Einfluss von hochdosierten intravenösen Kortikosteroiden auf das Magnetisierungstransfer Ratio (MTR) bei Patienten mit Multipler Sklerose im akuten Schub

Ziel der Arbeit war es, Einflüsse einer standardisierten Schubtherapie auf das Magnetisierungstransfer-Ratio (MTR) in Kontrastmittel (KM)-anreichernden Läsionen und in der normal aussehenden weißen Substanz (NAWM) bei Patienten mit Multipler Sklerose (MS) im akuten Schub nachzuweisen. 10 Patienten mit bekannter MS wurden vor Beginn der Therapie und nach Therapieende kernspintomographisch untersucht. Die Ergebnisse zeigen, dass trotz nachweislicher Reduktion der KM-Aufnahme unter Therapie, in den Läsionen ein Abfall der MTR-Werte zu finden ist. Dies lässt vermuten, dass durch das Kortison die BHS-Störung günstig beeinflusst wird, die in den Läsionen vermutete entzündliche Aktivität weiter voranschreitet. Innerhalb der NAWM lassen sich ansteigende MTR-Werte verzeichnen, möglicherweise resultierend aus einer Reduktion der dort stattfindenden mikroskopischen Prozesse, wie Entzündung und Ödem

Insight into metabolic 1 ^{1}H-MRS changes in natalizumab induced progressive multifocal leukoencephalopathy brain lesions

$\textbf {Background:}$ Progressive multifocal leukoencephalopathy (PML) is a severe complication of immunosuppressive therapies, especially of natalizumab in relapsing–remitting multiple sclerosis (MS). Metabolic changes within PML lesions have not yet been described in natalizumab-associated PML in MS patients. $\textbf {Objective:}$ To study metabolic profiles in natalizumab-associated PML lesions of MS patients by $^{1}$H magnetic resonance spectroscopy ($^{1}$H-MRS) at different stages during the PML course. To assess changes associated with the occurrence of the immune reconstitution inflammatory syndrome (IRIS). $\textbf {Methods:}$ 20 patients received $^{1}$H-MRS and imaging at 3 T either in the pre-IRIS, IRIS, early-post-PML, or late post-PML setting. Five of these patients received individual follow-up examinations, including the pre-IRIS or IRIS phase. Clinical worsening was described by changes in the Karnofsky Performance Scale (KPS) and the expanded disability status scale (EDSS) 1 year before PML and scoring at the time of $^{1}$H-MRS. $\textbf {Results:}$ In PML lesions, increased levels of the Lip/Cr ratio, driven by rising of lipid and reduction of Creatine, were found before the occurrence of IRIS ($\it p$ = 0.014) with a maximum in the PML–IRIS group ($\it p$ = 0.004). By contrast, marked rises of Cho/Cr in PML lesions were detected exclusively during the IRIS phase ($\it p$ = 0.003). The Lip/Cr ratio decreased to above-normal levels in early-post-PML ($\it p$ = 0.007, compared to normal appearing white matter (NAWM)) and to normal levels in the late-post-PML group. NAA/Cho was reduced compared to NAWM in the pre-IRIS, IRIS, and early-post-PML group. In NAA/Cr, the same effect was seen in the pre-IRIS and early-post-PML group. These cross-sectional results were confirmed by the individual follow-up examinations of four patients. NAA/Cho, Cho/Cr, and the lipid rise relative to NAWM in PML lesions were significantly correlated with the residual clinical worsening (KPS change) in post-PML patients (Spearman correlations $\it p$ = 0.481, $\it p$ = 0.018; $\it p$ = −0.505, $\it p$ = 0.014; and $\it p$ = −0.488, $\it p$ = 0.020). $\textbf {Conclusion:}$ $^{1}$H-MRS detected clinically significant dynamic changes of metabolic patterns in PML lesions during the course of natalizumab-associated PML in MS patients. Lip/Cr and Cho/Cr may provide additional information for detecting the onset of the IRIS phase in the course of the PML disease

