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

Abstract

Background and purpose This study was undertaken to determine the diagnostic and prognostic value of a panel of serum biomarkers and to correlate their concentrations with several clinical parameters in a large cohort of patients with amyotrophic lateral sclerosis (ALS). Methods One hundred forty‐three consecutive patients with ALS and a control cohort consisting of 70 patients with other neurodegenerative disorders (DEG), 70 patients with ALS mimic disorders (ALSmd), and 45 healthy controls (HC) were included. Serum neurofilament light chain (NfL), ubiquitin carboxyl‐terminal hydrolase isozyme L1 (UCHL1), glial fibrillary acidic protein (GFAP), and total tau protein levels were measured using ultrasensitive single molecule array. Results NfL correlated with disease progression rate (p < 0.001) and with the measures of upper motor neuron burden (p < 0.001). NfL was higher in the ALS patients with classic and pyramidal phenotype. GFAP was raised in ALS with cognitive–behavioral impairment compared with ALS with normal cognition. NfL displayed the best diagnostic performance in discriminating ALS from HC (area under the curve [AUC] = 0.990), DEG (AUC = 0.946), and ALSmd (AUC = 0.850). UCHL1 performed well in distinguishing ALS from HC (AUC = 0.761), whereas it was not helpful in differentiating ALS from DEG and ALSmd. In multivariate analysis, NfL (p < 0.001) and UCHL1 (p = 0.038) were independent prognostic factors. Survival analysis combining NfL and UCHL1 effectively stratified patients with lower NfL levels (p < 0.001). Conclusions NfL is a useful biomarker for the diagnosis of ALS and the strongest predictor of survival. UCHL1 is an independent prognostic factor helpful in stratifying survival in patients with low NfL levels, likely to have slowly progressive disease. GFAP reflects extramotor involvement, namely cognitive impairment or frontotemporal dementia.

Blood biomarkers in ALS : challenges, applications and novel frontiers

“…Recently, it has also been shown that biomarkers may be able to differentiate different patient phenotypes. Glial fibrillary acidic protein (GFAP), a marker of astrogliosis, was shown to be higher in ALS patients with cognitive and/or behavioural impairment compared to those without, with the highest levels present in patients with confirmed ALS‐FTD 105 . Further investigations into this preliminary observation are needed.…”

Markers of blood-brain barrier disruption increase early and persistently in COVID-19 patients with neurological manifestations

“…NFL is an established marker of axonal injury [41]. Although axonal degeneration is not a specific feature of ALS, NFL is considered its most characteristic biomarker since its concentration is higher than in any other neurological disease [42,43]. This may be because neurofilaments are abundantly expressed in the large myelinated axons involved in the degenerative process, which is particularly fast and severe in ALS compared to other diseases.…”

Reply to the Letter to the Editor in response to “Integrated evaluation of a panel of neurochemical biomarkers to optimize diagnosis and prognosis in amyotrophic lateral sclerosis”

“…We wish to thank Drs Aamir, Shah and Mansure for their valuable comments on our recently published report investigating an "integrated panel of neurochemical biomarkers to optimize diagnosis and prognosis in amyotrophic lateral sclerosis" (ALS) [1], and are glad to see that our article stimulates further discussion on the topic of novel biomarkers for motor neuron diseases. The authors correctly point out that screening for urinary biomarkers such as p75ECD may add value in predicting ALS prognosis, while other serum biomarkers, including anti beta-actin (ACTB) and anti proteasome subunit alpha 7 (PSMA7), may be adopted to optimize diagnosis.…”