Cystatin C: a candidate biomarker for amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurologic disease characterized by progressive motor neuron degeneration. Clinical disease management is hindered by both a lengthy diagnostic process and the absence of effective treatments. Reliable panels of diagnostic, surrogate, and prognostic biomarkers are needed to accelerate disease diagnosis and expedite drug development. The cysteine protease inhibitor cystatin C has recently gained interest as a candidate diagnostic biomarker for ALS, but further studies are required to fully characterize its biomarker utility. We used quantitative enzyme-linked immunosorbent assay (ELISA) to assess initial and longitudinal cerebrospinal fluid (CSF) and plasma cystatin C levels in 104 ALS patients and controls. Cystatin C levels in ALS patients were significantly elevated in plasma and reduced in CSF compared to healthy controls, but did not differ significantly from neurologic disease controls. In addition, the direction of longitudinal change in CSF cystatin C levels correlated to the rate of ALS disease progression, and initial CSF cystatin C levels were predictive of patient survival, suggesting that cystatin C may function as a surrogate marker of disease progression and survival. These data verify prior results for reduced cystatin C levels in the CSF of ALS patients, identify increased cystatin C levels in the plasma of ALS patients, and reveal correlations between CSF cystatin C levels to both ALS disease progression and patient survival.

Figure 1. Linear regressions for CSF cystatin C levels vs. time from symptom onset.

The slope of the best-fit lines (solid) for both total (A) and percent (B) cystatin C did not significantly differ from zero (p = 0.368 and p = 0.193, respectively). Dashed line = 95% confidence interval for best-fit line.

Figure 2. Kaplan-Meier survival curves.

For all ALS patients (A), survival was significantly longer (p<0.014) in patients with high cystatin C levels (n = 21) than in patients with low cystatin C levels (n = 11). For patients with limb onset ALS (B), the same trend was observed, but with a larger survival difference (p<0.010) between patients with high (n = 13) and low (n = 10) cystatin C levels.