Serum retinol-binding protein 4 in stroke patients: correlation with T helper 17/regulatory T cell imbalance and 3-year cognitive function decline

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Serum retinol-binding protein 4 in stroke patients: correlation with T helper 17/regulatory T cell imbalance and 3-year cognitive function decline

Fei Wang^† Yaqin Qin^† Zongyou Li^*

• Department of Neurology, Fuyang People’s Hospital, Fuyang, China

Objective: Retinol-binding protein 4 (RBP4) promotes atherosclerotic progression and neuronal loss, whereas its association with cognitive impairment in stroke is unclear. Hence, this prospective study aimed to explore the association of serum RBP4 with the T helper (Th)17/regulatory T (Treg) cell ratio and its correlation with cognitive impairment in stroke patients.

Methods: Peripheral blood samples from 265 stroke patients and 50 healthy controls (HCs) were collected at enrollment for serum RBP4 (by enzyme-linked immunosorbent assay) and Th17 and Treg cells (by flow cytometry) determination. Additionally, stroke patients underwent routine follow-ups, and their Mini-Mental State Examination (MMSE) scores were assessed at baseline and in years 1, 2, and 3 after enrollment.

Results: Serum RBP4 was elevated in stroke patients compared to HCs (p < 0.001), with a good ability to differentiate stroke patients from HCs (area under the curve: 0.815). Serum RBP4 was positively associated with Th17 cells (p < 0.001) and the Th17/Treg cell ratio (p < 0.001) and negatively associated with Treg cells (p = 0.003) in stroke patients, whereas it was only positively associated with the Th17/Treg cell ratio (p = 0.027) but not with Th17 (p = 0.075) or Treg (p = 0.130) cells in HCs. Furthermore, increased serum RBP4 was associated with a lower MMSE score (p < 0.001) and a lower incidence of cognition impairment (p = 0.005) at enrollment in stroke patients, as were Th17 cells and the Th17/Treg cell ratio (all p < 0.050). The 1-, 2-, and 3-year MMSE scores in stroke patients were 25.9 ± 2.0, 25.3 ± 2.3, and 24.9 ± 2.3, respectively. More importantly, serum RBP4 was negatively correlated with 1-, 2-, and 3-year MMSE scores (all p < 0.001) and positively associated with 1-year (p = 0.013), 2-year (p = 0.007), and 3-year (p = 0.001) MMSE score declines in stroke patients.

Conclusion: Serum RBP4 is positively associated with a Th17/Treg cell imbalance and, more importantly, it is indicative of cognitive function decline within 3 years in stroke patients. Thus, early and timely interventions and physical rehabilitation are more necessary in stroke patients with high serum RBP4.

Introduction

Stroke, including ischemic and hemorrhagic subtypes, is a common cerebrovascular disease characterized by high disability and fatality (1, 2). It is estimated that there are 2.4 million new cases of stroke and 1.1 million stroke-related deaths in China each year (3). At present, the standardized comprehensive treatment for ischemic stroke mainly involves intravenous thrombolysis, endovascular thrombectomy, antiplatelet therapy, etc. (4, 5). For the treatment of hemorrhagic stroke, craniopuncture, blood pressure and elevated intracranial pressure management, etc., are generally applied depending on the specific situation (6). Despite the progress and advancement in stroke treatment, the outcome of stroke is still not ideal, with cognitive impairment in over 70% of stroke survivors (7–9). At present, the management of post-stroke cognitive impairment mainly includes the following two aspects: pharmacological treatment (for example, with cholinesterase inhibitors, memantine, cerebrolysin, etc.) and cognitive rehabilitation; nonetheless, the occurrence and exacerbation of cognitive impairment are still prevalent and increase the risk of disability (8, 10). Consequently, seeking biomarkers to identify stroke patients at high risk for cognitive dysfunction is helpful to improve their rehabilitation and prognosis.

Retinol binding protein 4 (RBP4), a transport protein belonging to the lipocalin family, is implicated in the incidence and progression of atherosclerosis by inducing macrophage-divided foam cell formation and regulating the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway (11–14). From a clinical point of view, a previous study suggested that higher RBP4 was associated with increased disease severity and a worse physical and functional outcome in acute ischemic stroke (AIS) patients (15). Another study found that AIS patients with lower RBP4 were more likely to experience disease progression and disability (16). However, the correlation of RBP4 with cognitive impairment induced by multiple factors (such as the imbalance of T helper (Th)17 and regulatory T (Treg), neuronal loss, etc.) has rarely been reported in stroke patients thus far. Notably, in addition to facilitating atherosclerosis development, RBP4 also facilitates neuronal loss (17–19). For instance, one study revealed that RBP4 regulates cortical and hippocampal (CA3) neuronal loss (18). Another study showed that RBP4 aggravates neuronal loss by modulating lipoprotein-associated phospholipase A2 (Lp-PLA2) and netrin-1 (17). Conceivably, RBP4 is speculated to possess a predictive role for cognitive impairment in stroke patients.

Therefore, this prospective study aimed to investigate the association of serum RBP4 with Th17/Treg balance, disease characteristics, and the long-term progression of cognitive impairment in stroke patients.

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