UCHL1 from serum and CSF is a candidate biomarker for amyotrophic lateral sclerosis

Abstract

Objective To identify potential ALS biomarkers in patients and to evaluate their diagnostic performance using cerebrospinal fluid (CSF) and serum. Method We recruited a discovery cohort, comprising 20 ALS patients and 20 controls to screen for potential CSF biomarker, UCHL1, using a Luminex neurodegenerative disease panel. To validate UCHL1’s diagnostic performance, we used receiver operating characteristic (ROC) curves to determine the potential for early diagnosis in another cohort comprising 23 CSF and 69 serum ALS samples. Finally, we analyzed its correlation with clinical features. Results We found significantly elevated levels of CSF‐derived UCHL1 in both discovery and validation cohorts (P < 0.05). ROC curves revealed an AUC of 0.8288, with a sensitivity and specificity of 73.91% and 81.25%, respectively, when the cut‐off value for UCHL1 was >291.9 pg/mL. A similar result was observed in the serum cohort, with the ALS group exhibiting significantly higher serum UCHL1 levels than the controls (P < 0.05). AUC of the ROC in the serum UCHL1 cohort was 0.7709, with sensitivity and specificity of 61.43% and 79.59%, respectively, when the cut‐off value of serum UCHL1 was >15.22 pg/mL. At the early stage CSF and serum UCHL1 were significantly different between ALS patients and controls (P < 0.05). Furthermore, serum UCHL1 levels showed a positive relationship with the burden of UMN and LMN dysfunction, albeit with no statistical significance. Interpretation Taken together, our findings suggest that ALS patients exhibit significantly elevated CSF‐ and serum‐derived UCHL1. Moreover, our data warrant that UCHL1 displays good diagnostic performance and provide novel options for ALS early diagnosis. However, its prognostic value needs to be further investigated.

Integrated evaluation of a panel of neurochemical biomarkers to optimize diagnosis and prognosis in amyotrophic lateral sclerosis

“…UCHL1 is an enzyme selectively expressed in the cytoplasm of neurons and involved in the ubiquitin-proteasome system [48,49]. It has been found upregulated in the CSF of ALS and C9-ALS subjects, and significantly raised in both CSF and serum of ALS subjects compared with ALSmd [25,27,49]. In our study, UCHL1 concentration was higher in ALS compared with HC, but, contrary to a previous study [27] we did not detect any statistical difference between ALS and ALSmd.…”

“…It has been found upregulated in the CSF of ALS and C9-ALS subjects, and significantly raised in both CSF and serum of ALS subjects compared with ALSmd [25,27,49]. In our study, UCHL1 concentration was higher in ALS compared with HC, but, contrary to a previous study [27] we did not detect any statistical difference between ALS and ALSmd. The larger sample size of our study and the intrinsic heterogeneity of the ALSmd group might explain these diverging results.…”

“…Our results, consistent with previous findings, confirmed the potential of NfL as a diagnostic biomarker for ALS [11]. A previous study measured UCHL1, demonstrating good diagnostic performance in both CSF and serum and suggesting it as a promising biomarker for ALS [27]. Conversely, in our study, UCHL1 showed good diagnostic yield in discriminating ALS from HC (AUC = 0.761), but unsatisfactory performance in distinguishing ALS from DEG and ALSmd (Table S5).…”

“…Although performed on a large ALS cohort, the lack of a validation cohort represents a limitation; further investigations are required to confirm UCHL1 as an independent prognostic factor, and a larger cohort of positive and negative control groups is needed to confirm our findings. Although a previous study demonstrated a strong correlation between CSF and serum concentration [27] we were not able to assess the diagnostic and prognostic performance of UCHL1 in CSF due to the lack of serum and CSF matched samples in our cohort. Despite that, a blood‐based biomarker would be preferable to a CSF one, due to easier collection practices.…”

“…An example is ubiquitin carboxyl‐terminal hydrolase isozyme L1 (UCHL1), a multifunctional protein expressed in the cytoplasm of neurons [22–24]. It is elevated in both CSF and serum from sporadic ALS patients and from those carrying the C9orf72 hexanucleotide repeat expansion (C9‐ALS) [25–27]. Glial fibrillary acidic protein (GFAP) is an established brain marker of astrogliosis [28].…”