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. 2022 Apr 20;10(5):947.
doi: 10.3390/biomedicines10050947.

Vascular Endothelial Growth Factor as a Potential Biomarker of Neuroinflammation and Frontal Cognitive Impairment in Patients with Alcohol Use Disorder

Nerea Requena-Ocaña  1   2 , María Flores-Lopez  1 , Esther Papaseit  3   4 , Nuria García-Marchena  1   5 , Juan Jesús Ruiz  6 , Jesús Ortega-Pinazo  1 , Antonia Serrano  1 , Francisco Javier Pavón-Morón  1   7   8 , Magí Farré  3   4 , Juan Suarez  1   9 , Fernando Rodríguez de Fonseca  1 , Pedro Araos  1   10
Affiliations

Vascular Endothelial Growth Factor as a Potential Biomarker of Neuroinflammation and Frontal Cognitive Impairment in Patients with Alcohol Use Disorder

Nerea Requena-Ocaña et al. Biomedicines. .

Abstract

(1) Background: Alcohol Use Disorder (AUD) is associated with functional disruption of several brain structures that may trigger cognitive dysfunction. One of the mechanisms of alcohol-associated cognitive impairment has been proposed to arise from its direct impact on the immune system, which culminates in the release of cytokines and chemokines which can eventually reach the brain. Alcohol can also disrupt the blood-brain barrier, facilitating the penetration of pro-inflammatory molecules throughout vascular endothelial growth factor A (VEGFA). Thus, alcohol-induced alterations in chemokines and VEGFA might contribute to the neuroinflammation and cognitive impairment associated with AUD. (2) Methods: The present cross-sectional study investigates whether patients with AUD (n = 86) present cognitive disability associated to alterations in plasma concentration of SDF-1, fractalkine, eotaxin, MCP-1, MIP-1α and VEGFA when compared to control subjects (n = 51). (3) Results: The analysis indicated that SDF-1 and MCP-1 concentrations were higher in AUD patients than in controls. Concentrations of VEGFA were higher in AUD patients with severe frontal deficits, and the score of frontal lobe functions was negatively correlated with VEGFA and fractalkine. Acute alcohol effects on VEGFA plasma levels in healthy volunteers demonstrated the induction of VEGFA release by heavy alcohol drinking. VEGFA was positively correlated with pro-inflammatory chemokines in AUD patients with frontal cognitive impairment. (4) Conclusions: we propose VEGFA/chemokine monitoring as biomarkers of potential cognitive impairment in AUD patients.

Keywords: VEGFA; addiction; alcohol use disorders; blood–brain barrier; chemokines; cognitive dysfunction; dementia; fractalkine; neurodegeneration; neuroinflammation.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manu-script, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Diagram showing the design of the cross-sectional study.
Figure 2
Figure 2
Plasma concentrations of VEGFA and chemokines in the alcohol group vs the control group (n = 141). (A) MIP-1α (pg/mL), (B) SDF-1 (pg/mL), (C) Eotaxin (pg/mL), (D) Fractalkine (pg/mL), (E) MCP-1 (pg/mL), and (F) VEGFA (pg/mL). Box and whiskers plotted at the 5–95 percentile. Dots are individual values. Data were analyzed by Mann–Whitney U-test. (*) p < 0.05 and (***) p < 0.001 denote significant differences compared with the control group.
Figure 3
Figure 3
Plasma concentrations of VEGFA and chemokines in AUD patients with frontal cognitive impairment (n = 28). (A) MIP-1α (pg/mL), (B) SDF-1 (pg/mL), (C) Eo-taxin (pg/mL), (D) Fractalkine (pg/mL), (E) MCP-1 (pg/mL), and (F) VEGFA (pg/mL). Box and whiskers plotted at the 5–95 percentile. Dots are individual values. Data were analyzed by Kruskal Wallis test. (*) p < 0.05 denote a significant difference compared with AUD patients without frontal deficits. Abbreviations: FCI = Frontal Cognitive Impairment.
Figure 4
Figure 4
Correlations analysis between VEGFA and chemokines in AUD patients with and without frontal cognitive impairment (n = 51). Colors show Spearman’s rho correlation coefficient.
Figure 5
Figure 5
Exploratory principal component analysis in AUD patients with frontal deficits (n = 51). Two components together explained 80.67% of the variance associated with frontal cognitive impairment in AUD patients.
Figure 6
Figure 6
Plasma concentrations of alcohol (A) and VEGFA (B) at 2, 8 and 24 h after alcohol (100 g) ingestion in male (n = 9–10) healthy volunteers. 0 represents the time of ingestion. Alcohol resulted in increase in plasma concentrations of VEGF 8 h after its ingestion (Friedman’s non-parametric test for repeated measures, * p < 0.05 versus 0 time). (C) Percentage of change of VGEFA calculated over basal concentrations (ANOVA with repeated measures, *** p < 0.001 versus 0 time). ns = non-significant.
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