Neurofilament levels are associated with blood–brain barrier integrity, lymphocyte extravasation, and risk factors following the first demyelinating event in multiple sclerosis

Abstract

Background: Increased blood brain barrier (BBB) permeability, CNS inflammation and neuroaxonal damage are pathological hallmarks in early multiple sclerosis (MS). Objective: To investigate the associations of neurofilament light chain (NfL) levels with measures of BBB integrity and central nervous system (CNS) inflammation in MS during the first demyelinating event. Methods: Blood and cerebrospinal fluid (CSF) were obtained from 142 MS (McDonald 2017) treatment-naive patients from the SET study (63% female; age: 29.7 ± 7.9 years) following the disease onset. NfL, albumin, immunoglobulin G (IgG), and immunoglobulin M (IgM) levels were measured in CSF and blood samples. Albumin quotient was computed as a marker of BBB integrity. Immune cell subset counts in CSF were measured using flow cytometry. MS risk factors, such as Human leukocyte antigen DRB1 locus gene ( HLA DRB1)*1501, anti-Epstein–Barr virus (EBV) antibodies, and 25-hydroxy vitamin D3, were also measured. Results: Higher serum NfL (sNfL) levels were associated with higher albumin quotient ( p < 0.001), CSF CD80+ ( p = 0.012), and CD80+ CD19+ ( p = 0.015) cell frequency. sNfL levels were also associated with contrast-enhancing and T2 lesions on brain magnetic resonance imaging (MRI; all p ⩽ 0.001). Albumin quotient was not associated with any of the MS risk factors assessed. sNfL levels were associated with anti-EBV viral capsid antigen (VCA) IgG levels ( p = 0.0026). Conclusion: sNfL levels during the first demyelinating event of MS are associated with greater impairment of BBB integrity, immune cell extravasation, and brain lesion activity on MRI.

Altered CSF Albumin Quotient Links Peripheral Inflammation and Brain Damage in MS

“…The higher concentration of IgG and IgA observed in patients with MS with increased QAlb, as well as the higher frequency of monocytes, the higher amount of IFNg and the lower frequency of potentially protective Th2 CD4+ T cells might facilitate CNS damage in these patients. Accordingly, our results demonstrate that patients with MS with increased QAlb show significantly higher levels of biomarkers of CNS damage and inflammation such as NF-L and CHI3L1 and support previous studies, in which increased QAlb in patients with MS was found to be associated with atrophy and greater deterioration 7,8 as well as higher levels of serum NF-L. 18 In addition, we identified 10 intrathecal lipid species that are more abundant in patients with MS with increased QAlb.…”

Blood neurofilament light: a critical review of its application to neurologic disease

“…38,39 Patients with the highest CSF/serum albumin ratio also had the highest CSF and blood NfL levels, 40,41 suggesting that an altered permeability of the BCB contributes to serum NfL, though this relationship was not observed in all studies. [40][41][42][43] Of note, there is increased disruption of the BBB with aging which may contribute to the increased levels of blood NfL with age-related neurodegenerative diseases. 37 Investigation of the correlation between the NfL levels in CSF and blood was used to establish that blood NfL measurements accurately reflected what was happening in CNS ( Table 3).…”

“…Explorative works used the ratio between CSF and serum albumin as an estimation of the BBB permeability although this ratio is a marker of blood CSF barrier (BCB) and should be interpreted as such 38,39 . Patients with the highest CSF/serum albumin ratio also had the highest CSF and blood NfL levels, 40,41 suggesting that an altered permeability of the BCB contributes to serum NfL, though this relationship was not observed in all studies 40–43 . Of note, there is increased disruption of the BBB with aging which may contribute to the increased levels of blood NfL with age‐related neurodegenerative diseases 37 …”

Blood Neurofilament Light Chain: The Neurologist’s Troponin?

“…Blood–brain barrier permeability itself may be a confounder; neurofilament quotient in blood compared to CSF could be selectively increased following periods of inflammation such as that seen in MS relapse, positively skewing blood NfL levels. Two recent studies on this topic in MS patients present conflicting results [ 14 , 15 ].…”