A recent multicenter study published in SpringerMedizin has investigated the potential of cerebrospinal fluid (CSF) levels of neurofilament light chain (NfL), chitotriosidase or chitinase 1 (CHIT1), and microRNA-181b (miR-181b) as diagnostic and prognostic biomarkers for amyotrophic lateral sclerosis (ALS). The research, encompassing a large cohort of ALS patients and controls, sought to evaluate the individual and combined utility of these molecules in the diagnosis, prognosis, and monitoring of ALS.
The study enrolled 210 ALS patients and 218 controls, with detailed demographic and clinical data collected. CSF samples were analyzed for NfL, CHIT1, and miR-181b levels. The results indicated that CSF levels of all three biomarkers were significantly elevated in ALS patients compared to controls. Specifically, NfL levels demonstrated high accuracy in discriminating ALS from controls, with an area under the curve (AUC) of 0.899 (95% CI: 0.868 to 0.929, p<0.0001). CHIT1 and miR-181b showed lower diagnostic performance, with AUCs of 0.688 and 0.640, respectively.
Diagnostic Performance of CSF Biomarkers
The diagnostic performance of the biomarkers was assessed using Receiver Operating Characteristic (ROC) curves. CSF NfL levels displayed a high accuracy in discriminating ALS from controls with an AUC of 0.899 (95% confidence interval (CI): 0.868 to 0.929, p < 0.0001), corresponding to a sensitivity of 80% (95% CI: 73.6–85.2%) and a specificity of 84.3% (95% CI: 78.6–88.6%) at a cut-off of 2079 pg/mL. Conversely, CSF CHIT1 had a lower ability to predict the diagnosis of ALS vs. controls with an AUC of 0.688 (95% CI: 0.615–0.762, p < 0.0001), showing poor sensitivity (46.8%; 95% CI: 37.1–56.8%) and high specificity (90.2%; 95% CI: 83.9–94.2%) at a cut-off of 1564 pg/mL. CSF miR-181b had low sensitivity (41.4%; 95% CI: 31.6–51.9%) and high specificity (85.4%; 95% CI: 76.6–91.3%) at a cut-off of 0.424. The AUC for CSF miR-181b was 0.640 (95% CI: 0.558 to 0.722, p = 0.001).
Prognostic Value and Clinical Correlations
Correlation analyses revealed significant associations between biomarker levels and clinical variables. CSF NfL levels correlated inversely with disease duration (r = -0.331, p<0.0001) and ALS Functional Rating Scale-Revised (ALSFRS-R) scores (r = -0.219, p=0.004). Furthermore, NfL levels showed a strong direct correlation with disease progression rate (DPR) (r = 0.393, p<0.0001), distinguishing fast progressors from slow progressors. Kaplan-Meier survival analysis indicated that elevated CSF NfL levels were associated with significantly shorter survival times (p<0.0001).
CHIT1 Polymorphism and ALS
The study also investigated the impact of a common 24-bp duplication polymorphism in the CHIT1 gene, known to lower CHIT1 concentrations. Interestingly, ALS patients exhibited significantly increased CHIT1 concentrations in the CSF compared to controls, despite having a higher frequency of this polymorphism. This finding suggests that microglial activation, reflected by CHIT1 levels, plays a crucial role in ALS pathophysiology.
Implications for ALS Management
"Our findings support the relevance of CSF and blood NfL both in aiding diagnosis and in predicting disease progression and survival in ALS," the authors stated. The study underscores the potential of NfL as a robust prognostic indicator, while also highlighting the complex interplay between neuroinflammation, genetic factors, and disease progression in ALS. Further research is warranted to explore the additive value of combining multiple biomarkers for improved patient stratification and treatment monitoring in ALS.
