Serum C-Reactive Protein as a Prognostic Biomarker in Amyotrophic Lateral Sclerosis

Abstract

IMPORTANCE Various factors have been proposed as possible candidates associated with the prognosis of amyotrophic lateral sclerosis (ALS); however, there is still no consensus on which biomarkers are reliable prognostic factors. C-reactive protein (CRP) is a biomarker of the inflammatory response that shows significant prognostic value for several diseases. OBJECTIVE To examine the prognostic significance of CRP in ALS. DESIGN, SETTING, AND PARTICIPANTS Patients' serum CRP levels were evaluated from January 1, 2009, to June 30, 2015, in a large cohort of patients with ALS observed by an Italian tertiary multidisciplinary center. Results were replicated in an independent cohort obtained from a population-based registry of patients with ALS. A post hoc analysis was performed of the phase 2 trial of NP001 to determine whether stratification by levels of CRP improves differentiation of responders and nonresponders to the drug. MAIN OUTCOMES AND MEASURES Serum CRP levels from the first examination were recorded to assess their effect on disease progression and survival. RESULTS A total of 394 patients with ALS (168 women and 226 men; mean [SD] age at diagnosis, 60.18 [13.60] years) were observed in a tertiary multidisciplinary center, and the analysis was replicated in an independent cohort of 116 patients with ALS (50 women and 66 men; mean [SD] age at diagnosis, 67.00 [10.74] years) identified through a regional population-based registry. Serum CRP levels in the 394 patients with ALS correlated with severity of functional impairment, as measured by total score on the ALS Functional Rating Scale-Revised, at first evaluation (r =-0.14818; P = .004), and with patient survival (hazard ratio, 1.129; 95% CI, 1.033-1.234; P = .007). Similar results were found in the independent cohort (hazard ratio, 1.044; 95% CI, 1.016-1.056; P Յ .001). Moreover, a post hoc analysis of the phase 2 trial of NP001 using the same CRP threshold showed that patients with elevated baseline CRP levels receiving the higher dose of NP001 had significantly less functional impairment after the treatment period compared with patients with normal baseline CRP, regardless of whether patients with normal CRP levels received NP001 or placebo (3.00 [3.62] vs-7.31 [6.23]; P = .04). CONCLUSIONS AND RELEVANCE These findings suggest that patients with ALS and elevated serum CRP levels progress more rapidly than do those with lower CRP levels and that this elevation may reflect a neuroinflammatory state potentially responsive to the immune regulators such as NP001.

Local and Systemic Humoral Response to Autologous Lineage-Negative Cells Intrathecal Administration in ALS Patients

“…However, a more recent study by Nagel et al on 289 ALS patients and 506 controls showed a moderate inverse correlation of CRP with ALS-FRSr, which is in concordance with our results [59]. Also in 2017, another study on 394 ALS patients confirmed the CRP-ALS-FRSr correlation [60]. Not only the aforementioned clinical trials but also several other studies support the hypothesis that neuroinflammation is a poor prognostic factor that worsens with disease progression, just as degeneration progresses.…”

“…However, these correlations were appropriate for serum CRP concentrations. As suggested previously, CRP in the peripheral blood may be a reflection of the local inflammation in the central nervous system [60]. In our case, only CRP in CSF was negatively correlated with ALS-FRSr (p = 0.009), and no significant correlation was observed in the case of plasma CRP.…”

Low Serum High-Density Lipoprotein Cholesterol Levels Associate with the C9orf72 Repeat Expansion in Frontotemporal Lobar Degeneration Patients

“…Furthermore, there are no previous reports regarding hs-CRP or GlycA in FTLD or their correlations with the C9orf72 repeat expansion. Lunette and colleagues connected ALS progression with hs-CRP [55], but also inconclusive results have been presented [56]. In the latter study, Nagel et al did not see an association between hs-CRP levels and the risk of ALS.…”

The Peripheral Immune System and Amyotrophic Lateral Sclerosis

“…There is also evidence of increased levels of C reactive protein and erythrocyte sedimentation rate (ESR) in subjects with ALS compared to controls, and evidence that levels correlate with the levels of disability as measured by the ALS functional rating scale (89,(92)(93)(94). Levels of lipopolysaccharide are elevated in patients with ALS, (149), as have levels of nitric oxide, suggesting systemic inflammation (78).…”