Serum neurofilament levels reflect outer retinal layer changes in multiple sclerosis.

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.

Structure-based exploration and pharmacological evaluation of N-substituted piperidin-4-yl-methanamine CXCR4 chemokine receptor antagonists.

Using the available structural information of the chemokine receptor CXCR4, we present hit finding and hit exploration studies that make use of virtual fragment screening, design, synthesis and structure-activity relationship (SAR) studies. Fragment 2 was identified as virtual screening hit and used as a starting point for the exploration of 31 N-substituted piperidin-4-yl-methanamine derivatives to investigate and improve the interactions with the CXCR4 binding site. Additionally, subtle structural ligand changes lead to distinct interactions with CXCR4 resulting in a full to partial displacement of CXCL12 binding and competitive and/or non-competitive antagonism. Three-dimensional quantitative structure-activity relationship (3D-QSAR) and binding model studies were used to identify important hydrophobic interactions that determine binding affinity and indicate key ligand-receptor interactions.

Discriminative power of intra-retinal layers in early multiple sclerosis using 3D OCT imaging.

OBJECTIVE: To evaluate volumetric changes and discriminative power of intra-retinal layers in early-stage multiple sclerosis (MS) using a 3D optical coherence tomography (OCT) imaging method based on an in-house segmentation algorithm. METHODS: 3D analysis of intra-retinal layers was performed in 71 patients with early-stage MS (mean disease duration 2.2 ± 3.5 years) at baseline and 40 healthy controls (HCs). All patients underwent a follow-up OCT scan within 23 ± 9 months. Patients with a clinical episode of optic neuritis (ON) more than 6 months prior to study entrance were compared with patients who never experienced clinical symptoms of an ON episode (NON). RESULTS: Significantly decreased total retinal volume (TRV), macular retinal nerve fiber layer (mRNFL) and ganglion cell-inner plexiform layer (GCIPL) volumes were detected in ON patients compared to NON patients (all p values < 0.05) at baseline. Each parameter on its own allowed identification of prior clinical ON based on a discriminative model (ROC analysis). Over time, TRV decreased in both ON (p = 0.013) and NON patients (p = 0.002), whereas mRNFL volume (p = 0.028) decreased only in ON and GCIPL volume (p = 0.003) decreased only in NON patients. CONCLUSION: Our 3D-OCT data demonstrated that TRV, mRNFL and GCIPL allow discrimination between ON and NON patients in a cross-sectional analysis. However, the subsequent retinal atrophy pattern diverges in the initial phase of MS: Prior ON promotes sustained axonal thinning over time indicated by mRNFL loss, whereas longitudinal measurement of GCIPL volume better depicts continuous retrograde neurodegeneration in NON patients in early-stage MS.