Background:
Serum neurofilament light chain (sNfL) and distinct intra-retinal layers are both promising biomarkers of neuro-axonal injury in multiple sclerosis (MS). We aimed to unravel the ...association of both markers in early MS, having identified that neurofilament has a distinct immunohistochemical expression pattern among intra-retinal layers.
Methods:
Three-dimensional (3D) spectral domain macular optical coherence tomography scans and sNfL levels were investigated in 156 early MS patients (female/male: 109/47, mean age: 33.3 ± 9.5 years, mean disease duration: 2.0 ± 3.3 years). Out of the whole cohort, 110 patients had no history of optic neuritis (NHON) and 46 patients had a previous history of optic neuritis (HON). In addition, a subgroup of patients (n = 38) was studied longitudinally over 2 years. Support vector machine analysis was applied to test a regression model for significant changes.
Results:
In our cohort, HON patients had a thinner outer plexiform layer (OPL) volume compared to NHON patients (B = −0.016, SE = 0.006, p = 0.013). Higher sNfL levels were significantly associated with thinner OPL volumes in HON patients (B = −6.734, SE = 2.514, p = 0.011). This finding was corroborated in the longitudinal subanalysis by the association of higher sNfL levels with OPL atrophy (B = 5.974, SE = 2.420, p = 0.019). sNfL levels were 75.7% accurate at predicting OPL volume in the supervised machine learning.
Conclusions:
In summary, sNfL levels were a good predictor of future outer retinal thinning in MS. Changes within the neurofilament-rich OPL could be considered as an additional retinal marker linked to MS neurodegeneration.
The aim of this study was to demonstrate that both neurological and hepatic symptoms respond to copper chelation therapy in Wilson disease (WD). However, the time course of their recovery is ...different.
Eighteen patients with neurological WD from a single specialized center who had been listed for liver transplantation during the last ten years and two newly diagnosed homozygous twins were recruited for this retrospective study. The mean duration of conventional treatment was 7.3 years (range: 0.25 to 36.2 years). A custom Wilson disease score with seven motor items, three non-motor items, and 33 biochemical parameters of the blood and urine, as well as the MELD score, was determined at various checkup visits during treatment. These data were extracted from the charts of the patients.
Treatment was initiated with severity-dependent doses (≥900 mg) of D-penicillamine (DPA) or triethylene-tetramin-dihydrochloride (TRIEN). The motor score improved in 10 and remained constant in 8 patients. Worsening of neurological symptoms was observed only in two patients who developed comorbidities (myasthenia gravis or hemispheric stroke). The neurological symptoms continuously improved over the years until the majority of patients became only mildly affected. In contrast to this slow recovery of the neurological symptoms, the MELD score and liver enzymes had already started to improve after 1 month and rapidly improved over the next 6 months in 19 patients. The cholinesterase levels continued to increase significantly (
< 0.0074) even further. One patient whose MELD score indicated further progression of liver disease received an orthotopic liver transplantation 3 months after the diagnosis of WD and the onset of DPA treatment.
Neurological and hepatic symptoms both respond to copper chelation therapy. For patients with acute liver failure, the first 4 months are critical. This is the time span in which patients have to wait either for a donor organ or until significant improvement has occurred under conventional therapy. For patients with severe neurological symptoms, it is important that they are treated with fairly high doses over several years.
Therapeutic efficacy of cisplatin-based chemotherapy for advanced-stage urothelial carcinoma (UC) is limited by drug resistance. The nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway is a ...major regulator of cytoprotective responses. We investigated its involvement in cisplatin resistance in long-term cisplatin treated UC cell lines (LTTs). Expression of NRF2 pathway components and targets was evaluated by qRT-PCR and western blotting in LTT sublines from four different parental cells. NRF2 transcriptional activity was determined by reporter assays and total glutathione (GSH) was quantified enzymatically. Effects of siRNA-mediated NRF2 knockdown on chemosensitivity were analysed by viability assays, γH2AX immunofluorescence, and flow cytometry. Increased expression of NRF2, its positive regulator p62/SQSTM1, and elevated NRF2 activity was observed in 3/4 LTTs, which correlated with KEAP1 expression. Expression of cytoprotective enzymes and GSH concentration were upregulated in some LTTs. NRF2 knockdown resulted in downregulation of cytoprotective enzymes and resensitised 3/4 LTTs towards cisplatin as demonstrated by reduced IC
values, increased γH2AX foci formation, and elevated number of apoptotic cells. In conclusion, while LTT lines displayed diversity in NRF2 activation, NRF2 signalling contributed to cisplatin resistance in LTT lines, albeit in diverse ways. Accordingly, inhibition of NRF2 can be used to resensitise UC cells to cisplatin, but responses in patients may likewise be variable.
