What is Plasma NFL (Neurofilament Light Chain)?
Plasma NFL is a blood-based biomarker that measures neuroaxonal injury and reflects the degree of neurodegeneration occurring in the central nervous system across various neurological conditions. 1, 2
Core Function and Biology
NFL is a neuronal cytoskeletal protein that is released into cerebrospinal fluid and blood when neurons are damaged, making it a direct marker of active axonal destruction. 1, 2
The protein is highly expressed in large caliber myelinated axons, and its concentration in blood correlates strongly with CSF levels, allowing blood sampling to replace lumbar puncture for this specific biomarker. 1
Plasma NFL can be measured using highly sensitive immunoassays (such as SIMOA platform) that detect ultralow concentrations, making it practical for routine clinical use. 3, 2
Primary Clinical Applications
Diagnostic Differentiation
Plasma NFL effectively distinguishes neurodegenerative diseases from psychiatric disorders, with CSF NFL achieving an AUC of 0.93 in discriminating behavioral variant frontotemporal dementia from primary psychiatric disorders. 1, 4
In Creutzfeldt-Jakob disease screening, plasma NFL shows diagnostic utility in differentiating rapidly progressive dementias from other conditions, though plasma tau may perform slightly better in this specific context. 1
For suspected functional neurological disorders versus organic neurodegeneration, normal or minimally elevated NFL favors functional disorder, while significantly elevated levels indicate active neurodegenerative processes. 4
Disease Monitoring and Prognosis
In multiple sclerosis, serum NFL serves as a monitoring tool for disease activity, treatment efficacy, and prediction of subclinical disease progression and relapse risk. 5
In amyotrophic lateral sclerosis, both plasma and CSF NFL demonstrate excellent prognostic performance, with higher baseline levels predicting shorter survival (highest tertile vs. lowest: HR 4.58 for CSF, HR 2.59 for plasma). 3
In familial Alzheimer's disease, blood NFL begins rising approximately 10 years before symptom onset, marking the beginning of neurodegeneration and predicting rate of clinical progression. 1, 6
Trial Screening and Drug Monitoring
Plasma NFL is increasingly used as a pre-screener in clinical trials to identify individuals with active neurodegeneration who are more likely to have underlying pathology requiring confirmation with PET or CSF. 1
In disease-modifying treatment trials for multiple sclerosis, spinal muscular atrophy, and HIV-associated neurocognitive dysfunction, decreasing plasma NFL concentrations indicate reduced neurodegeneration and treatment response. 1, 5
Disease-Specific Elevation Patterns
Highest elevations occur in: amyotrophic lateral sclerosis, frontotemporal dementia, atypical parkinsonian disorders, multiple sclerosis, and HIV-associated neurocognitive dysfunction. 1, 2
Modest elevations occur in: Alzheimer's disease, particularly at more advanced dementia stages, with associations to amyloid and tau positivity. 1, 6
In sporadic Alzheimer's disease, the overlap between disease stages is larger than in familial AD due to multiple age-related changes contributing to NFL elevation in individuals over 70 years. 1, 6
Critical Interpretation Considerations
Age Relationship
Age is the single most important confounding factor when interpreting plasma NFL, with a strong age-dependent increase that complicates evaluation, especially in patients over 70 years old. 1, 6, 4
Values that would be pathological in younger individuals may represent normal aging in older adults, requiring age-adjusted reference ranges for accurate interpretation. 6, 4
Other Confounding Factors
Peripheral neuropathies, body mass index, and renal disease can all influence plasma NFL levels independent of CNS pathology. 1, 4, 7
Despite these confounders, plasma NFL has strong pre-analytical robustness and is relatively unaffected by common variations in sample handling, room temperature exposure (up to 8 days), or repetitive freeze-thaw cycles (up to 4 cycles). 1, 8
Key Limitations
Plasma NFL is not disease-specific—it reflects only the degree of neuronal damage, not the underlying pathology, limiting its use as a standalone diagnostic tool. 6, 4
The biomarker shows stable levels during disease course in established disease (such as ALS), making it less useful for tracking short-term progression but valuable for monitoring treatment effects. 3
In very early neurodegenerative disease, NFL may be normal before significant neuronal damage occurs, potentially missing earliest disease stages. 9
Practical Clinical Algorithm
When ordering plasma NFL:
Always adjust interpretation for patient age using age-specific reference ranges. 6, 4
Evaluate confounding factors: check renal function, assess for peripheral neuropathy, and consider BMI effects. 1, 4
Combine with other biomarkers when available (such as plasma p-tau or GFAP) for improved diagnostic accuracy, as NFL alone cannot identify specific pathology. 6, 4
For differential diagnosis: significantly elevated NFL indicates organic neurodegeneration; normal/minimally elevated NFL favors functional disorders or very early disease. 4
For monitoring: use serial measurements to track treatment response or disease progression, recognizing that changes are more meaningful than single values. 5
Common Pitfalls to Avoid
Never interpret NFL in isolation—it must be combined with clinical findings, imaging, and other biomarkers to determine specific diagnosis. 4, 9
Do not neglect age adjustment—failure to account for age-related increases leads to false positives in older adults. 6, 4
Do not dismiss early neurodegeneration based solely on normal NFL—initial disease stages may present with normal levels before substantial axonal damage. 9
Do not assume AD-specificity—in dementia evaluation, high NFL with normal p-tau may suggest non-AD dementia with substantial axonal degeneration rather than Alzheimer's disease. 6