PMID- 33813096 OWN - NLM STAT- MEDLINE DCOM- 20210707 LR - 20220531 IS - 2211-0356 (Electronic) IS - 2211-0348 (Linking) VI - 51 DP - 2021 Jun TI - Microstructural and functional brain abnormalities in multiple sclerosis predicted by osteopontin and neurofilament light. PG - 102923 LID - S2211-0348(21)00190-5 [pii] LID - 10.1016/j.msard.2021.102923 [doi] AB - BACKGROUND: Osteopontin (OPN) is a proinflammatory biomarker, and neurofilament light chain (NFL) levels reflect axonal damage. Resting-state functional MRI (rs-fMRI) defines brain networks during wakeful rest. OBJECTIVE: To examine, if levels of OPN and NFL are associated on the long term with (i) lesion evolution, (ii) changes in normal-appearing white matter (NAWM) microstructure and (iii) functional connectivity in multiple sclerosis (MS). METHODS: Concentration of NFL and OPN in the blood and CSF were related to MRI findings 10.3 +/- 2.8 years later in 53 patients with MS. NFL was examined by Simoa method, OPN by ELISA. Lesion volume in the brain and cervical spinal cord was examined by 3D FLAIR images. Voxel-wise images of fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) were examined by tract-based spatial statistics corrected for gender, age and lesion volume. Metabolites were examined by single-voxel MR-spectroscopy in the NAWM. Fifty-five default mode network connections were examined by rs-fMRI corrected for gender, age, MS subtype and current therapy as covariates. RESULTS: While NFL in paired serum and CSF positively correlated (p = 0.019), there was no correlation between serum and CSF OPN. Higher OPN levels in the CSF but not in the serum showed association with increased brain WM lesion volume (p = 0.009) in 10.3 +/- 2.8 years. Higher OPN in the CSF was associated with reduced FA, increased MD, and reduced RD in different NAWM areas 10.3 +/- 2.8 years later. Higher OPN in the serum and CSF were associated with increased connectivity strength between the medial prefrontal cortex (MPFC) and other regions except with inferior parietal lobule. NFL in the CSF and in the serum was associated with decreased connectivity strength except for ventral MPFC-hippocampal formation. Neither serum OPN nor NFL at the time of the MRI were associated with functional connectivity changes. CONCLUSION: While serum NFL levels reflects CNS production, OPN in serum and CSF may have different cellular sources. OPN within the CSF but not in the serum may forecast development of lesions and microstructural abnormalities in 10 years, indicating the detrimental role of CNS inflammation on the long-term. Although both OPN and NFL in the CSF were associated with functional connectivity changes in 10 years, NFL was associated with decreased strength possibly indicating general axonal loss. In contrast, the positive association of OPN levels in the CSF with increased connectivity strength in 10 years may point to adaptive re-organization due to inflammatory WM lesions and microstructural changes. CI - Copyright (c) 2021. Published by Elsevier B.V. FAU - Orsi, Gergely AU - Orsi G AD - MTA-PTE Clinical Neuroscience MR Research Group, Eotvos Lorand Research Network (ELKH), Pecs, Hungary; Department of Neurology, Medical School, University of Pecs, Pecs, Hungary. FAU - Cseh, Tamas AU - Cseh T AD - Department of Neurology, Medical School, University of Pecs, Pecs, Hungary. FAU - Hayden, Zsofia AU - Hayden Z AD - Department of Immunology and Biotechnology, Medical School, University of Pecs, Pecs, Hungary. FAU - Perlaki, Gabor AU - Perlaki G AD - MTA-PTE Clinical Neuroscience MR Research Group, Eotvos Lorand Research Network (ELKH), Pecs, Hungary; Department of Neurology, Medical School, University of Pecs, Pecs, Hungary. FAU - Nagy, Szilvia Anett AU - Nagy SA AD - MTA-PTE Clinical Neuroscience MR Research Group, Eotvos Lorand Research Network (ELKH), Pecs, Hungary; Department of Neurology, Medical School, University of Pecs, Pecs, Hungary. FAU - Giyab, Omar AU - Giyab O AD - Department of Medical Imaging, Medical School, University of Pecs, Pecs, Hungary. FAU - Olsen, Dorte Aalund AU - Olsen DA AD - Department of Biochemistry and Immunology, Lillebaelt Hospital, University Hospital of Southern Denmark, Vejle, Denmark. FAU - Madsen, Jonna Skov AU - Madsen JS AD - Department of Biochemistry and Immunology, Lillebaelt Hospital, University Hospital of Southern Denmark, Vejle, Denmark; Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark. FAU - Berki, Timea AU - Berki T AD - Department of Immunology and Biotechnology, Medical School, University of Pecs, Pecs, Hungary. FAU - Illes, Zsolt AU - Illes Z AD - Department of Neurology, Medical School, University of Pecs, Pecs, Hungary; Department of Neurology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark. Electronic address: zsolt.illes@rsyd.dk. LA - eng PT - Journal Article DEP - 20210324 PL - Netherlands TA - Mult Scler Relat Disord JT - Multiple sclerosis and related disorders JID - 101580247 RN - 0 (Neurofilament Proteins) RN - 0 (SPP1 protein, human) RN - 106441-73-0 (Osteopontin) SB - IM MH - Brain/diagnostic imaging MH - Humans MH - Intermediate Filaments MH - *Multiple Sclerosis/diagnostic imaging MH - Neurofilament Proteins MH - Osteopontin MH - *White Matter/diagnostic imaging OTO - NOTNLM OT - Diffusion OT - Functional connectivity OT - MR spectroscopy OT - Multiple sclerosis OT - NAWM OT - Neurofilament OT - Osteopontin OT - Resting-state OT - fMRI COIS- Declaration of Competing Interest The Author(s) declare(s) that there is no conflict of interest. EDAT- 2021/04/05 06:00 MHDA- 2021/07/08 06:00 CRDT- 2021/04/04 20:44 PHST- 2021/02/03 00:00 [received] PHST- 2021/03/18 00:00 [revised] PHST- 2021/03/21 00:00 [accepted] PHST- 2021/04/05 06:00 [pubmed] PHST- 2021/07/08 06:00 [medline] PHST- 2021/04/04 20:44 [entrez] AID - S2211-0348(21)00190-5 [pii] AID - 10.1016/j.msard.2021.102923 [doi] PST - ppublish SO - Mult Scler Relat Disord. 2021 Jun;51:102923. doi: 10.1016/j.msard.2021.102923. Epub 2021 Mar 24.