What is the role of Neurofilament light chain (NfL) in assessing and managing neurodegenerative diseases like frontotemporal dementia?

The Role of Neurofilament Light Chain (NfL) in Assessing and Managing Neurodegenerative Diseases

Neurofilament light chain (NfL) is a valuable biomarker for diagnosing and monitoring frontotemporal dementia (FTD), with high diagnostic accuracy in distinguishing FTD from psychiatric disorders (AUC >0.93) and predicting disease progression. 1

What is NfL?

Neurofilament light chain is a neuron-specific cytoskeletal protein that:

• Forms part of the axonal skeleton in neurons
• Releases into cerebrospinal fluid (CSF) and blood when axonal damage occurs
• Serves as a marker of neurodegeneration, regardless of underlying cause
• Can be detected in both CSF and blood (serum/plasma) samples

Diagnostic Value in Frontotemporal Dementia

Distinguishing FTD from Other Conditions

• FTD vs. Psychiatric Disorders: NfL shows excellent diagnostic accuracy (AUC 0.93) in differentiating behavioral variant FTD (bvFTD) from primary psychiatric disorders 1
• FTD vs. Healthy Controls: Both CSF and serum NfL demonstrate outstanding discrimination (AUC >0.99) between FTD patients and healthy individuals 2
• FTD vs. Alzheimer's Disease: NfL helps differentiate FTD from Alzheimer's disease, though with more moderate accuracy 2

Genetic FTD

• Significantly elevated in symptomatic carriers of FTD-causing mutations (GRN, C9orf72, MAPT) compared to presymptomatic carriers 3
• Higher levels observed in genetic cases, particularly in GRN mutation carriers 4
• Increases in "converters" (those transitioning from presymptomatic to symptomatic state) before clinical symptoms appear 3

Prognostic Value

NfL demonstrates important prognostic capabilities:

• Predicts Cognitive Decline: Baseline NfL levels correlate with future cognitive deterioration in FTD 4
• Conversion to Dementia: Higher NfL levels in presymptomatic mutation carriers who later develop symptoms (converters) 3
• Disease Progression: Correlates with rate of brain atrophy in multiple grey matter regions 3
• Functional Decline: Associated with overall cognitive function, abstract reasoning, executive functions, memory, and language performance 4

Clinical Applications

Recommended Uses

1. Differential Diagnosis: Consider serum or CSF NfL to differentiate bvFTD from psychiatric disorders when clinical presentation is ambiguous 1
2. Disease Monitoring: Track NfL levels over time to assess disease progression and potentially treatment response 3
3. Early Detection: Identify presymptomatic mutation carriers approaching symptom onset 3
4. Prognosis: Use baseline NfL to predict future cognitive decline and conversion to dementia 4, 5

Practical Implementation

• Sample Type: Plasma/serum NfL levels highly correlate with CSF levels, making blood sampling a less invasive alternative to lumbar puncture 1
• Assay Selection: Two commercially available platforms (SiMoA and Ella) show strong correlation (r=0.94) but with different absolute values, requiring knowledge of the specific assay used 6
• Reference Values: Different studies report varying optimal cutoffs (e.g., >5016 pg/ml or >10500 pg/ml for CSF NfL in FTD) 1

Limitations and Considerations

• Non-Specificity: NfL increases in various neurodegenerative conditions, not just FTD 1
• Subtype Variations: NfL levels differ among FTD subtypes, with higher levels in semantic primary progressive aphasia compared to behavioral FTD 2
• Peripheral Confounders: NfL is also found peripherally, so direct tissue injury may elevate levels independent of brain pathology 1
• Assay Variability: Different assays yield different absolute values, requiring standardization 6
• Limited Change Detection: Some studies suggest NfL may not change significantly over short time periods in certain conditions like cerebral small vessel disease 5

Integration with Other Biomarkers

For optimal diagnostic accuracy, consider combining NfL with:

• CSF Biomarkers: Amyloid-β42, tau, and p-tau to rule out Alzheimer's disease 1
• Plasma Biomarkers: P-tau217 combined with NfL improves prediction of cognitive decline in MCI patients 7
• Neuroimaging: MRI to assess structural changes and FDG-PET in ambiguous cases 1

NfL represents a promising biomarker in the assessment and management of FTD and other neurodegenerative diseases, offering valuable information for diagnosis, prognosis, and potentially treatment monitoring, with the convenience of blood-based testing making it increasingly accessible for clinical use.