Serum Transcription Factor EB Levels in Relation to Poor Neurological Prognosis and Mediation Effect of Stroke-Associated Pneumonia in Acute Intracerebral Hemorrhage: Evidence from a Two-Center Prospective Cohort Study

Abstract

Background: Transcription factor EB (TFEB) is an endogenous protective protein. Serum TFEB levels were measured after acute intracerebral hemorrhage (ICH), in addition to determining their connection to the severity and neurological outcomes of patients.

Methods: Serum TFEB levels were measured in a prospective cohort study of 186 ICH patients and 100 controls. Severity was estimated using the National Institutes of Health Stroke Scale (NIHSS) and hematoma volume. Poor neurological status mirrored by the post-ICH six-month modified Rankin Scale (mRS), along with stroke-associated pneumonia (SAP), was considered as the two outcome variables.

Results: Patients showed a marked decline in serum TFEB levels compared with controls. Serum TFEB levels were significantly inversely correlated with both NIHSS scores and hematoma volume; had a linear relationship with likelihoods of both SAP and poor prognosis (mRS scores 3-6), were independent of ordinal mRS scores, SAP, and poor prognosis; and were efficiently predictive of SAP and poor prognosis with analogous areas under the receiver operating characteristic curve as NIHSS scores and hematoma volume. The association between serum TFEB levels and poor prognosis is partly mediated by SAP.

Conclusion: Reduced serum TFEB levels post-ICH of evident relevance to bleeding intensity are powerfully linked to poor neurological prognosis, wherein there is a partial mediative effect by SAP, thereby reinforcing TFEB as a serological prognostic indicator of good prospect in ICH.

Keywords: biomarkers; intracerebral hemorrhage; outcome; severity; stroke-associated pneumonia; transcription factor EB.

Figure 1

Schematic diagram of the study design and enrollment details in the acute intracerebral hemorrhage-related investigation. This analytic survey encompassed a cross-sectional sub-study and a prospective cohort sub-study to determine the alteration of serum-based transcription factor EB levels after acute ICH and its prognostic value separately.

Figure 2

Bland-Altman graph with an exhibition of consistency in the double measurements of serum-based transcription factor EB levels among sufferers from acute intracerebral hemorrhage. Good consistency was revealed between the two quantifications of transcription factor EB levels in the serum of patients with acute intracerebral hemorrhage.

Figure 3

Distinction of serum transcription factor EB levels between controls and patients following acute intracerebral hemorrhage. Substantial differences were observed in serum-based transcription factor EB levels, with lower levels in individuals with acute intracerebral than in the controls (P<0.001).

Figure 4

Serum-based transcription factor EB levels and National Institutes of Health Stroke Scale scores among subjects diagnosed of acute intracerebral hemorrhage. Using the Spearman test, serum-based transcription factor EB levels were demonstrated to be negatively proportional to the National Institutes of Health Stroke Scale scores after acute intracerebral hemorrhage (P<0.001).

Figure 5

Serum-based transcription factor EB levels and hematoma size following acute intracerebral hemorrhage. By applying the Spearman test, serum-based transcription factor EB levels were confirmed to be significantly inversely associated with hematoma volume after acute ICH (P<0.001).

Figure 6

Restricted cubic spline for assessment of relationship between serum transcription factor EB levels and risk of poor prognosis at six-month mark following intracerebral hemorrhage. A statistical demonstration of linear correlation was observed between serum-based transcription factor EB levels and the likelihood of a poor six-month prognosis post-acute intracerebral hemorrhage (P for nonlinear >0.05).

Figure 7

Discrimination efficiency as to serum transcription factor EB levels on possibility of poor prognosis at six months post-acute intracerebral hemorrhage. With the help of the receiver operating characteristic curve, a poor prognosis was anticipated based on serum transcription factor EB levels. In addition, using the Youden approach, a selected value of serum-based transcription factor EB levels was suitable for prognosis prediction. AUC was indicative of the area under the curve (95% CI, 95% confidence interval).

Figure 8

Comparison of discrimination capabilities of different factors on probability of poor prognosis at six months following acute intracerebral hemorrhage. By manipulating the receiver operating characteristic curve, serum transcription factor EB levels had an area under the curve of nonsignificant distinction between the National Institutes of Health Stroke Scale scores and hematoma volume (both P>0.05).

Figure 9

Restricted cubic spline with respect to the relationship between serum-based transcription factor EB levels and the probability of stroke-associated pneumonia following intracerebral hemorrhage. Statistical confirmation revealed a linear relationship between serum-based transcription factor EB levels and the possibility of stroke-associated pneumonia following acute intracerebral hemorrhage (P for nonlinear >0.05).

Figure 10

Anticipation effect of serum transcription factor EB levels on stroke-associated pneumonia following acute intracerebral hemorrhage. Within the framework of the receiver operating characteristic curve, stroke-associated pneumonia was well predicted by the serum transcription factor EB levels. Alternatively, using the Youden method, a chosen value of serum-based transcription factor EB levels is appropriate for pneumonia prediction.

Figure 11

Differences of discrimination performances of multiple variables on probability of stroke-associated pneumonia following acute intracerebral hemorrhage. Serum transcription factor EB levels took possession of the area under the receiver operating characteristic curve of statistical similarity as the National Institutes of Health Stroke Scale scores and hematoma volume (both P>0.05).

Figure 12

Mediation effect analysis of stroke-associated pneumonia on relationship between serum transcription factor EB levels and poor six-month prognosis following acute intracerebral hemorrhage. Stroke-associated pneumonia partially mediated the relationship between serum transcription factor EB levels and poor six-month prognosis following acute intracerebral hemorrhage.

Figure 13

Verification of mediation effect of stroke-associated pneumonia on association of serum transcription factor EB levels with poor six-month prognosis following acute intracerebral hemorrhage. Sensitivity analysis showed that the mediation effect was statistically significant (ρ=0.355; P<0.001).