Collagen XIX Alpha 1 Improves Prognosis in Amyotrophic Lateral Sclerosis

Abstract

The identification of more reliable diagnostic or prognostic biomarkers in age-related neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS), is urgently needed. The objective in this study was to identify more reliable prognostic biomarkers of ALS mirroring neurodegeneration that could be of help in clinical trials. A total of 268 participants from three cohorts were included in this study. The muscle and blood cohorts were analyzed in two cross-sectional studies, while the serial blood cohort was analyzed in a longitudinal study at 6-monthly intervals. Fifteen target genes and fourteen proteins involved in muscle physiology and differentiation, metabolic processes and neuromuscular junction dismantlement were studied in the three cohorts. In the muscle biopsy cohort, the risk for a higher mortality in an ALS patient that showed high Collagen type XIX, alpha 1 (COL19A1) protein levels and a fast progression of the disease was 70.5% (P < 0.05), while in the blood cohort, this risk was 20% (P < 0.01). In the serial blood cohort, the linear mixed model analysis showed a significant association between increasing COL19A1 gene levels along disease progression and a faster progression during the follow-up period of 24 months (P < 0.05). Additionally, higher COL19A1 levels and a faster progression increased 17.9% the mortality risk (P < 0.01). We provide new evidence that COL19A1 can be considered a prognostic biomarker that could help the selection of homogeneous groups of patients for upcoming clinical trial and may be pointed out as a promising therapeutic target in ALS.

Keywords: ALS; Collagen XIX type A1; disease progression; neurodegeneration; prognostic biomarker.

Figure 1.

Flow diagram of the three study cohorts and overview of the study design. A total of 148 ALS patients were enrolled in two cross-sectional studies and one longitudinal study to detect associations among molecular markers and clinical variables in skeletal muscle biopsy (ALS muscle biopsy cohort) and blood samples (ALS blood cohort) and to identify prognostic biomarkers along the disease progression, especially in serial blood samples.

Figure 2.

Relative gene and protein expression levels of COL19A1 in the muscle biopsy study cohort. Gene and protein expression levels of COL19A1 in healthy subjects, ALS patients and other neuropathies patients (A). Kruskal Wallis tests showed significant differences among ALS patients and the other two groups under study, when gene and protein expression levels were tested (P < 0.001, **). (B) Areas under ROC curves (AUC) of gene and protein expression of COL19A1 were calculated to test its support for diagnosis criterion in ALS patients (P <0.001, **). A total of 49 ALS (FALS and SALS) participants were included in this study and matched with 24 control individuals, and 14 ONP; SE: standard error.

Figure 3.

Relative gene expression analysis in the blood study cohort. Transcriptional expression levels of MEF2C , NOGO A , SOD1 , COL19A1 and SNX10 in healthy subjects, ALS patients and other neuropathies patients. (A) Kruskal Wallis tests showed significant differences among ALS patients and healthy participants in all the cases except for SNX10 . Significant differences among other neuropathies patient group and ALS patient group were found in all the cases except for NOGO A and SOD1 . (B) Area under ROC curves of COL19A1 and the ratios COL19A1 /NOGO A and SOD1 /NOGO A were calculated in the sporadic ALS patient group. Significant differences were found between COL19A1 and the ratio COL19A1 /NOGO A , and between COL19A1 and the ratio SOD1 /NOGO A . A total of 141 participants were included in this study: 58 control individuals, 24 other neuropathology’s individuals and 59 ALS patients (FALS and SALS patients); (*P < 0.05; ** P < 0.001), SE: standard error.

Figure 4.

Linear mixed model analysis in the serial blood study cohort. (A) Linear mixed model analysis showed a significant relationship among a faster disease progression and high COL19A1 levels from symptom onset, each dashed line corresponds to the COL19A1 levels from each patient. (B) Mean change from baseline in the ALSFRS-r score in patients that were monitored at 6-monthly intervals during a follow-up period of 24 months from the symptom onset that show COL19A1 levels above (green dot and line) and below (blue dot and line) average at first evaluation. Student's-t test was performed to analyze statistical differences between groups (P < 0.001). A total of 40 SALS patients from the serial blood study cohort were included.