Cortical and subcortical grey and white matter atrophy in myotonic dystrophies type 1 and 2 is associated with cognitive impairment, depression and daytime sleepiness

$\textbf {Objectives:}$ Central nervous system involvement is one important clinical aspect of myotonic dystrophy type 1 and 2 (DM1 and DM2). We assessed CNS involvement DM1 and DM2 by 3T MRI and correlated clinical and neuocognitive symptoms with brain volumetry and voxel-based morphometry (VBM). $\textbf {Methods:}$ 12 patients with juvenile or classical DM1 and 16 adult DM2 patients underwent 3T MRI, a thorough neurological and neuropsychological examination and scoring of depression and daytime sleepiness. Volumes of brain, ventricles, cerebellum, brainstem, cervical cord, lesion load and VBM results of the patient groups were compared to 33 matched healthy subjects. $\textbf {Results:}$ Clinical symptoms were depression (more pronounced in DM2), excessive daytime sleepiness (more pronounced in DM1), reduced attention and flexibility of thinking, and deficits of short-term memory and visuo-spatial abilities in both patient groups. Both groups showed ventricular enlargement and supratentorial GM and WM atrophy, with prevalence for more GM atrophy and involvement of the motor system in DM1 and more WM reduction and affection of limbic structures in DM2. White matter was reduced in DM1 in the splenium of the corpus callosum and in left-hemispheric WM adjacent to the pre- and post-central gyrus. In DM2, the bilateral cingulate gyrus and subgyral medio-frontal and primary somato-sensory WM was affected. Significant structural-functional correlations of morphological MRI findings (global volumetry and VBM) with clinical findings were found for reduced flexibility of thinking and atrophy of the left secondary visual cortex in DM1 and of distinct subcortical brain structures in DM2. In DM2, depression was associated with brainstem atrophy, Daytime sleepiness correlated with volume decrease in the middle cerebellar peduncles, pons/midbrain and the right medio-frontal cortex. $\textbf {Conclusion:}$ GM and WM atrophy was significant in DM1 and DM2. Specific functional-structural associations related morphological changes to cognitive impairment, depression and daytime sleepiness, partly indicating involvement of complex neuronal networks

Metabolic profiles by 1^{1}H-magnetic resonance spectroscopy in natalizumab-associated post-PML lesions of multiple sclerosis patients who survived progressive multifocal leukoencephalopathy (PML)

$\bf Purpose$ Early diagnosis and treatment of multiple sclerosis-related progressive multifocal leukoencephalopathy (PML) significantly improve clinical outcomes. However, there is a lack of information regarding the restart of immunomodulatory therapy in the post-PML setting, when multiple sclerosis activity reappears. We aimed at the examination of metabolic differences using $^{1}$H-magnetic resonance spectroscopy ($^{1}$H-MRS) in multiple sclerosis patients at various post-PML stages and at the exploration of differences according to their disease and JC virus (JCV) status. $\bf Methods$ $^{1}$H-MRS of PML lesions was carried out on 15 relapsing-remitting multiple sclerosis patients with natalizumab-associated PML. Patients were grouped according to their stage after PML infection as early post-PML, less than 19 months after PML onset ($\it n$ = 5), or late post-PML group, more than 23 months after PML onset ($\it n$ = 10). The latter group was further categorized according to persisting JCV load in the cerebrospinal fluid. $\bf Results$ Early post-PML patients showed significantly higher Lipid/Creatine ratios within PML lesions than late post-PML ($\it p$ = 0.036). Furthermore, N-Acetyl-Aspartate/Creatine and N-Acetyl-Aspartate/Choline were significantly reduced in early post-PML and late post-PML lesions relative to normal-appearing white matter. In late post-PML, virus-positive patients showed significantly higher ratios of Choline/Creatine ($\it p$ = 0.019) and consequently a reduced N-Acetyl-Aspartate/Choline ratio ($\it p$ = 0.010) in contrast to virus-negative patients. In late post-PML patients with persisting viral load, an elevated Choline/Creatine ratio correlated significantly with higher disability. $\bf Conclusions$ $^{1}$H-MRS may provide additional information related to underlying PML disease activity in various post-PML stages. In particular, Choline/Creatine levels, Lipid levels, and N-Acetyl-Aspartate/Choline are relevant markers in the post-PML setting, taking also the JCV status into account

