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. 2023 Aug;270(8):3851-3861.
doi: 10.1007/s00415-023-11676-4. Epub 2023 Apr 27.

A multimodal marker for cognitive functioning in multiple sclerosis: the role of NfL, GFAP and conventional MRI in predicting cognitive functioning in a prospective clinical cohort

Maureen van Dam  1 , Brigit A de Jong  2 , Eline A J Willemse  3   4 , Ilse M Nauta  2 , Marijn Huiskamp  5 , Martin Klein  6 , Bastiaan Moraal  7 , Sanne de Geus-Driessen  6 , Jeroen J G Geurts  5 , Bernard M J Uitdehaag  2 , Charlotte E Teunissen  3 , Hanneke E Hulst  5   8
Affiliations

A multimodal marker for cognitive functioning in multiple sclerosis: the role of NfL, GFAP and conventional MRI in predicting cognitive functioning in a prospective clinical cohort

Maureen van Dam et al. J Neurol. 2023 Aug.

Abstract

Background: Cognitive impairment in people with MS (PwMS) has primarily been investigated using conventional imaging markers or fluid biomarkers of neurodegeneration separately. However, the single use of these markers do only partially explain the large heterogeneity found in PwMS.

Objective: To investigate the use of multimodal (bio)markers: i.e., serum and cerebrospinal fluid (CSF) levels of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) and conventional imaging markers in predicting cognitive functioning in PwMS.

Methods: Eighty-two PwMS (56 females, disease duration = 14 ± 9 years) underwent neuropsychological and neurological examination, structural magnetic resonance imaging, blood sampling and lumbar puncture. PwMS were classified as cognitively impaired (CI) if scoring ≥ 1.5SD below normative scores on ≥ 20% of test scores. Otherwise, PwMS were defined as cognitively preserved (CP). Association between fluid and imaging (bio)markers were investigated, as well as binary logistics regression to predict cognitive status. Finally, a multimodal marker was calculated using statistically important predictors of cognitive status.

Results: Only higher NfL levels (in serum and CSF) correlated with worse processing speed (r = - 0.286, p = 0.012 and r = - 0.364, p = 0.007, respectively). sNfL added unique variance in the prediction of cognitive status on top of grey matter volume (NGMV), p = 0.002). A multimodal marker of NGMV and sNfL yielded most promising results in predicting cognitive status (sensitivity = 85%, specificity = 58%).

Conclusion: Fluid and imaging (bio)markers reflect different aspects of neurodegeneration and cannot be used interchangeably as markers for cognitive functioning in PwMS. The use of a multimodal marker, i.e., the combination of grey matter volume and sNfL, seems most promising for detecting cognitive deficits in MS.

Keywords: CSF; Cognition; GFAP; MRI; Multiple sclerosis; Neurofilament light; Serum.

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Conflict of interest statement

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.v.D. is supported by a research grant from BMS. I.M.N. is supported by the Dutch MS Research Foundation, grant nr. 15-911. M.H. is supported by the Dutch MS Research Foundation, grant nr. 16-954b. J.J.G.G. has served as a consultant for or received research support from Biogen, Celgene, Genzyme, MedDay, Merck, Novartis and Teva. B.M.J.U. reports personal fees for consultancies from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, and Teva, outside the submitted work. C.E.T. has a collaboration contract with ADx Neurosciences and Quanterix, performed contract research or received grants from AC-Immune, Axon Neurosciences, Biogen, BioOrchestra, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, Grifols, Novo Nordisk, PeopleBio, Quanterix, Roche, Toyama, Vivoryon. She serves on editorial boards of Alzheimer Research and Therapy, and Neurology. H.E.H. serves on the editorial board of Multiple Sclerosis Journal, receives research support from the Dutch MS Research Foundation and the Dutch Research Council. She has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Novartis, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, MedDay and Merck BV. B.A.d.J., E.A.W., M.K., B.M., and S.d.G.D. report no disclosures relevant to the manuscript.

Figures

Fig. 1
Fig. 1
An overview of the included PwMS after applying the in- and exclusion criteria. APwMS were only included if they underwent a performance validity test (Amsterdam Short-Term Memory test) and had reached a sufficient score on this test. PwMS People with MS, SOMSCOG Second Opinion Multiple Sclerosis and Cognition
Fig. 2
Fig. 2
Differences in fluid biomarkers between cognitively preserved (CP) and cognitively impaired (CI) PwMS. Results indicate that sNfL and sGFAP are increased in CI PwMS, compared to CP PwMS (*p < 0.05). For illustrative purposes, the raw (non-transformed, not corrected) values of fluid biomarkers are shown. PwMS people with MS, CP cognitively preserved, CI cognitively impaired, sNfL serum neurofilament light (NfL), sGFAP serum glial fibrillary acidic protein (GFAP), cNfL CSF NfL, cGFAP CSF GFAP
Fig. 3
Fig. 3
An overview of the correlations between fluid biomarkers, imaging markers and cognitive domains. The correlation coefficient is displayed inside the blocks. Only significant correlations are shown in color (after correction for multiple comparisons; in italic if borderline significant). Correlations between cognitive domains and a post-hoc calculated composite score (a combination of significant predictors (sNfL and NGMV)) is depicted on the bottom row. sNfL serum neurofilament light (NfL), sGFAP serum glial fibrillary acidic protein (GFAP), cNfL CSF NfL, cGFAP CSF GFAP, NGMV normalized grey matter volume, NWMV normalized white matter volume, NLV normalized lesion volume, EF executive function
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References

    1. Benedict RHB, Amato MP, DeLuca J, Geurts JJG. Cognitive impairment in multiple sclerosis: clinical management, MRI, and therapeutic avenues. Lancet Neurol. 2020;19(10):860–871. doi: 10.1016/S1474-4422(20)30277-5. - DOI - PMC - PubMed
    1. Eijlers AJ, et al. Predicting cognitive decline in multiple sclerosis: a 5-year follow-up study. Brain. 2018;141(9):2605–2618. - PubMed
    1. Schoonheim MM, et al. Disability in multiple sclerosis is related to thalamic connectivity and cortical network atrophy. Mult Scler J. 2021;28(1):61–70. doi: 10.1177/13524585211008743. - DOI - PubMed
    1. Di Filippo M, Portaccio E, Mancini A, Calabresi P. Multiple sclerosis and cognition: synaptic failure and network dysfunction. Nat Rev Neurosci. 2018;19(10):599–609. doi: 10.1038/s41583-018-0053-9. - DOI - PubMed
    1. Zivadinov R, et al. Clinical relevance of brain atrophy assessment in multiple sclerosis. Implications for its use in a clinical routine. Expert Rev Neurother. 2016;16(7):777–793. doi: 10.1080/14737175.2016.1181543. - DOI - PubMed