Tumefactive multiple sclerosis (MS) is a rare variant of MS that may lead to a rapidly progressive clinical deterioration requiring a multidisciplinary diagnostic workup. Our report describes the ...diagnostic and therapeutic approach of a rare and extremely severe course of MS. A 51-year-old man with an 8-year history of relapsing-remitting MS (RRMS) was admitted with a subacute progressive left lower limb weakness and deterioration of walking ability. After extensive investigations including repeated MRI, microbiological, serological, cerebrospinal fluid (CSF) studies, and finally brain biopsy, the diagnosis of a tumefactive MS lesion was confirmed. Despite repeated intravenous (IV) steroids as well as plasma exchanges and IV foscarnet and ganciclovir owing to low copy numbers of human herpesvirus 6 (HHV-6) DNA in polymerase chain reaction (PCR) analysis, the patient did not recover. The clinical presentation of tumefactive MS is rare and variable. Brain biopsy for histopathological workup should be considered in immunocompromised patients with rapidly progressive clinical deterioration with brain lesions of uncertain cause.
Background and aims:
Various attempts have been made to support recovery following optic neuritis (ON), but the respective trials have mostly been negative. The aim of this study was to determine ...whether disease-modifying treatment (DMT) following ON as first manifestation of relapsing-remitting multiple sclerosis influences long-term outcomes.
Methods:
A total of 79 patients with ON were identified and evaluated at relapse, DMT induction, and 12 months following treatment induction with either glatiramer acetate (GLAT), interferon-beta (IFN), or teriflunomide (TRF). Low-contrast letter acuity (LCLA) and full-field visual-evoked potentials (FF-VEP) were compared between treatment groups using multivariable regression models. The impact of TRF treatment induction compared with IFN or GLAT following relapses outside the optic nerves was evaluated in an independent cohort of 122 patients. Magnetic resonance imaging (MRI) outcomes and rates of confirmed improvement of relapse-related disability were evaluated.
Results:
TRF-treated patients exhibited higher LCLA and lower relative P100 latencies normalized to the fellow-eye. Findings were significant following covariate-adjustment by multivariable analyses. Cranial MRI lesion load as well as disability progression rates were not significantly different between groups. The cohort of patients following relapses other than ON showed no differences in confirmed improvement of disability.
Conclusion:
TRF treatment is associated with favorable outcomes regarding functional optic nerve recovery following ON in early multiple sclerosis.
► cGMP protected best from oxidative stress among 54 putative extracellular ligands. ► The degradation products GMP and guanosine are even more protective. ► Guanosine increases system xc− activity. ...► Guanosine inhibits the toxic calcium influx during oxidative glutamate toxicity.
Cell death in response to oxidative stress plays a role in a variety of neurodegenerative diseases and can be studied in detail in the neuronal cell line HT22, where extracellular glutamate causes glutathione depletion by inhibition of the glutamate/cystine antiporter system xc−, elevation of reactive oxygen species and eventually programmed cell death caused by cytotoxic calcium influx. Using this paradigm, we screened 54 putative extracellular peptide or small molecule ligands for effects on cell death and identified extracellular cyclic guanosine monophosphate (cGMP) as a protective substance. Extracellular cGMP was protective, whereas the cell-permeable cGMP analog 8-pCPT-cGMP or the inhibition of cGMP degradation by phosphodiesterases was toxic. Interestingly, metabolites GMP and guanosine were even more protective than cGMP and the inhibition of the conversion of GMP to guanosine attenuated its effect, suggesting that GMP offers protection through its conversion to guanosine. Guanosine increased system xc− activity and cellular glutathione levels in the presence of glutamate, which can be explained by transcriptional upregulation of xCT, the functional subunit of system xc−. However, guanosine also provided protection when added late in the cell death cascade and significantly reduced the number of calcium peaking cells, which was most likely not mediated by transcriptional mechanisms. We observed no changes in the classical protective pathways such as phosphorylation of Akt, ERK1/2 or induction of Nrf2 or ATF4. We conclude that extracellular guanosine protects against endogenous oxidative stress by two probably independent mechanisms involving system xc− induction and inhibition of cytotoxic calcium influx.