Temporal dynamics of diffusion metrics in early multiple sclerosis and clinically isolated syndrome

$\bf Background:$ Tract-based spatial statistics (TBSS) is suitable for the assessment of voxel-wise changes in fiber integrity in WM tracts in the entire brain. Longitudinal TBSS analyses of early multiple sclerosis (MS) using 3 Tesla magnetic resonance imaging (MRI) are not common. $\bf Objective:$ To characterize microstructural WM alterations at initial diagnosis in clinically isolated syndrome (CIS) and early MS at baseline and longitudinally over 2 years. $\bf Methods:$ DTI (Diffusion tensor imaging) at 3 Tesla was used to evaluate 106 therapy-naive patients with CIS or definite MS at baseline and at 1-year ($\it N$ = 83) and 2-year ($\it N$ = 43) follow-up compared to healthy controls (HC, $\it N$ = 49). TBSS was used for voxel-wise analyses of the DTI indices of fractional anisotropy (FA) and radial, mean, and axial diffusivity (RD, MD, AD) for cross-sectional and longitudinal comparisons. Mean values of FA, RD, and cluster voxel numbers were extracted from significant clusters using an atlas-based approach. Correlations with disability (EDSS) were calculated for FA and RD changes related to affected brain regions. $\bf Results:$ Reductions in FA compared to HC were found at baseline in patients with CIS and RRMS and involved most supra- and infratentorial WM tracts. In the cerebellum and cerebral peduncles, these changes negatively correlated with EDSS after 2 years. FA changes in patients with CIS and RRMS evolved in the second year, particularly in the descending projection pathways and the cerebellum, and were significantly associated with EDSS. RD alterations compared to HC were undetectable in patients at baseline but were observed after 1 year and were exacerbated during the second year in all major supratentorial WM tracts, the corpus callosum, and the cerebellum. FA did not change between baseline and year 1 follow-up, but longitudinal investigation between the first and second year revealed combined dynamic FA and RD changes in the corpus callosum and corona radiata. $\bf Conclusion:$ TBSS of diffusion metrics at initial diagnosis and at 2-year follow-up showed microstructural WM pathology and associations between FA reduction and future disability, respectively. Combined longitudinal changes in FA and RD occurred in specific structures, where RD increases likely reflected progressing axonal degeneration. The distinct temporal dynamics of FA and RD, implying constancy during the first year, supports early therapeutic intervention for CIS and RRMS

Relaxometry and brain myelin quantification with synthetic MRI in MS subtypes and their associations with spinal cord atrophy

