High levels of kappa free light chain synthesis predict cognitive decline in relapsing-remitting multiple sclerosis

Igal Rosenstein; Markus Axelsson; Lenka Novakova; Sofia Rasch; Kaj Blennow; Henrik Zetterberg; Jan Lycke

doi:10.3389/fimmu.2023.1106028

High levels of kappa free light chain synthesis predict cognitive decline in relapsing-remitting multiple sclerosis

Front Immunol. 2023 Jan 20:14:1106028. doi: 10.3389/fimmu.2023.1106028. eCollection 2023.

Authors

Igal Rosenstein¹, Markus Axelsson¹, Lenka Novakova¹, Sofia Rasch², Kaj Blennow^{2

3}, Henrik Zetterberg^{2

3

4

5

6

7}, Jan Lycke¹

Affiliations

¹ Department of Clinical Neuroscience, Institute of Neuroscience and Physiology at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
² Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
³ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Mölndal, Sweden.
⁴ United Kingdom (UK) Dementia Research Institute at University College London (UCL), London, United Kingdom.
⁵ Department of Neurodegenerative Disease, University College London (UCL) Queen Square Institute of Neurology, London, United Kingdom.
⁶ Hong Kong Centre for Neurodegenerative Diseases, Hong Kong SAR, China.
⁷ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States.

Abstract

Background: Evolving evidence suggests that measurement of cerebrospinal fluid (CSF) kappa free light chain (KFLC) synthesis has high diagnostic sensitivity and specificity for multiple sclerosis (MS), but its prognostic ability is less investigated. The usefulness of KFLC in predicting cognitive impairment (CI) is still unknown.

Methods: In a monocentric longitudinal retrospecitve cohort study, KFLC-index ([CSF KFLC/serum KFLC]/[CSF albumin/serum albumin]) measured by latex-enhanced immunonephelometry was prospectively determined as part of the diagnostic workup in patients with early relapsing-remitting MS (RRMS, n=77). The ability of KFLC-index to predict information processing speed (IPS) worsening as assessed with the symbol digit modalities test (SDMT) was investigated in univariable and multivariable models.

Results: In patients with KFLC-index>100 (n=31), 11 subjects (35.5%) showed reduced SDMT scores by ≥8 points at follow-up (mean follow-up time 7.3 ± 2.6 years), compared with their baseline scores (p=0.01). Baseline KFLC-index>100 was strongly associated with a higher hazard of SDMT score reduction at follow-up (adjusted hazard ratio 10.5, 95% confidence interval 2.2-50.8, p=0.003; median time to SDMT reduction 7 years).

Conclusion: Intrathecal KFLC synthesis has become an attractive diagnostic tool for MS. We show for the first time that in a real-world setting of early RRMS, KFLC-index predicted cognitive decline. Whether this predictive ability of KFLC-index also concerns other cognitive domains than IPS, warrants further investigations.

Keywords: biomarkers; cognitive impairment (CI); kappa free light chains; multiple sclerosis; symbol digit modalities test (SDMT).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cognitive Dysfunction* / diagnosis
Cohort Studies
Humans
Immunoglobulin kappa-Chains / cerebrospinal fluid
Multiple Sclerosis* / diagnosis
Multiple Sclerosis, Relapsing-Remitting* / diagnosis

Substances

Immunoglobulin kappa-Chains

Grants and funding

The study was supported by grants from the Swedish State Support for Clinical Research (ALFGBG-722081, ALFGBG-71320), Regional FoU grant Västra Götalandsregionen (260 101), NEURO Sweden, NEURO Gothenburg, Edith Jacobson’s Foundation and Helena Ahlin’s Foundation. KB is supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615), the Swedish Alzheimer Foundation (#AF-930351, #AF-939721 and #AF-968270), Hjärnfonden, Sweden (#FO2017-0243 and #ALZ2022-0006), the Swedish state under the agreement betweenthe Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986 and #ALFGBG-965240), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the National Institute of Health (NIH), USA, (grant #1R01AG068398-01), and the Alzheimer’s Association 2021 Zenith Award (ZEN-21-848495).HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712 and #101053962), Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21-831376-C, #ADSF-21- 831381-C and #ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2019-0228), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska- Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021-00694), and the UK Dementia Research Institute at UCL (UKDRI-1003).