Brain‐specific biomarkers in urine as a non‐invasive approach to monitor neuronal and glial damage

Abstract

Background and purpose This study evaluates the quantitative measurability of glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), ubiquitin carboxy‐terminal hydrolase L1 (UCH‐L1) and total tau (t‐tau) in urine of patients with acute cerebral damage. Methods Serum and urine samples were prospectively collected from patients with an acute ischemic stroke or intracerebral hemorrhage (target group) and compared to healthy subjects (control group); samples were measured using ultrasensitive single‐molecule arrays (Simoa®). Glomerular barrier function was assessed based on albumin–creatinine ratio (ACR); biomarker–creatinine ratios were calculated for correction of urine dilution. Results Ninety‐three urine–serum pairs in the target group and 10 urine–serum pairs in the control group were measured. The mean absolute concentration ± standard deviation in urine of the target and control groups were 184.7 ± 362.4 pg/ml and 27.3 ± 24.1 pg/ml for GFAP (r = 0.3 [Wilcoxon effect size], p = 0.007), 17.5 ± 38.6 pg/ml and 0.9 ± 0.3 pg/ml for NfL (r = 0.4, p < 0.005), 320.2 ± 443.3 pg/ml and 109.6 ± 116.8 pg/ml for UCH‐L1 (r = 0.26, p = 0.014), and 219.5 ± 255.8 pg/ml and 21.1 ± 27.1 pg/ml for t‐tau (r = 0.37, p < 0.005), respectively, whereas biomarker–creatinine ratio was significantly different only for NfL (r = 0.29, p = 0.015) and t‐tau (r = 0.32, p < 0.01). In patients with intact glomerular barrier (ACR < 30 mg/g), only NfL in urine was significantly different between the target and control group and showed a significant correlation with the respective serum concentrations (r = 0.58 [Pearson's correlation‐coefficient], p < 0.005). Conclusion All four investigated biomarkers could be measured in urine, with NfL and t‐tau showing the strongest effect size after correction for urine dilution. NfL revealed the most accurate relation between serum and urine concentrations in patients with intact kidney function.

Brain‐specific biomarkers: on the winding path to accessibility and clinical relevance

“…There is still a way to go to the routine use of brain-specific biomarkers in clinical practice. The study of Kohlhase et al [1] suggests that the assessment of brain-derived biomarkers in urine is feasible and could be another potentially useful tool for their use in the diagnosis and monitoring of brain disease.…”

“…The specific rate of filtration varies for different biomarker proteins in different fluids. Interestingly, in the study of Kholhase et al [1] only concentrations of NfL and t‐tau urine remained higher compared with healthy controls, after calculation of the dilution‐corrected biomarker–creatinine ratio. This makes NfL and t‐tau in urine the first candidates to be considered for reproducibility studies.…”

“…This is due to the particularities of the CNS (lack of easy access; fine‐tuned biology difficult to assess via surrogate biomarkers) and equally to challenges in developing sensitive techniques to detect the relevant CNS biomarkers in body fluids. In this issue of the European Journal of Neurology , Kohlhase et al [1] provide novel information on the quantitative measurability using ultrasensitive single molecule arrays of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), ubiquitin carboxy‐terminal hydrolase L1 (UCH‐L1) and total tau (t‐tau) in urine from patients with acute ischaemic and haemorrhagic stroke. Kohlhase et al [1] showed that four brain‐specific biomarkers can be detected in urine, and that the absolute urine concentrations of GFAP, NfL, UCH‐L1 and t‐tau are significantly higher in people with acute stroke compared to healthy controls.…”

“…In this issue of the European Journal of Neurology , Kohlhase et al [1] provide novel information on the quantitative measurability using ultrasensitive single molecule arrays of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), ubiquitin carboxy‐terminal hydrolase L1 (UCH‐L1) and total tau (t‐tau) in urine from patients with acute ischaemic and haemorrhagic stroke. Kohlhase et al [1] showed that four brain‐specific biomarkers can be detected in urine, and that the absolute urine concentrations of GFAP, NfL, UCH‐L1 and t‐tau are significantly higher in people with acute stroke compared to healthy controls. This proof‐of‐concept work shows that urine studies are suitable to study brain disease, and it provides useful information regarding the urine–serum concentration correlations of these neuronal and glial biomarkers.…”

“…Kohlhase et al [1] performed multiple biomarker assessment. Panels of biomarkers could be more suitable to assess the complex pathophysiological processes in acute or chronic brain damage than a single biomarker test.…”