Immune-mediated demyelination and neurodegeneration are pathophysiological hallmarks of Multiple Sclerosis (MS) and main drivers of disease related disability. The principal method for evaluating qualitatively demyelinating events in the clinical context is contrast-weighted magnetic resonance imaging (MRI). Moreover, advanced MRI sequences provide reliable quantification of brain myelin offering new opportunities to study tissue pathology in vivo. Towards neurodegenerative aspects of the disease, spinal cord atrophy – besides brain atrophy – is a powerful and validated predictor of disease progression. The etiology of spinal cord volume loss is still a matter of research, as it remains unclear whether the impact of local lesion pathology or the interaction with supra- and infratentorial axonal degeneration and demyelination of the long descending and ascending fiber tracts are the determining factors. Quantitative synthetic MR using a multiecho acquisition of saturation recovery pulse sequence provides fast automatic brain tissue and myelin volumetry based on R1 and R2 relaxation rates and proton density quantification, making it a promising modality for application in the clinical routine. In this cross sectional study a total of 91 MS patients and 31 control subjects were included to investigate group differences of global and regional measures of brain myelin and relaxation rates, in different MS subtypes, using QRAPMASTER sequence and SyMRI postprocessing software. Furthermore, we examined associations between these quantitative brain parameters and spinal cord atrophy to draw conclusions about possible pathophysiological relationships. Intracranial myelin volume fraction of the global brain exhibited statistically significant differences between control subjects (10.4%) and MS patients (RRMS 9.4%, PMS 8.1%). In a LASSO regression analysis with total brain lesion load, intracranial myelin volume fraction and brain parenchymal fraction, the intracranial myelin volume fraction was the variable with the highest impact on spinal cord atrophy (standardized coefficient 4.52). Regional supratentorial MRI metrics showed altered average myelin volume fraction, R1, R2 and proton density in MS patients compared to controls most pronounced in PMS. Interestingly, quantitative MRI parameters in supratentorial regions showed strong associations with upper cord atrophy, suggesting an important role of brain diffuse demyelination on spinal cord pathology possibly in the context of global disease activity. R1, R2 or proton density of the thalamus, cerebellum and brainstem correlated with upper cervical cord atrophy, probably reflecting the direct functional connection between these brain structures and the spinal cord as well as the effects of retrograde and anterograde axonal degeneration. By using Synthetic MR-derived myelin volume fraction, we were able to effectively detect significant differences of myelination in relapsing and progressive MS subtypes. Total intracranial brain myelin volume fraction seemed to predict spinal cord volume loss better than brain atrophy or total lesion load. Furthermore, demyelination in highly myelinated supratentorial regions, as an indicator of diffuse disease activity, as well as alterations of relaxation parameters in adjacent infratentorial and midbrain areas were strongly associated with upper cervical cord atrophy

Quantification of individual remyelination during short-term disease course by synthetic magnetic resonance imaging

MRI is an important diagnostic tool for evaluation of myelin content in multiple sclerosis and other CNS diseases, being especially relevant for studies investigating remyelinating pharmacotherapies. In this study, we evaluated a new synthetic MRI–based myelin estimation in methylenetetrahydrofolate reductase deficiency as a treatable primary demyelinating disorder and compared this method with established diffusion tensor imaging in both methylenetetrahydrofolate reductase deficiency patients and healthy controls. This is the first synthetic MRI–based $\textit {in vivo}$ evaluation of treatment-associated remyelination. 1.5 T synthetic MRI and 3 T diffusion MRI were obtained from three methylenetetrahydrofolate reductase deficiency patients at baseline and 6 months after therapy initiation, as well as from age-matched healthy controls (diffusion tensor imaging: $\it n$ = 14, synthetic MRI: $\it n$ = 9). Global and regional synthetic MRI parameters (myelin volume fraction, proton density, and relaxation rates) were compared with diffusion metrics (fractional anisotropy, mean/radial/axial diffusivity) and related to healthy controls by calculating z-scores and z-deviation maps. Whole-brain myelin (% of intracranial volume) of the index patient was reduced to 6 versus 10% in healthy controls, which recovered to a nonetheless subnormal level of 6.6% following initiation of high-dosage betaine. Radial diffusivity was higher at baseline compared with healthy controls (1.34 versus $(0.79 × 10^{−3} mm^{2}/s)$, recovering at follow-up $(1.19 × 10^{−3} mm^{2}/s)$. The index patient’s lesion volume diminished by 58% under treatment. Regional analysis within lesion area and atlas-based regions revealed lower mean myelin volume fraction $(12.7_{Baseline}/14.71_{Follow-up}$ and relaxation rates, higher proton density, as well as lower fractional anisotropy and higher radial diffusivity $(1.08 × 10^{−3}_{Baseline}/0.94 × 10^{−3}_{Follow-up}$) compared with healthy controls. The highest z-scores were observed for myelin volume fraction in the posterior thalamic radiation, with greater deviation from controls at baseline and reduced deviation at follow-up. Z-deviations of diffusion metrics were less pronounced for radial and mean diffusivity than for myelin volume fraction. Z-maps for myelin volume fraction of the index patient demonstrated high deviation within and beyond lesion areas, among others in the precentral and postcentral gyrus, as well as in the cerebellum, and partial remission of these alterations at follow-up, while radial diffusivity demonstrated more widespread deviations in supra- and infratentorial regions. Concordant changes of myelin volume fraction and radial diffusivity after treatment initiation, accompanied by dramatic clinical and paraclinical improvement, indicate the consistency of the methods, while myelin volume fraction seems to characterize remyelinated regions more specifically. Synthetic MRI–based myelin volume fraction provides myelin estimation consistent with changes of diffusion metrics to monitor short-term myelin changes on individual patient level

