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.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease that affects approximately 1.5 to 2.5 per 100,000 individuals of all races and ethnicities throughout the world [1]
We found that the estimated means for both measures of cystatin C were lower in ALS patients than in disease controls and healthy controls, similar to prior studies (Table 2)
In a post-hoc pairwise comparison of diagnostic groups, percent cystatin C was found to be significantly lower in cerebrospinal fluid (CSF) of both ALS patients and disease controls relative to healthy controls, but there was no statistical difference between cystatin C levels in ALS patients and disease controls
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease that affects approximately 1.5 to 2.5 per 100,000 individuals of all races and ethnicities throughout the world [1]. ALS patients typically undergo rapid disease progression, though a subset exhibits slow progression and may live over a decade from symptom onset [2,3]. Clinical disease management is hindered by an often lengthy diagnostic process based predominately on clinical criteria [5]. As new drugs that slow or arrest disease progression become available, early initiation of treatment will become paramount. For this reason, diagnostic biomarkers for ALS must be identified and validated to maximize treatment efficacy for future patients. Several individual panels of CSF proteins have shown promise as candidate biomarkers, but none have been fully validated or integrated into clinical practice [6,7,8]
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