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

Journal of Neurology, vol. 270, pp. 3851–3861

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.

Authors 12

1. Maureen van Dam corresponding

   Amsterdam Neuroscience · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

   Affiliation as printed

   MS Center Amsterdam, Anatomy and Neurosciences, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands. m.vandam2@amsterdamumc.nl

   MS Center Amsterdam, Anatomy and Neurosciences, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands

2. Brigit A. de Jong

   Amsterdam Neuroscience · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

   Affiliation as printed

   MS Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands

3. Eline A.J. Willemse

   University of Basel · University Hospital of Basel · Amsterdam Neuroscience · Amsterdam University Medical Centers · Vrije Universiteit Amsterdam

   Affiliation as printed

   Neurochemistry Lab, Department of Clinical Chemistry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, De Boelelaan 1117, Amsterdam, The Netherlands

   Neurology Clinic and Policlinic, Departments of Head, Spine and Neuromedicine, Biomedicine and Clinical Research, Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), University Hospital Basel, University of Basel, Basel, Switzerland

4. Ilse M. Nauta

   Amsterdam Neuroscience · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

   Affiliation as printed

   MS Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands

5. Marijn Huiskamp

   Amsterdam Neuroscience · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

   Affiliation as printed

   MS Center Amsterdam, Anatomy and Neurosciences, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands

6. Martin Klein

   Amsterdam Neuroscience · Amsterdam University Medical Centers · Vrije Universiteit Amsterdam

   Affiliation as printed

   Department of Medical Psychology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, De Boelelaan 1117, Amsterdam, The Netherlands

7. Bastiaan Moraal

   Amsterdam Neuroscience · Amsterdam University Medical Centers · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

   Affiliation as printed

   Department of Radiology and Nuclear Medicine, MS Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, De Boelelaan 1117, Amsterdam, The Netherlands

8. Sanne de Geus-Driessen

   Amsterdam Neuroscience · Amsterdam University Medical Centers · Vrije Universiteit Amsterdam

   Affiliation as printed

   Department of Medical Psychology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, De Boelelaan 1117, Amsterdam, The Netherlands

9. Jeroen J.G. Geurts

   Amsterdam Neuroscience · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

   Affiliation as printed

   MS Center Amsterdam, Anatomy and Neurosciences, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands

10. Bernard M.J. Uitdehaag

    Amsterdam Neuroscience · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

    Affiliation as printed

    MS Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands

11. Charlotte Elisabeth Teunissen

    Amsterdam Neuroscience · Amsterdam University Medical Centers · Vrije Universiteit Amsterdam

    Affiliation as printed

    Neurochemistry Lab, Department of Clinical Chemistry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, De Boelelaan 1117, Amsterdam, The Netherlands

12. Hanneke E. Hulst Aachen Institute of Psychology, Health Medical and Neuropsychology Unit

    Leiden University · Amsterdam Neuroscience · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

    Affiliation as printed

    Institute of Psychology, Health, Medical and Neuropsychology Unit, Leiden University, Wassenaarseweg 52, Leiden, The Netherlands

    MS Center Amsterdam, Anatomy and Neurosciences, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands