Neurofilament Light: A Promising Biomarker in Brain Health

Neurofilament light (NfL) is emerging as a key biomarker for brain health, offering insights into neurological and psychiatric conditions. Found in neurons, its presence in blood and cerebrospinal fluid signals damage or degeneration, making it valuable for early diagnosis and disease monitoring.

With growing research supporting its clinical relevance, NfL could improve how brain disorders are detected and tracked. Understanding its structure, detection methods, and role in various conditions highlights its potential compared to other biomarkers.

Structural Profile

Neurofilament light (NfL) is a key component of the neuronal cytoskeleton, maintaining axonal integrity and aiding intracellular transport. It is the smallest of the three major neurofilament subunits—alongside neurofilament heavy (NFH) and neurofilament medium (NFM)—but is highly abundant in myelinated axons. Its structure includes a central α-helical rod domain flanked by N- and C-terminal regions, which contribute to filament assembly and interactions with other cytoskeletal elements. NfL forms heteropolymers with NFH and NFM, creating a stable scaffold that supports axonal caliber and conduction velocity.

Neurofilaments undergo a regulated cycle of assembly, transport, and degradation to maintain axonal stability. Phosphorylation influences NfL’s interactions with other cytoskeletal proteins, affecting solubility and turnover. While this modification helps maintain structural integrity, its dysregulation can lead to abnormal accumulation or increased degradation. Studies link altered phosphorylation states of NfL to axonal damage, reinforcing its sensitivity as an indicator of neuronal injury.

Axonal transport further underscores NfL’s structural role. Unlike microtubules, which facilitate rapid vesicular transport, neurofilaments move in a slower, intermittent manner known as “stop-and-go” transport, ensuring even distribution along axons. Disruptions in this system, whether from genetic mutations or external insults, can lead to axonal degeneration and increased NfL release into extracellular fluids. Research confirms that elevated NfL levels correlate with axonal damage in various neurological conditions, reinforcing its role as a marker of neuronal integrity.

Laboratory Detection

Measuring neurofilament light (NfL) in biological fluids requires highly sensitive techniques due to its low baseline concentration in healthy individuals. Advances in immunoassay technologies have significantly improved detection, particularly in blood and cerebrospinal fluid (CSF). While CSF remains the gold standard due to its direct contact with the central nervous system, blood-based assays offer a more practical alternative. The development of ultrasensitive immunoassays, such as the single-molecule array (Simoa), has revolutionized NfL detection by enabling precise quantification in serum and plasma, reducing reliance on invasive lumbar punctures.

The Simoa platform detects NfL at femtomolar concentrations, surpassing conventional enzyme-linked immunosorbent assays (ELISA) in sensitivity. Large-scale clinical studies have shown that blood NfL levels strongly correlate with CSF concentrations, reinforcing its reliability for monitoring neuronal injury. Other detection methods, including electrochemiluminescence immunoassays (ECLIA) and mass spectrometry, have also been explored, though Simoa remains the most widely adopted due to its superior sensitivity. The ability to measure NfL in peripheral blood has expanded its diagnostic use, allowing for longitudinal monitoring of disease progression and treatment response.

Pre-analytical variables influence NfL measurements, necessitating standardized protocols for sample collection, processing, and storage. Studies show that NfL remains stable in serum and plasma when stored at -80°C. Hemolysis, which releases intracellular components from erythrocytes, can artificially elevate NfL readings, emphasizing the need for proper sample handling. Factors such as age and body mass index (BMI) also affect baseline NfL concentrations, requiring reference ranges tailored to specific populations. Efforts to harmonize assay methodologies across laboratories aim to improve cross-study comparability for consistent clinical interpretation.

Relevance in Neurological Disorders

Neurofilament light (NfL) serves as a marker of axonal damage, with elevated levels reflecting neurodegeneration across various conditions. Progressive diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, and multiple sclerosis (MS) consistently show increased NfL concentrations in CSF and blood, correlating with disease severity and progression. In ALS, higher NfL levels are linked to faster functional decline and shorter survival. In Alzheimer’s disease, rising NfL levels track with cognitive impairment and brain atrophy, complementing traditional amyloid and tau biomarkers.

In demyelinating disorders like MS, NfL fluctuations provide insight into both inflammatory activity and long-term neuronal loss. Clinical trials show that effective treatment reduces NfL levels, suggesting its role as a surrogate marker for therapeutic response. In relapsing-remitting MS, elevated NfL levels often precede clinical relapse and MRI-detected lesions, highlighting its potential for early detection and prognosis.

Beyond MS, traumatic brain injury (TBI) is another condition where NfL indicates neuronal damage. Research on professional athletes has shown that even mild repetitive head impacts can cause sustained NfL elevations, raising concerns about long-term neurological consequences in contact sports.

In cerebrovascular diseases such as stroke, post-stroke NfL levels correlate with infarct size and predict long-term recovery, complementing imaging techniques. In Parkinson’s and Huntington’s diseases, where neurodegeneration affects specific neuronal populations, NfL helps track disease progression. Its ability to reflect real-time neuronal injury makes it valuable in clinical trials assessing neuroprotective strategies.

Utilization in Psychiatric Settings

Although traditionally linked to neurodegenerative diseases, neurofilament light (NfL) is gaining relevance in psychiatric disorders where subtle neurobiological changes occur. Schizophrenia, bipolar disorder, and major depressive disorder (MDD) have been associated with structural brain abnormalities, with evidence suggesting axonal damage may contribute to disease progression. Elevated NfL levels in individuals with first-episode psychosis suggest neuronal injury may precede overt clinical symptoms, raising the possibility of using NfL as an early marker for identifying individuals at risk of severe psychiatric conditions.

Longitudinal studies suggest NfL fluctuations may correspond with symptom severity or treatment response. In bipolar disorder, transient increases in NfL during manic episodes may reflect heightened neuronal stress. In treatment-resistant depression, persistently high NfL levels have been linked to poorer responses to conventional antidepressants, hinting at a neurobiological component that could inform more targeted therapeutic strategies. While psychiatric disorders have historically been diagnosed based on clinical observation, biomarkers like NfL could introduce a more objective dimension to assessment, aiding in differentiation between primary psychiatric conditions and those with underlying neurodegenerative components.

Comparison With Other Markers

Comparing neurofilament light (NfL) with other biomarkers highlights its advantages and limitations in neurological and psychiatric assessments. While NfL reflects axonal injury, other biomarkers such as tau, amyloid-beta, and glial fibrillary acidic protein (GFAP) capture different aspects of neurodegeneration and neuroinflammation. Each has distinct applications, influencing their utility in clinical and research settings.

Tau proteins, particularly phosphorylated tau (p-tau), are closely associated with Alzheimer’s disease and other tauopathies. Unlike NfL, which reflects broad axonal injury across multiple disorders, p-tau is more disease-specific. While both can be detected in cerebrospinal fluid and blood, p-tau is more predictive of Alzheimer’s-type neurodegeneration, whereas NfL provides a broader measure of neuronal damage. Amyloid-beta, another key biomarker in Alzheimer’s research, differs in function. Its accumulation in plaques is a hallmark of disease pathology, but its presence does not necessarily correlate with active neurodegeneration. In contrast, NfL levels respond dynamically to neuronal injury, making it a more immediate marker for tracking disease progression.

GFAP, a glial-derived biomarker, reflects astrocytic activation and neuroinflammation. Studies show GFAP levels often rise alongside NfL in conditions like multiple sclerosis and traumatic brain injury, suggesting both provide valuable but distinct information. While GFAP highlights glial reactivity, NfL is more directly tied to axonal integrity, making them useful in combination for assessing neurodegenerative processes. The increasing availability of ultrasensitive assays has enhanced the feasibility of measuring these biomarkers in blood, but NfL’s strong correlation with cerebrospinal fluid concentrations gives it a practical edge for non-invasive monitoring. By integrating NfL with other biomarkers, clinicians can achieve a more comprehensive understanding of disease mechanisms, improving diagnostic accuracy and treatment strategies.