Long-term prognostic value of longitudinal measurements of blood neurofilament levels

Abstract

ObjectiveTo assess the long-term prognostic value of an integral of longitudinal measurements of plasma neurofilament light chain levels (NfLlong) over 12 and 24 months vs single neurofilament light chain (NfL) measurements in patients with relapsing-remitting MS (RRMS) and its additional value when combined with clinical and MRI measures.MethodsThis analysis included continuously fingolimod-treated patients with RRMS from the 24-month FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS)/12-month Trial Assessing Injectable Interferon vs FTY720 Oral in Relapsing–Remitting Multiple Sclerosis (TRANSFORMS) phase 3 trials and their long-term extension, LONGTERMS. Patients were classified into high (≥30 pg/mL, n = 110) and low (<30 pg/mL, n = 164) NfL categories based on the baseline (BL) NfL value or the geometric mean NfLlong calculated over 12 and 24 months to predict disability-related outcomes and brain volume loss (BVL). The additional prognostic value of NfL was quantified using the area under the receiver operating characteristic (ROC) curve.ResultsA single high (vs low) NfL measure at BL was prognostic of a higher risk of reaching Expanded Disability Status Scale (EDSS) score ≥4 earlier (hazard ratio [HR] = 2.19; 95% CI = 1.21–3.97) and higher BVL over 120 months (difference: −1.12%; 95% CI = −2.07 to −0.17). When NfLlong was measured over 24 months, high NfL was associated with a higher risk of reaching EDSS score ≥4 (HR = 7.91; 95% CI = 2.99–20.92), accelerated 6-month confirmed disability worsening (HR = 3.14; 95% CI = 1.38–7.11), and 20% worsening in the Timed 25-Foot Walk Test (HR = 3.05; 95% CI = 1.38–6.70). Area under the ROC curve was consistently highest in models combining NfL with clinical and MRI measures.ConclusionsNfLlong had a higher prognostic value than single NfL assessments on long-term outcomes in RRMS. Combining it with clinical and MRI measures increased sensitivity and specificity to predict long-term disease outcomes.Classification of evidenceThis study provides Class I evidence that NfLlong was more strongly associated with long-term outcomes than single NfL assessments in patients with RRMS.

Therapeutic Response and Possible Biomarkers in Acute Attacks of Neuromyelitis Optica Spectrum Disorders: A Prospective Observational Study

“…Meanwhile, we measured serum biomarkers by MSD other than SIMOA which previous study always applied. Although the concentration of serum biomarkers included NfL and cytokines/chemokines detected in our study was tend to be consistent with that detected by SIMOA in other studies (16,39,41,42), prospective studies are warranted to confirm the current findings.…”

The Evolution of Neurofilament Light Chain in Multiple Sclerosis

“…A composite model including bNfL and T2 lesion load was, therefore, deemed robust for predicting long term disability ( Chitnis et al, 2018 ). A similar conclusion was reached by Häring et al (2020) and Bittner et al (2020) , who measured bNfL and MRI lesion load in 814 individuals with CIS or newly diagnosed MS from 22 centers across Germany.…”

“…Axonal damage resulting in brain volume loss plays a key role in long term disability ( Furby et al, 2008 ; Domingues et al, 2019 ; Marciniewicz et al, 2019 ). As expected, bNfL levels have been used as potential predictors of long-term progression according to the Expanded Disability Status Scale (EDSS; Häring et al, 2020 ), however, findings are inconsistent. A study that included 607 individuals with MS followed up for 12 years, showed a significant increase of 80% in bNfL levels per increase in EDSS score ( Cantó et al, 2019 ).…”

“…Others have instead used percentiles across different ages ( Disanto et al, 2017 ). More recently, authors have been calling for longitudinal measurements of sNfL rather than absolute cut-off values ( Bittner et al, 2020 ; Ferraro et al, 2020 ; Häring et al, 2020 ).…”

Neuropathological and Biomarker Findings in Parkinson’s Disease and Alzheimer’s Disease: From Protein Aggregates to Synaptic Dysfunction

“…Although it is not in the scope of this review, the increasing interest in neurofilaments and markers of neuroinflammation as biomarkers in both AD and PD, needs also to be mentioned. Neurofilament has been identified as a marker of disease progression or prognostic marker in several neurological conditions from multiple sclerosis [ 107 ] to amyotrophic lateral sclerosis [ 108 ] and, importantly also in both AD [ 109 ] and PD [ 110 ]. A major breakthrough in the research of this biomarker has been the demonstration that its levels in plasma significantly correlate with those in the CSF [ 111 ], making it a much more accessible biomarker.…”