Amyotrophic Lateral Sclerosis (ALS) is a phenotypically diverse neurodegenerative disorder characterized by the degeneration of motor neurons, ultimately resulting in loss of motor function. Currently, patients are classified based on clinical factors which does not fully capture the heterogeneity. Using the Olink Explore HT, we pro-filed ~5400 plasma proteins in ALS patients (n = 235) from the ALSrisc Study at Karolinska Institutet, Sweden, and applied consensus clustering, which revealed three patient subgroups significantly differing in survival outcome. Weighted gene correlation network analysis (WGCNA) and gene ontology (GO) analysis identified protein modules related to biological functions including cellular stress response and Rho-GTPase activity for the shorter surviving patient group. Cell-type enrichment analysis indicating a broad cellular origin of the circulating proteome, with contributions from nervous system cells, vascular cells, immune cells, and muscle cells. Our work highlights the potential of plasma proteomics for clinically meaningful patient stratification in ALS.
I. Aksoylu, L. Azizi, L. OÌijerstedt et al.· medRxiv· 0 citations
Neurofilament light chain (NfL) is an established marker of neuronal injury and disease aggressiveness in amyotrophic lateral sclerosis (ALS). In contrast, the clinical and biological significance of cardiac troponin T (cTnT) in ALS is not fully understood. We aimed to evaluate the relationship between plasma cTnT and disease aggressiveness, progression stage, and clinical phenotype in comparison with NfL. Plasma cTnT and cerebrospinal fluid (CSF) NfL were analysed at diagnosis in a population-based cohort of 526 patients with ALS. Disease aggressiveness was modelled using the D50 framework, which quantifies the time taken to lose 50% of functional capacity (ALSFRS-R) and normalises individual disease trajectories. Biomarker associations with disease aggressiveness, phase, and clinical variables were assessed through group comparisons, logistic and linear regression, and receiver operating characteristic analyses. Neurofilament light chain in CSF was strongly associated with disease aggressiveness, with higher levels in patients with more aggressive disease. In contrast, plasma hs-cTnT did not correlate with D50. Across disease phases, CSF NfL remained relatively stable, whereas plasma hs-cTnT increased with advancing rD50, suggesting accumulation with disease progression. Plasma hs-cTnT levels were higher in patients with spinal compared to bulbar onset. Combined biomarker models improved sensitivity and negative predictive value for identifying less aggressive disease. Plasma hs-cTnT and CSF NfL capture distinct but complementary dimensions of ALS pathology. While NfL reflects disease aggressiveness, hs-cTnT aligns with disease phase and clinical phenotype, supporting its use as a complementary biomarker for ALS characterisation and monitoring.
Julia Sellin, Linn Öijerstedt, Janina von der Gablentz et al.· Journal of Neurology· 0 citations
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