Human herpesvirus 6A and axonal injury before the clinical onset of multiple sclerosis
(2024) In Brain 147(1). p.177-185- Abstract
Recent research indicates that multiple sclerosis is preceded by a prodromal phase with elevated levels of serum neurofilament light chain (sNfL), a marker of axonal injury. The effect of environmental risk factors on the extent of axonal injury during this prodrome is unknown. Human herpesvirus 6A (HHV-6A) is associated with an increased risk of developing multiple sclerosis. The objective of this study was to determine if HHV-6A serostatus is associated with the level of sNfL in the multiple sclerosis prodrome, which would support a causative role of HHV-6A. A nested case-control study was performed by crosslinking multiple sclerosis registries with Swedish biobanks. Individuals with biobank samples collected before the clinical onset... (More)
Recent research indicates that multiple sclerosis is preceded by a prodromal phase with elevated levels of serum neurofilament light chain (sNfL), a marker of axonal injury. The effect of environmental risk factors on the extent of axonal injury during this prodrome is unknown. Human herpesvirus 6A (HHV-6A) is associated with an increased risk of developing multiple sclerosis. The objective of this study was to determine if HHV-6A serostatus is associated with the level of sNfL in the multiple sclerosis prodrome, which would support a causative role of HHV-6A. A nested case-control study was performed by crosslinking multiple sclerosis registries with Swedish biobanks. Individuals with biobank samples collected before the clinical onset of multiple sclerosis were included as cases. Controls without multiple sclerosis were randomly selected, matched for biobank, sex, sampling date and age. Serostatus of HHV-6A and Epstein-Barr virus was analysed with a bead-based multiplex assay. The concentration of sNfL was analysed with single molecule array technology. The association between HHV-6A serology and sNfL was assessed by stratified t-tests and linear regressions, adjusted for Epstein-Barr virus serostatus and sampling age. Within-pair ratios of HHV-6A seroreactivity and sNfL were calculated for each case and its matched control. To assess the temporal relationship between HHV-6A antibodies and sNfL, these ratios were plotted against the time to the clinical onset of multiple sclerosis and compared using locally estimated scatterplot smoothing regressions with 95% confidence intervals (CI). Samples from 519 matched case-control pairs were included. In cases, seropositivity of HHV-6A was significantly associated with the level of sNfL (+11%, 95% CI 0.2-24%, P = 0.045) and most pronounced in the younger half of the cases (+24%, 95% CI 6-45%, P = 0.007). No such associations were observed among the controls. Increasing seroreactivity against HHV-6A was detectable before the rise of sNfL (significant within-pair ratios from 13.6 years versus 6.6 years before the clinical onset of multiple sclerosis). In this study, we describe the association between HHV-6A antibodies and the degree of axonal injury in the multiple sclerosis prodrome. The findings indicate that elevated HHV-6A antibodies both precede and are associated with a higher degree of axonal injury, supporting the hypothesis that HHV-6A infection may contribute to multiple sclerosis development in a proportion of cases.
(Less)
- author
- organization
- publishing date
- 2024-01
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- axonal injury, Epstein-Barr virus, human herpesvirus 6-A, multiple sclerosis, neurofilament light chain
- in
- Brain
- volume
- 147
- issue
- 1
- pages
- 9 pages
- publisher
- Oxford University Press
- external identifiers
-
- pmid:37930324
- scopus:85181761078
- ISSN
- 0006-8950
- DOI
- 10.1093/brain/awad374
- language
- English
- LU publication?
- yes
- id
- a399ecf7-b216-4865-8a21-669b16c7fc16
- date added to LUP
- 2024-02-13 11:57:21
- date last changed
- 2024-04-14 22:45:23
@article{a399ecf7-b216-4865-8a21-669b16c7fc16,
abstract = {{<p>Recent research indicates that multiple sclerosis is preceded by a prodromal phase with elevated levels of serum neurofilament light chain (sNfL), a marker of axonal injury. The effect of environmental risk factors on the extent of axonal injury during this prodrome is unknown. Human herpesvirus 6A (HHV-6A) is associated with an increased risk of developing multiple sclerosis. The objective of this study was to determine if HHV-6A serostatus is associated with the level of sNfL in the multiple sclerosis prodrome, which would support a causative role of HHV-6A. A nested case-control study was performed by crosslinking multiple sclerosis registries with Swedish biobanks. Individuals with biobank samples collected before the clinical onset of multiple sclerosis were included as cases. Controls without multiple sclerosis were randomly selected, matched for biobank, sex, sampling date and age. Serostatus of HHV-6A and Epstein-Barr virus was analysed with a bead-based multiplex assay. The concentration of sNfL was analysed with single molecule array technology. The association between HHV-6A serology and sNfL was assessed by stratified t-tests and linear regressions, adjusted for Epstein-Barr virus serostatus and sampling age. Within-pair ratios of HHV-6A seroreactivity and sNfL were calculated for each case and its matched control. To assess the temporal relationship between HHV-6A antibodies and sNfL, these ratios were plotted against the time to the clinical onset of multiple sclerosis and compared using locally estimated scatterplot smoothing regressions with 95% confidence intervals (CI). Samples from 519 matched case-control pairs were included. In cases, seropositivity of HHV-6A was significantly associated with the level of sNfL (+11%, 95% CI 0.2-24%, P = 0.045) and most pronounced in the younger half of the cases (+24%, 95% CI 6-45%, P = 0.007). No such associations were observed among the controls. Increasing seroreactivity against HHV-6A was detectable before the rise of sNfL (significant within-pair ratios from 13.6 years versus 6.6 years before the clinical onset of multiple sclerosis). In this study, we describe the association between HHV-6A antibodies and the degree of axonal injury in the multiple sclerosis prodrome. The findings indicate that elevated HHV-6A antibodies both precede and are associated with a higher degree of axonal injury, supporting the hypothesis that HHV-6A infection may contribute to multiple sclerosis development in a proportion of cases.</p>}},
author = {{Grut, Viktor and Biström, Martin and Salzer, Jonatan and Stridh, Pernilla and Jons, Daniel and Gustafsson, Rasmus and Fogdell-Hahn, Anna and Huang, Jesse and Butt, Julia and Lindam, Anna and Alonso-Magdalena, Lucia and Bergström, Tomas and Kockum, Ingrid and Waterboer, Tim and Olsson, Tomas and Zetterberg, Henrik and Blennow, Kaj and Andersen, Oluf and Nilsson, Staffan and Sundström, Peter}},
issn = {{0006-8950}},
keywords = {{axonal injury; Epstein-Barr virus; human herpesvirus 6-A; multiple sclerosis; neurofilament light chain}},
language = {{eng}},
number = {{1}},
pages = {{177--185}},
publisher = {{Oxford University Press}},
series = {{Brain}},
title = {{Human herpesvirus 6A and axonal injury before the clinical onset of multiple sclerosis}},
url = {{http://dx.doi.org/10.1093/brain/awad374}},
doi = {{10.1093/brain/awad374}},
volume = {{147}},
year = {{2024}},
}