Prognostic potential of serum mesencephalic astrocyte-derived neurotrophic factor in acute intracerebral hemorrhage: a prospective observational study
Authors: Zhang Cheng-Liang , Fang Ling-Li , Wang Chuan-Liu , Li Ping , Yang Ming , Xu Jian-Wei 
Published: June 2023

Abstract
Objective
Mesencephalic astrocyte-derived neurotrophic factor (MANF) expressions are dramatically up-regulated in injured brain tissues, thereby conferring neurological protective effects. We intended to determine significance of serum MANF as a prognostic biomarker of intracerebral hemorrhage (ICH).

Methods
In this prospective, observational study done from February 2018 to July 2021, 124 patients with new-onset primary supratentorial ICH were consecutively enrolled. Also, a group of 124 healthy individuals constituted controls. Their serum MANF levels were detected using the Enzyme-Linked Immunosorbent Assay. National Institutes of Health Stroke Scale (NIHSS) and hematoma volume were designated as the two severity indicators. Early neurologic deterioration (END) was referred to as an increase of 4 or greater points in NIHSS scores or death at post-stroke 24 h. Post-stroke 90-day modified Rankin scale (mRS) scores of 3–6 was considered as a poor prognosis. Serum MANF levels were analyzed using multivariate analysis with respect to its association with stroke severity and prognosis.

Results
Patients, in comparison to controls, displayed markedly elevated serum MANF levels (median, 24.7 versus 2.7 ng/ml; P < 0.001), and serum MANF levels were independently correlated with NIHSS scores (beta, 3.912; 95% confidence interval (CI), 1.623-6.200; VIF = 2.394; t = 3.385; P = 0.002), hematoma volumes (beta, 1.688; 95% CI, 0.764–2.612; VIF = 2.661; t = 3.617; P = 0.001) and mRS scores (beta, 0.018; 95% CI, 0.013–0.023; VIF = 1.984; t = 2.047; P = 0.043). Serum MANF levels significantly predicted END and poor 90-day prognosis with areas under receiver operating characteristic curve at 0.752 and 0.787 respectively. END and prognostic predictive abilities were similar between serum MANF levels and NIHSS scores plus hematoma volumes (all P > 0.05). Combination of serum MANF levels with NIHSS scores and hematoma volumes had significantly higher prognostic capability than each of them (both P < 0.05). Serum MANF levels above 52.5 ng/ml and 62.0 ng/ml distinguished development of END and poor prognosis respectively with median-high sensitivity and specificity values. Using multivariate analysis, serum MANF levels > 52.5 ng/ml predicted END with odds ratio (OR) value of 2.713 (95% CI, 1.004–7.330; P = 0.042) and > 62.0 ng/ml predicted a poor prognosis with OR value of 3.848 (95% CI, 1.193–12.417; P = 0.024). Using restricted cubic spline, there was a linear correlation between serum MANF levels and poor prognosis or END risk (both P > 0.05). Nomograms were well established to predict END and a poor 90-day prognosis. Under calibration curve, such combination models were comparatively stable (using Hosmer & Lemeshow test, both P > 0.05).

Conclusion
Increased serum MANF levels after ICH, in independent correlation with disease severity, independently distinguished risks of END and 90-day poor prognosis. Therefore, serum MANF may be a potential prognostic biomarker of ICH.