Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date.
Abstract Localized short echo time ( TE = 20 ms), stimulated echo acquisition mode, and double spin echo ( TE = 135 ms) proton spectroscopy were performed in clearly defined, acute Gadolinium (Gd)‐enhancing multiple sclerosis (MS) plaques of 22 patients with clinically definite MS. The resonances of N ‐acetylated metabolites (NA), creatine/phosphocreatine (Cr), choline‐containing compounds (Cho), glycine/ myo ‐inositol (Ino), and lactate were evaluated. The ratios of NA/Cr and NA/Cho were significantly decreased, Cho/Cr increased, and Ino/Cr remained unchanged. No marker peaks or elevated lactate levels were found. The measured metabolic changes were practically independent of the relative plaque size within the volume of interest (8 ml). Thus, the spectral changes measured with 1 H MRS in acute Gd‐enhancing MS plaques originate not only from the lesion as depicted by MRI, but also from the surrounding normal‐appearing white matter.
To evaluate neurofilament light chain (NfL) levels, a biomarker of neuroaxonal damage, as a prognostic and a potential surrogate marker of evobrutinib treatment response (MRI and relapse outcomes) in patients with relapsing multiple sclerosis (PwRMS).
Background:
Evobrutinib is a highly selective, CNS-penetrant Bruton's tyrosine kinase inhibitor, currently in Phase III for RMS. The efficacy of evobrutinib (MRI and clinical outcomes) observed in double blind phase (DBP) of a Phase II trial (NCT02975349) in PwRMS was maintained in the open-label extension (OLE; beginning at Week [W] 48 from DBP baseline). Previous analyses of the Phase II trial showed sustained reductions in NfL levels with evobrutinib up to W144.
Design/Methods:
NfL levels were measured over time in the pooled OLE safety population and reported as control-adjusted NfL Z-scores (expression of standard deviations [SDs] away from mean NfL level in a control population [participants without evidence of CNS disease]). The number of T1 Gd+ and new/emerging T2 lesions at W96 and W144 and qualified relapses over W96–144 were assessed, stratified by W96 NfL Z-scores (<1; ≥1 [Z-score 1 being one SD above the control mean]). MRI outcomes at W48 and W96 and relapses over W48–96 were also assessed using stratified W48 NfL Z-scores [<1; ≥1].
Results:
Stratified by W96 Z-scores (<1[N=66]; ≥1[N=34]), the proportion of patients with no T1 Gd+ lesions, no new/enlarging T2 lesions (both at W144) and no relapse between W96–144 were 84.5% (n=49/58) vs 57.1% (n=16/28), 65.5% (n=38/58) vs 28.6% (n=8/28) and 95.4% (n=62/65) vs 94.1% (n=32/34), respectively. Similar findings were observed in patients stratified by W48 Z-scores (<1[N=84]; ≥1[N=40]).
Conclusions:
Evobrutinib reduced NfL levels in a sustained manner (up to W144). Low NfL levels were associated with improved MRI and relapse outcomes, supporting the role of NfL as a prognostic marker of disease activity and a potential surrogate marker for evobrutinib's treatment effect. Disclosure: Dr. Kuhle has nothing to disclose. The institution of Dr. Kappos has received research support from Bayer. The institution of Dr. Kappos has received research support from Biogen. The institution of Dr. Kappos has received research support from Genentech. The institution of Dr. Kappos has received research support from Genzyme. The institution of Dr. Kappos has received research support from Janssen. The institution of Dr. Kappos has received research support from Merck Serono. The institution of Dr. Kappos has received research support from Minoryx. The institution of Dr. Kappos has received research support from Novartis. The institution of Dr. Kappos has received research support from Roche. The institution of Dr. Kappos has received research support from Sanofi. The institution of Dr. Kappos has received research support from Santhera. The institution of Dr. Kappos has received research support from Swiss MS Society, Swiss National Research Foundation, European Union, Roche Research Foundation, Innosuisse. The institution of Dr. Kappos has received research support from Shionogi. The institution of Dr. Kappos has received research support from Japan Tobacco. The institution of Dr. Kappos has received research support from Auriga Vision AG. The institution of Dr. Kappos has received research support from EMD Serono. The institution of Dr. Kappos has received research support from Glaxo Smith Kline. The institution of Dr. Kappos has received research support from Wellmera AG. The institution of Dr. Kappos has received research support from Eli Lilly (Suisse) SA. The institution of Dr. Kappos has received research support from Bristol Myers Squibb. The institution of Dr. Kappos has received research support from Celltrion Inc. Dr. Kappos has received intellectual property