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.

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

“…However, only the trend in the slow progressors was significant. In contrast to these findings, plasma levels of cystatin C were significantly higher in patients with ALS as compared with healthy controls [105]. While protein levels can provide insight into the physiology and pathology, protein levels do not necessarily correlate with enzymatic activity, highlighting a significant limitation to the studies performed to date.…”

“…Levels of cystatin C positively correlated with survival time for patients with limb onset but did not correlate with the disease duration [98]. A longitudinal study was also performed on CSF and plasma over a 1 to 2-year time period [105]. In this study, analyses of cystatin C levels in the CSF showed that fast and slow progressors exhibited trends towards decreased and increased levels over time, respectively.…”

“…This was previously demonstrated where several studies have indicated significantly high correlations between blood (serum and plasma) and CSF levels of the same biomarker [34,38,44,118]. However, other studies have also demonstrated that levels of biomarkers, that were discovered in blood, did not correlate with the levels of that same biomarker found in the CSF, suggesting that these 2 fluids are independently regulated [105,117]. Blood-based biomarkers may also be generated by other organ systems affected during ALS, such as peripheral blood cells or degenerating muscle.…”

“…Some examples of these approaches, albeit from targeted analyses, have been performed [38,105,169], and have been discussed throughout this review. These studies require large sample sizes consisting of patients with ALS, neurologic disease controls, and healthy controls, in order to assess how particular biomarkers change over time.…”

Clinical Measures of Disease Progression in Amyotrophic Lateral Sclerosis

“…In addition to these readily obtained laboratory tests, a variety of disease-specific biomarkers have been sought including neurofilament heavy subunit, both in serum and cerebrospinal fluid (CSF) [88,89], and CSF cystatin C [90,91]. Cystatin C levels have also been found to correlate with the rate of disease progression and are predictive of survival [90].…”