Serum neurofilament light chain is a biomarker of acute and chronic neuronal damage in early multiple sclerosis.

BACKGROUND: Monitoring neuronal injury remains one key challenge in early relapsing-remitting multiple sclerosis (RRMS) patients. Upon axonal damage, neurofilament - a major component of the neuro-axonal cytoskeleton - is released into the cerebrospinal fluid (CSF) and subsequently peripheral blood. OBJECTIVE: To investigate the relevance of serum neurofilament light chain (sNfL) for acute and chronic axonal damage in early RRMS. METHODS: sNfL levels were determined in 74 patients (63 therapy-naive) with recently diagnosed clinically isolated syndrome (CIS) or RRMS using Single Molecule Array technology. Standardized 3 T magnetic resonance imaging (MRI) was performed at baseline and 1-3 consecutive follow-ups (42 patients; range: 6-37 months). RESULTS: Baseline sNfL correlated significantly with T2 lesion volume ( r = 0.555, p < 0.0001). There was no correlation between baseline sNfL and age, Expanded Disability Status Scale (EDSS) score or other calculated MRI measures. However, T2 lesion volume increased ( r = 0.67, p < 0.0001) and brain parenchymal volume decreased more rapidly in patients with higher baseline sNfL ( r = -0.623, p = 0.0004). Gd-enhancing lesions correlated positively with sNfL levels. Initiation of disease-modifying treatment led to a significant decrease in sNfL levels. CONCLUSION: sNfL indicates acute inflammation as demonstrated by correlation with Gd+ lesions. It is a promising biomarker for neuro-axonal damage in early multiple sclerosis (MS) patients, since higher baseline sNfL levels predicted future brain atrophy within 2 years.

Association of smoking but not HLA-DRB1*15:01, APOE or body mass index with brain atrophy in early multiple sclerosis.

BACKGROUND: The course of multiple sclerosis (MS) shows substantial inter-individual variability. The underlying determinants of disease severity likely involve genetic and environmental factors. OBJECTIVE: The aim of this study was to assess the impact of APOE and HLA polymorphisms as well as smoking and body mass index (BMI) in the very early MS course. METHODS: Untreated patients ( n = 263) with a recent diagnosis of relapsing-remitting (RR) MS or clinically isolated syndrome underwent standardized magnetic resonance imaging (MRI). Genotyping was performed for single-nucleotide polymorphisms (SNPs) rs3135388 tagging the HLA-DRB1*15:01 haplotype and rs7412 (Ɛ2) and rs429358 (Ɛ4) in APOE. Linear regression analyses were applied based on the three SNPs, smoking and BMI as exposures and MRI surrogate markers for disease severity as outcomes. RESULTS: Current smoking was associated with reduced gray matter fraction, lower brain parenchymal fraction and increased cerebrospinal fluid fraction in comparison to non-smoking, whereas no effect was observed on white matter fraction. BMI and the SNPs in HLA and APOE were not associated with structural MRI parameters. CONCLUSIONS: Smoking may have an unfavorable effect on the gray matter fraction as a potential measure of MS severity already in early MS. These findings may impact patients' counseling upon initial diagnosis of MS.

Decreased Cytochrome P450 3A activity in palliative patients with haematological diseases: Potential impact on supportive drug therapies.

Cytochrome P450 3A (CYP3A) is the most relevant drug-metabolizing enzyme in human beings involved in the elimination of about 50% of the marketed drugs. Comprehensive in vivo data of CYP3A activity in palliative patients with haematological diseases are missing. Therefore, CYP3A activity was determined under real-life clinical conditions in patients to gain knowledge about dose adjustments for supportive therapies and symptom management in haematology. The single-arm, prospective trial obtained a 4-hours pharmacokinetic profile of midazolam after oral administration of a microdose as marker substance from each enrolled patient. Plasma concentrations of midazolam and its primary metabolite 1'-hydroxy-midazolam were quantified by mass spectrometry techniques. CYP3A activity was calculated as partial metabolic clearance from an established limited sampling area under the curve. All other drugs taken by the participating patients were considered as well as recent laboratory test results and the patients' diagnoses. Partial metabolic clearance of midazolam in patients with haematological diseases was highly variable (36.9 ± 52.7 L/h). In comparison with the CYP3A activity of healthy individuals, this was a highly significant 30% reduction of activity (P < 0.0001). Dosing of major CYP3A substrate drugs needs to be reduced in palliative patients with haematological diseases, otherwise escalation of debilitating symptoms due to drug interactions might occur.

Preservation of neuronal function as measured by clinical and MRI endpoints in relapsing-remitting multiple sclerosis: how effective are current treatment strategies?

INTRODUCTION: Approved medications for relapsing-remitting multiple sclerosis have shown to be effective in terms of their anti-inflammatory potential. However, it is also crucial to evaluate what long-term effects a patient can expect from current MS drugs in terms of preventing neurodegeneration. Here we aim to provide an overview of the current treatment strategies in MS with a specific focus on potential neuroprotective effects. Areas covered: Randomized, double-blind and placebo or referral-drug controlled phase 2a/b and phase 3 trials were examined; non-blinded phase 4 studies (extension studies) were included to provide long-term data, if not otherwise available. Endpoints considered were expanded disability status scale, various neuropsychological tests, percent brain volume change and T1-hypointense lesions as well as multiple sclerosis functional composite, confirmed disease progression, and no evidence of disease activity. Expert commentary: Overall, neuroprotective functions of classical MS therapeutics are not sufficiently investigated, but available data show limited effects. Thus, further research and development in neuroprotection are warranted. When counselling patients, potential long-term beneficial effects should be presented more conservatively.

Single-cell profiling reveals GPCR heterogeneity and functional patterning during neuroinflammation.

GPCR expression was intensively studied in bulk cDNA of leukocyte populations, but limited data are available with respect to expression in individual cells. Here, we show a microfluidic-based single-cell GPCR expression analysis in primary T cells, myeloid cells, and endothelial cells under naive conditions and during experimental autoimmune encephalomyelitis, the mouse model of multiple sclerosis. We found that neuroinflammation induces characteristic changes in GPCR heterogeneity and patterning, and we identify various functionally relevant subgroups with specific GPCR profiles among spinal cord-infiltrating CD4 T cells, macrophages, microglia, or endothelial cells. Using GPCRs CXCR4, S1P1, and LPHN2 as examples, we show how this information can be used to develop new strategies for the functional modulation of Th17 cells and activated endothelial cells. Taken together, single-cell GPCR expression analysis identifies functionally relevant subpopulations with specific GPCR repertoires and provides a basis for the development of new therapeutic strategies in immune disorders.