interests from a discovery or technology relating to health care. The institution of Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. The institution of Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Merck/ EMD Serono. The institution of Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. The institution of Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Teva. The institution of Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Hoffmann-La Roche. The institution of Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Actelion/ Janssen. The institution of Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for BMS/ Celgene. The institution of Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi/ Genzyme. Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Actelion/ Janssen. Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BMS/ Celgene. Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck/ EMD Serono. Dr. Montalban has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Montalban has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Hoffmann-La Roche. Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi-Genzyme. The institution of Dr. Montalban has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Immunic Therapeutics. The institution of Dr. Montalban has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Viatris/ Mylan. The institution of Dr. Montalban has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sandoz. The institution of Dr. Montalban has received research support from Biogen. The institution of Dr. Montalban has received research support from Hoffmann-La Roche. The institution of Dr. Montalban has received research support from Sanofi/ Genzyme. The institution of Dr. Montalban has received research support from Merck/ EMD Serono. The institution of Dr. Montalban has received research support from Novartis. The institution of Dr. Montalban has received research support from Teva Pharmaceuticals. The institution of Dr. Montalban has received research support from Actelion/ Janssen. The institution of Dr. Montalban has received research support from BMS/ Celgene. Pascal Benkert has nothing to disclose. Ying Li has received personal compensation for serving as an employee of EMD Serono. Karthinathan Thangavelu has received personal compensation for serving as an employee of Sanofi Genzyme. Karthinathan Thangavelu has received personal compensation for serving as an employee of EMD Serono . Dr. Hyvert has received personal compensation for serving as an employee of The healthcare business of Merck KGaA, Darmstadt, Germany. An immediate family member of Dr. Hyvert has received personal compensation for serving as an employee of The healthcare business of Merck KGaA, Darmstadt, Germany. Davorka Tomic has nothing to disclose.
April 22, 2018April 10, 2018Free AccessAnnualized Relapse Rate and Confirmed Disability Progression in Patients Receiving Continuous Ocrelizumab or Switching From Interferon Beta-1a to Ocrelizumab Therapy in the Open-Label Extension Period of the Phase III Trials of Ocrelizumab in Patients With Relapsing Multiple Sclerosis (P1.366)Stephen Hauser, Bruno Brochet, Xavier Montalban, Robert Naismith, Jerry Wolinsky, Marianna Manfrini, Monika Garas, Pablo Villoslada, Fabian Model, Stanislas Hubeaux, and Ludwig KapposAuthors Info & AffiliationsApril 10, 2018 issue90 (15_supplement)https://doi.org/10.1212/WNL.90.15_supplement.P1.366 Letters to the Editor
Abstract Postmortem magnetic resonance imaging (MRI) of the fixed healthy and diseased human brain facilitates spatial resolutions and image quality that is not achievable with in vivo MRI scans. Though challenging - and almost exclusively performed at 7T field strength - depicting the tissue architecture of the entire brain in fine detail is invaluable since it enables the study of neuroanatomy and uncovers important pathological features in neurological disorders. The objectives of the present work were (i) to develop a 3D isotropic ultra-high-resolution imaging approach for human whole-brain ex vivo acquisitions working on a standard clinical 3T MRI system, and (ii) to explore the sensitivity and specificity of this concept for specific pathoanatomical features of multiple sclerosis. The reconstructed images demonstrate unprecedented resolution and soft tissue contrast of the diseased human brain at 3T, thus allowing visualization of sub-millimetric lesions in the different cortical layers and in the cerebellar cortex, as well as unique cortical lesion characteristics such as the presence of incomplete / complete iron rims, and patterns of iron accumulation. Further details such as the subpial molecular layer, the line of Gennari, and some intrathalamic nuclei are also well distinguishable.
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