Urinary Extracellular Domain of Neurotrophin Receptor p75 as a Biomarker for Amyotrophic Lateral Sclerosis in a Chinese cohort

Abstract

To comprehensively assess whether p75ECD in urine could be a candidate biomarker for ALS evaluation. Urine samples were collected from 101 ALS patients, 108 patients with other neurological disease (OND) and 97 healthy controls. 61 ALS patients were followed up with clinical data including ALSFRS-r every 6 to 12 months, 23 ALS patients died and 17 ALS patients lost touch during follow up period. Enzyme-linked immunoassay was employed to determine urine p75ECD concentration. The ALSFRS-r was employed to assess the severity of ALS. The concentration of p75ECD in ALS was significantly higher than that of OND and CTRL (p < 0.001). Additionally, urine p75ECD concentrations in ALS-definite grade patients were significantly higher than that in ALS-probable grade and ALS-possible grade patients (p < 0.001). Higher urine p75ECD concentrations were correlated with increased clinical stage (p = 0.0309); urine p75ECD concentrations and ALSFRS-r were negatively correlated (p = 0.022); and urine p75ECD concentration in the fast-progressing ALS group was significantly higher than that in slow-progression (p = 0.0026). Our finding indicates that urine p75ECD concentration provides additional evidence for patients with clinically suspected ALS, and can be employed to evaluate ALS-severity.

Extracellular RNAs as Biomarkers of Sporadic Amyotrophic Lateral Sclerosis and Other Neurodegenerative Diseases

“…Activation of the neurotrophin receptor p75 in response to the nerve growth factor released by activated astrocytes plays a role in developmental motor neuron death and neuronal injury [125]. The levels of urinary p75 ECD are increased in ALS patients compared with normal control subjects and patients with other neurological diseases such as PD and MS [126,127,128]. The levels of neurotrophin receptor p75 in tissues are upregulated also in AD, ischemic stroke, and seizure, suggesting a response to non-specific neuronal injury and cell stress [129].…”

“…Reduced TDP-43 levels (≤27.9 ng/mL) in CSF are associated with shorter survival times [112], while higher NEFL and pNEFH levels in the CSF and serum are associated with more rapid progression speed and poorer prognosis [117,120,123,124], and higher urinary p75 ECD levels are associated with more rapid progression [126,127,128]. Urinary p75 ECD levels increase linearly with disease progression from the time of diagnosis and are correlated with clinical disease parameters, ALS functional rating scale-revised (ALSFS-R) [120,127].…”

New molecular diagnostic trends and biomarkers for amyotrophic lateral sclerosis

“…These finding were validated in a recent study encompassing 54 ALS patients and 45 healthy individuals (Shepheard et al., ). In a Chinese cohort, urine analysis was conducted in 101 ALS patients, 108 patients with other neurological disease (PD and MS), and 97 healthy controls (Jia et al., ). p75 ECD was again found higher in the ALS group compared with the others.…”

Peripheral Glycolysis in Neurodegenerative Diseases

“…Research into immune cell metabolism in ALS is limited despite the role of the immune system in ALS pathogenesis [ 99 , 100 ]. Current literature has focused on lymphoblastoid cell lines (LCL’s), with a recent metabolic analysis performed on LCL’s obtained from patients with sporadic ALS, in addition to patients with familial mutations in FUS, SOD1 and TDP-43 [ 101 ]. Bioenergetic flux analysis showed that mitochondrial respiration was increased in all LCL ALS cell models but glycolysis (measured by extracellular acidification rate (ECAR)) was only altered in the SOD1 LCL’s.…”

“…The extracellular domain of p75 neurotrophin receptor (p75-ECD) is a potential urinary biomarker for ALS [ 101 , 102 , 103 , 104 ]. During neuronal stress and injury, the extracellular domain of the receptor can be cleaved [ 105 ].…”