Glioblastoma (GBM) remains the most malignant primary brain tumor, with a median survival rarely exceeding 2 years. Tumor heterogeneity and an immunosuppressive microenvironment are key factors ...contributing to the poor response rates of current therapeutic approaches. GBM-associated macrophages (GAMs) often exhibit immunosuppressive features that promote tumor progression. However, their dynamic interactions with GBM tumor cells remain poorly understood. Here, we used patient-derived GBM stem cell cultures and combined single-cell RNA sequencing of GAM-GBM co-cultures and real-time in vivo monitoring of GAM-GBM interactions in orthotopic zebrafish xenograft models to provide insight into the cellular, molecular, and spatial heterogeneity. Our analyses revealed substantial heterogeneity across GBM patients in GBM-induced GAM polarization and the ability to attract and activate GAMs-features that correlated with patient survival. Differential gene expression analysis, immunohistochemistry on original tumor samples, and knock-out experiments in zebrafish subsequently identified LGALS1 as a primary regulator of immunosuppression. Overall, our work highlights that GAM-GBM interactions can be studied in a clinically relevant way using co-cultures and avatar models, while offering new opportunities to identify promising immune-modulating targets.
Background:
Visual field defects are a common and disabling consequence of stroke and a negative prognostic factor of patient's quality of life. They result from lesions in different parts of the ...visual system, most commonly the visual cortex and optic radiation. An important pathophysiological mechanism is transsynaptic retrograde degeneration (TRD).
Methods:
In a case series 21 patients with posterior cerebral artery (PCA) territory infarctions were analyzed by spectral-domain optical coherence tomography (SD-OCT) and multifocal visual evoked potentials (mfVEPs) cross-sectionally and longitudinally for up to 6 months. In OCT, symptomatic affected nasal and temporal sectors and corresponding visual fields in mfVEPs were compared to the contralateral side.
Results:
SD-OCT revealed a significant reduction (−2.92 ±2.53 μm, mean ± SD) of the symptomatic nasal macular retinal nerve fiber layer (RNFL) thickness and of the symptomatic temporal peripapillary RNFL after 6 months compared to baseline whereas the symptomatic temporal macular quadrant already showed a significantly thinner RNFL at baseline. The mfVEP first peak latency at baseline was significantly different (nasal visual field +11.69 ±11.17 ms, mean ± SD; temporal visual field +16.63 ±7.97 ms, mean ± SD) on the symptomatic compared to the asymptomatic field. The nasal visual fields partly recovered in amplitude and first peak latency of mfVEPs over the following 6 months compared to baseline.
Conclusion:
The dynamics of OCT and mfVEP outcomes for degeneration and recovery after PCA infarction differ between the nasal and temporal retinal sector. We postulate that retinal sectors may differ in their temporal pattern of TRD over time after retrogeniculate cerebral infarction.
Charcot-Marie tooth disease is a hereditary polyneuropathy caused by mutations in Mitofusin-2 (MFN2), a GTPase in the outer mitochondrial membrane involved in the regulation of mitochondrial fusion ...and bioenergetics. Autosomal-dominant inheritance of a R94Q mutation in MFN2 causes the axonal subtype 2A2A which is characterized by early onset and progressive atrophy of distal muscles caused by motoneuronal degeneration. Here, we studied mitochondrial shape, respiration, cytosolic, and mitochondrial ATP content as well as mitochondrial quality control in MFN2-deficient fibroblasts stably expressing wildtype or R94Q MFN2. Under normal culture conditions, R94Q cells had slightly more fragmented mitochondria but a similar mitochondrial oxygen consumption, membrane potential, and ATP production as wildtype cells. However, when inducing mild oxidative stress 24 h before analysis using 100 µM hydrogen peroxide, R94Q cells exhibited significantly increased respiration but decreased mitochondrial ATP production. This was accompanied by increased glucose uptake and an up-regulation of hexokinase 1 and pyruvate kinase M2, suggesting increased pyruvate shuttling into mitochondria. Interestingly, these changes coincided with decreased levels of PINK1/Parkin-mediated mitophagy in R94Q cells. We conclude that mitochondria harboring the disease-causing R94Q mutation in MFN2 are more susceptible to oxidative stress, which causes uncoupling of respiration and ATP production possibly by a less efficient mitochondrial quality control.
PDF