Biomechanical and functional indicators in male semiprofessional soccer players with increased hip alpha angles vs. amateur soccer players

$\bf Background:$ Femoroacetabular impingement (FAI) is predominant in young male athletes, but not much is known about gait differences in cases of increased hip alpha angles. In our study, the hip alpha angle of Nötzli of soccer players was quantified on the basis of magnetic resonance imaging (MRI) with axial oblique sequences. The aim of the current study was to compare the rearfoot motion and plantar pressure in male semiprofessional soccer players with increased alpha angles to age-matched amateur soccer players. $\bf Methods:$ In a prospective analysis, male semiprofessional and amateur soccer players had an MRI of the right hip to measure the alpha angle of Nötzli. In a biomechanical laboratory setting, 14 of these participants in each group ran in two shoe conditions. Simultaneously in-shoe pressure distribution, tibial acceleration, and rearfoot motion measurements of the right foot were performed. $\bf Results:$ In the semiprofessional soccer group, the mean value of the alpha angle of group was 55.1 $\pm$ 6.58° (range 43.2-76.6°) and 51.6 $\pm$ 4.43° (range 41.9-58.8°) in the amateur group. In both shoe conditions, we found a significant difference between the two groups concerning the ground reaction forces, tibial acceleration, rearfoot motion and plantar pressure parameters (P < 0.01, P < 0.05, P = 0.04). Maximum rearfoot motion is about 22% lower in the semiprofessional group compared to the amateur group in both shoe conditions. $\bf Conclusions:$ This study confirmed that semiprofessional soccer players with increased alpha angles showed differences in gait kinematics compared to the amateur group. These findings support the need for a screening program for competitive soccer players. In cases of a conspicuous gait analysis and symptomatic hip pain, FAI must be ruled out by further diagnostic tests

Characterization of iron accumulation in deep gray matter in myotonic dystrophy type 1 and 2 using quantitative susceptibility mapping and R2* relaxometry

Quantitative mapping of the magnetic susceptibility and the effective transverse relaxation rate (R2*) are suitable to assess the iron content in distinct brain regions. In this prospective, explorative study the iron accumulation in deep gray matter nuclei (DGM) in myotonic dystrophy type 1 (DM1) and 2 (DM2) and its clinical and neuro-cognitive relevance using susceptibility and R2* mapping was examined. Twelve classical DM1, four childhood-onset DM1 (DM1$_{c.o.}$), twelve DM2 patients and twenty-nine matched healthy controls underwent MRI at 3 Tesla, neurological and neuro-cognitive tests. Susceptibility, R2* and volumes were determined for eleven DGM structures and compared between patients and controls. Twelve classical DM1, four childhood-onset DM1, and 12 DM2 patients as well as 29 matched healthy controls underwent MRI at 3 Tesla, and neurological and neuro-cognitive tests. Susceptibility, R2* and volumes were determined for 11 DGM structures and compared between patients and controls. Iron accumulation in DGM reflected by R2* or susceptibility was found in the putamen and accumbens of DM1 and in DM2, but was more widespread in DM1 (caudate, pallidum, hippocampus, subthalamic nucleus, thalamus, and substantia nigra). Opposed changes of R2* or susceptibility were detected in caudate, putamen and accumbens in the childhood-onset DM1 patients compared to classical DM1. R2* or susceptibility alterations in DGM were significantly associated with clinical symptoms including muscular weakness (DM1), daytime sleepiness (DM1), depression (DM2), and with specific cognitive deficits in DM1 and DM2

