Interpretation

Blood neurofilament light chain (NfL) is a non-specific marker of neuro-axonal injury showing promising associations with outcomes in several neurological conditions. In neurodegenerative diseases, NfL may also serve as a prognostic marker of decline and an efficacy biomarker of experimental therapies. In a meta-analysis of Alzheimer disease (AD), frontotemporal dementia, and amyotrophic lateral sclerosis (ALS), plasma NfL levels were elevated in patients compared to controls with utility in differentiating neurodegenerative conditions from non-neurodegenerative mimics. However, due to a lack of specificity to a particular neurodegenerative disease, its role as a diagnostic marker is limited.

In multiple sclerosis (MS), NfL is elevated in the blood of newly diagnosed patients and concentrations correlate with disease severity and prognosis. However, measured circulating NfL in patients with MS often overlaps with concentrations found in healthy individuals, potentially limiting its utility. Early measures of blood NfL in patients newly diagnosed with MS can predict brain atrophy and lesion load on magnetic resonance imaging. The use of blood NfL in serial disease monitoring and treatment response has been evaluated in various prospective clinical trials. Reductions in NfL concentrations after different treatments tend to follow the hierarchy of treatment efficacy, with greatest reductions observed with the most intensive treatments. A study that included over 1000 patients with MS receiving various treatments, reported the largest reductions in plasma NfL concentrations following alemtuzumab treatment (54% reduction), and the smallest reduction with teriflunomide treatment (7%).

Pediatric-onset MS prevalence and incidence rates are increasing globally. Between 3% and 10% of patients with MS present under 16 years of age. Guidelines for pediatric MS recommend that treatment can be started early in the disease course. Circulating NfL is a useful biomarker for monitoring disease activity and treatment response in pediatric MS. It is most likely helpful to predict disease severity and to guide treatment decisions in patients with pediatric MS. Elevated blood NfL levels were significantly associated with higher numbers of cerebral and spinal MRI lesions at baseline. High concentrations of blood NfL (>100 pg/mL) are predictive of disease events within four months.

In AD, blood NfL concentrations have been shown to correlate with cortical thinning and cognitive decline in both sporadic and familial AD. While there are elevations of NfL in patients with AD, at this point the clinical value of blood NfL is not fully understood, especially in light of the availability of other more sensitive and specific biomarkers for AD.

Circulating NfL has been evaluated both in the context of mild traumatic brain injury (mTBI) diagnosis (acute setting) and prognosis (outcome prediction). In the acute setting, the utility of NfL in identifying mTBI within 24 hours of an injury has been controversial, likely due to the different timepoints used in studies for evaluating NfL concentrations after the injury (ranging from 1-, 4-, 6-, 12-, and 24-hours post-injury). A recent 2022 review describes the findings of six different publications looking at the role of NfL in acute mTBI. Three out of four studies involving athletes reported data supporting the efficacy of NfL in identifying mTBI within 24 hours of an injury. However, studies using either military cadets or emergency department patients presenting with possible mTBI as subjects did not show evidence supporting NfL use in the acute setting. As a prognostic marker, data has been inconclusive as to whether NfL is able to predict recovery time, post-concussion syndrome, or potential return to sport after mTBI.

In ALS, NfL concentrations have been suggested to be able to discriminate ALS from ALS-mimics. NfL levels at symptom onset may be prognostic of disease progression rate and may be used to stratify patients into groups with a similar prognosis in clinical trials. Blood NfL concentrations remain relatively stable throughout the disease. The US Food and Drug Administration has approved Qalsody (tofersen) to treat patients with ALS associated with a genetic variant in the superoxide dismutase 1 (SOD1) gene. The approval was based on a reduction in plasma NfL at the end treatment compared to the placebo arm. Therefore, NfL might be a useful biomarker of assess effectiveness of some ALS therapies.

Parkinson disease (PD) patients with elevated NfL concentrations have been reported to have worse cognitive decline, brain cortical atrophy, and motor scores. Blood NfL concentrations in atypical forms of Parkinson disease are higher than in PD and may be used to help differentiate PD from atypical parkinsonian disorders.

In frontotemporal dementia (FTD), blood NfL was able to discriminate patients with the behavioral form of FTD from patients with primary psychiatric disorders. It has been suggested that blood NfL could be used to support the diagnosis of the behavioral form of FTD, monitor disease progression, and prognosis of FTD.

A study that evaluated blood NfL concentrations in 13 neurodegenerative disorders, Down syndrome, depression, and cognitive normal controls showed that plasma NfL concentrations were elevated in all cortical neurodegenerative disorders, ALS, and atypical parkinsonian disorders. Plasma NfL was clinically useful in differentiating atypical parkinsonian disorders from PD, in identifying dementia in Down syndrome, distinguishing neurodegenerative disorders from depression in older adults, and potentially identifying frontotemporal dementia in patients with cognitive impairment. Individuals with ALS, FTD, and Down syndrome with AD presented with the highest concentrations of plasma NfL.