (AQP4-IgG)-seropositive neuromyelitis optica spectrum disorders (NMOSD) in a large international cohort after previous studies have been limited by small and heterogeneous cohorts. Methods The cross-sectional Collaborative Retrospective Study on retinal optical coherence tomography (OCT) in neuromyelitis optica collected retrospective data from 22 centers. Of 653 screened participants, we included 283 AQP4-IgG–seropositive patients with NMOSD and 72 healthy controls (HCs). Participants underwent OCT with central reading including quality control and intraretinal segmentation. The primary outcome was thickness of combined ganglion cell and inner plexiform (GCIP) layer; secondary outcomes were thickness of peripapillary retinal nerve fiber layer (pRNFL) and visual acuity (VA). Results Eyes with ON (NMOSD-ON, N = 260) or without ON (NMOSD-NON, N = 241) were assessed compared with HCs (N = 136). In NMOSD-ON, GCIP layer (57.4 ± 12.2 μm) was reduced compared with HC (GCIP layer: 81.4 ± 5.7 μm, p < 0.001). GCIP layer loss (−22.7 μm) after the first ON was higher than after the next (−3.5 μm) and subsequent episodes. pRNFL observations were similar. NMOSD-NON exhibited reduced GCIP layer but not pRNFL compared with HC. VA was greatly reduced in NMOSD-ON compared with HC eyes, but did not differ between NMOSD-NON and HC. Discussion Our results emphasize that attack prevention is key to avoid severe neuroaxonal damage and vision loss caused by ON in NMOSD. Therapies ameliorating attack-related damage, especially during a first attack, are an unmet clinical need. Mild signs of neuroaxonal changes without apparent vision loss in ON-unaffected eyes might be solely due to contralateral ON attacks and do not suggest clinically relevant progression but need further investigation.Guthy-Jackson Charitable Foundation (GJCF) and German Research Foundation (DFG)

Pain in AQP4-IgG-positive and MOG-IgG-positive neuromyelitis optica spectrum disorders

Background: Pain is a frequent symptom in aquaporin-4-immunoglobulin-G-positive neuromyelitis optica spectrum disorders (AQP4-IgG-pos. NMOSD). Data on pain in myelin-oligodendrocyteglycoprotein- immunoglobulin-G autoimmunity with a clinical NMOSD phenotype (MOG-IgG-pos. NMOSD) are scarce. Objective: The objective of this paper is to investigate pain in MOG-IgG-pos. NMOSD, AQP4-IgG-pos. NMOSD and NMOSD without AQP4/MOG-IgG detection (AQP4/MOG-IgG-neg. NMOSD). Methods: Forty-nine MOG-IgG-pos. (n=14), AQP4-IgG-pos. (n=29) and AQP4/MOG-IgG-neg. (n=6) NMOSD patients were included in this cross-sectional baseline analysis from an ongoing observational study. We identified spinal cord lesions on magnetic resonance imaging, assessed pain by the painDETECT and McGill Pain questionnaires, quality of life by Short Form Health Survey, and depression by Beck Depression Inventory. Results: Twelve MOG-IgG-pos. NMOSD patients (86%), 24 AQP4-IgG-pos. NMOSD patients (83%), and all AQP4/MOG-IgG-neg. NMOSD patients (100%) suffered from pain. MOG-IgG-pos. NMOSD patients had mostly neuropathic pain and headache; AQP4-IgG-pos. and AQP4/MOG-IgG-neg. NMOSD patients had mostly neuropathic pain. A history of myelitis was less frequent in MOG-IgGpos. NMOSD than in AQP4-IgG-pos. NMOSD patients. Pain influenced quality of life in all patients. Thirty-six percent of patients with pain received pain medication; none of them were free of pain. Conclusions: Pain is a frequent symptom of patients with MOG-IgG-pos. NMOSD and is as important as in AQP4-IgG-pos. and AQP4/MOG-IgG-neg. NMOSD. Despite its impact on quality of life, pain is insufficiently alleviated by medication

Standardization of T1w/T2w Ratio Improves Detection of Tissue Damage in Multiple Sclerosis

Normal appearing white matter (NAWM) damage develops early in multiple sclerosis (MS) and continues in the absence of new lesions. The ratio of T1w and T2w (T1w/T2w ratio), a measure of white matter integrity, has previously shown reduced intensity values in MS NAWM. We evaluate the validity of a standardized T1w/T2w ratio (sT1w/T2w ratio) in MS and whether this method is sensitive in detecting MS-related differences in NAWM. T1w and T2w scans were acquired at 3 Tesla in 47 patients with relapsing-remitting MS and 47 matched controls (HC). T1w/T2w and sT1w/T2w ratios were then calculated. We compared between-group variability between T1w/T2w and sT1w/T2w ratio in HC and MS and assessed for group differences. We also evaluated the relationship between the T1w/T2w and sT1w/T2w ratios and clinically relevant variables. Compared to the classic T1w/T2w ratio, the between-subject variability in sT1w/T2w ratio showed a significant reduction in MS patients (0 <. 0.001) and HC < 0.001). However, only sT1w/T2w ratio values were reduced in patients compared to HC (p < 0.001). The sT1w/T2w ratio intensity values were significantly influenced by age, T2 lesion volume and group status (MS vs. HC) (adjusted R-2 = 0.30, p 0.001). We demonstrate the validity of the sT1w/T2w ratio in MS and that it is more sensitive to MS-related differences in NAWM compared to T1w/T2w ratio. The sT1w/T2w ratio shows promise as an easily-implemented measure of NAWM in MS using readily available scans and simple post-processing methods

Differences in Advanced Magnetic Resonance Imaging in MOG-IgG and AQP4-IgG Seropositive Neuromyelitis Optica Spectrum Disorders: A Comparative Study

Aims: To explore differences in advanced brain magnetic resonance imaging (MRI) characteristics between myelin oligodendrocyte (MOG) immunoglobulin (IgG) and aquaporin-4 (AQP4) IgG seropositive (+) neuromyelitis optica spectrum disorders (NMOSD). Methods: 33 AQP4-IgG and 18 MOG-IgG seropositive NMOSD patients and 61 healthy control (HC) subjects were included. All 112 participants were scanned with the same standardized MRI-protocol on a 3-Tesla MRI-scanner. Brain volume and diffusion tensor imaging (DTI) parameters were assessed. Results: MOG-IgG+ patients showed reduced parallel diffusivity within white matter tracts compared to HC whereas AQP4-IgG+ showed no significant brain parenchymal damage in DTI analysis. AQP4-IgG+ patients showed reduced whole brain volumes and reduced volumes of several deep gray matter structures compared to HC whereas MOG-IgG+ patients did not show reduced brain or deep gray matter volumes compared to HC. Conclusions: Microstructural brain parenchymal damage in MOG-IgG+ patients was more pronounced than in AQP4-IgG+ patients, compared with HC, whereas normalized brain volume reduction was more severe in AQP4-IgG+ patients. Longitudinal imaging studies are warranted to further investigate this trend in NMOSD. Our results suggest that MOG-IgG+ and AQP4-IgG+ NMOSD patients differ in cerebral MRI characteristics. Advanced MRI analysis did not help to differentiate between MOG-IgG+ and AQP4-IgG+ patients in our study