Enhanced cardiomyocyte function in hypertensive rats with diastolic dysfunction and human heart failure patients after acute treatment with soluble guanylyl cyclase (sGC) activator

$\textbf {Aims:}$ Our aim was to investigate the effect of nitric oxide (NO)-independent activation of soluble guanylyl cyclase (sGC) on cardiomyocyte function in a hypertensive animal model with diastolic dysfunction and in biopsies from human heart failure with preserved ejection fraction (HFpEF). $\textbf {Methods:}$ Dahl salt-sensitive (DSS) rats and control rats were fed a high-salt diet for 10 weeks and then acutely treated $\textit {in vivo}$ with the sGC activator BAY 58-2667 (cinaciguat) for 30 min. Single skinned cardiomyocyte passive stiffness ($F_{passive}$) was determined in rats and human myocardium biopsies before and after acute treatment. Titin phosphorylation, activation of the NO/sGC/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) cascade, as well as hypertrophic pathways including NO/sGC/cGMP/PKG, PKA, calcium–calmodulin kinase II (CaMKII), extracellular signal-regulated kinase 2 (ERK2), and PKC were assessed. In addition, we explored the contribution of pro-inflammatory cytokines and oxidative stress levels to the modulation of cardiomyocyte function. Immunohistochemistry and electron microscopy were used to assess the translocation of sGC and connexin 43 proteins in the rat model before and after treatment. $\textbf {Results:}$ High cardiomyocyte $F_{passive}$ was found in rats and human myocardial biopsies compared to control groups, which was attributed to hypophosphorylation of total titin and to deranged site-specific phosphorylation of elastic titin regions. This was accompanied by lower levels of PKG and PKA activity, along with dysregulation of hypertrophic pathway markers such as CaMKII, PKC, and ERK2. Furthermore, DSS rats and human myocardium biopsies showed higher pro-inflammatory cytokines and oxidative stress compared to controls. DSS animals benefited from treatment with the sGC activator, as $F_{passive}$, titin phosphorylation, PKG and the hypertrophic pathway kinases, pro-inflammatory cytokines, and oxidative stress markers all significantly improved to the level observed in controls. Immunohistochemistry and electron microscopy revealed a translocation of sGC protein toward the intercalated disc and t-tubuli following treatment in both control and DSS samples. This translocation was confirmed by staining for the gap junction protein connexin 43 at the intercalated disk. DSS rats showed a disrupted connexin 43 pattern, and sGC activator was able to partially reduce disruption and increase expression of connexin 43. In human HFpEF biopsies, the high $F_{passive}$, reduced titin phosphorylation, dysregulation of the NO–sGC–cGMP–PKG pathway and PKA activity level, and activity of kinases involved in hypertrophic pathways CaMKII, PKC, and ERK2 were all significantly improved by sGC treatment and accompanied by a reduction in pro-inflammatory cytokines and oxidative stress markers. $\textbf {Conclusion:}$ Our data show that sGC activator improves cardiomyocyte function, reduces inflammation and oxidative stress, improves sGC–PKG signaling, and normalizes hypertrophic kinases, indicating that it is a potential treatment option for HFpEF patients and perhaps also for cases with increased hypertrophic signaling