Stroke represents a critical global health challenge, with ischemic stroke accounting for 65.3% of all stroke cases and ranking as the third leading cause of mortality worldwide (1). Between 1990 and 2021, inadequate management of modifiable risk factors—including obesity, elevated systolic blood pressure, and hyperglycemia—has further contributed to the rising incidence and socioeconomic burden of stroke (1). Therefore, the continuous development and implementation of effective and accessible strategies for early detection and prevention of stroke are of paramount importance. Ischemic stroke is a multifaceted pathological condition driven by a complex interplay of multiple factors, including aberrant immune activation, chronic inflammatory cascades, dysregulated lipid metabolism, and synergistic effects of various risk factors. It can be categorized into several subtypes: large artery atherosclerosis (LAA), cardioembolism (CE), small artery occlusion (SAO), stroke of other determined etiology (SOE), and stroke of undetermined etiology (SUE) (2). Among these, LAA is the most prevalent subtype and is characterized as an immune-mediated chronic inflammatory process occurring within the arterial wall (3). Dysfunction in nutritional and metabolic pathways may disrupt immune homeostasis, promote chronic inflammation, and heighten susceptibility to immune-related disorders. According to anatomical location and vascular origin, cerebral vessels can be classified as intracranial, extracranial, anterior circulation and posterior circulation. Posterior circulation stroke, primarily resulting from lesions in the vertebrobasilar arterial system, is often insidious in onset and associated with poor clinical outcomes and high mortality rates (4, 5). In contrast to the more recognizable manifestations of anterior circulation stroke, such as hemiparesis or aphasia, early symptoms of posterior circulation stroke frequently present as dizziness, which may delay timely diagnosis and treatment. Therefore, the early identification and monitoring of vascular stenosis across intracranial and extracranial regions, as well as within both anterior and posterior circulations, are essential for improving outcomes.

Albumin-to-globulin ratio (AGR) is a metabolic biomarker that reflect nutritional and immune status. BMI is a globally recognized screening index for obesity and serves as an established risk factor for ischemic stroke (6, 7). Serum albumin is commonly used as a biochemical marker for evaluating nutritional status; reduced albumin levels may indicate malnutrition or compromised health. Globulin levels are closely associated with the degree of systemic inflammation. In addition to the metabolic burden caused by the inflammatory response itself, increased capillary permeability during inflammation can facilitate the extravasation of serum albumin into interstitial spaces, resulting in hypoproteinemia, which has been linked to adverse clinical outcomes (8). Compared with individual measurements of serum albumin or globulin, AGR demonstrates greater diagnostic and prognostic value (9). Emerging evidence suggests that AGR is associated with depression (10), frailty (11), prognosis in malignant tumors (12), chronic disease progression, and the risk of postoperative infections. A prospective cohort study demonstrated that, among patients with acute ischemic stroke, a lower serum albumin-to-globulin ratio was independently associated with an increased risk of poor functional outcome and all-cause mortality at both 3-month and 1-year follow-up (13). The study by Han et al. (14) demonstrated that a lower albumin-to-globulin ratio is associated with more pronounced carotid atherosclerosis; in acute ischemic stroke, the albumin-to-globulin ratio serves as a superior predictor of “vascular aging” compared with globulin alone. A large-scale population study based on NHANES further confirmed that individuals with lower AGR levels exhibit increased incidence of both hemorrhagic and ischemic stroke (15).

However, it remains unclear whether AGR has a direct association with the risk of cerebral atherosclerotic stenosis. To address this gap, the present study employed digital subtraction angiography (DSA) to investigate the potential relationship between serum AGR levels and cerebral atherosclerotic stenosis, including both intracranial and extracranial involvement, as well as lesions located in the anterior or posterior circulation. Stratified analyses were further conducted based on BMI, age, and sex, aiming to provide evidence that may inform future research on the risk stratification and etiology of cerebrovascular stenosis.

In this study, we observed that the AGR was negatively associated with the presence of cerebral atherosclerotic stenosis, including both anterior and posterior circulation stenosis as well as intracranial and extracranial stenosis. This association remained consistent across subgroups stratified by BMI, age, and sex. Furthermore, our findings revealed, for the first time, a linear relationship between AGR levels and the severity of posterior circulation and intracranial stenosis. These results suggest that AGR may serve as a novel biomarker for cerebral artery stenosis and could potentially offer enhanced predictive value for stenosis risk in specific vascular territories.

Albumin is a plasma protein synthesized by the hepatic tissue and serves as a critical component in maintaining colloid osmotic pressure and facilitating the transport of various substances within the circulatory system. It exerts multiple physiological functions, including modulation of immune responses, mitigation of inflammatory injury, and scavenging of free radicals (17). Globulin, predominantly synthesized by lymphoid organs, is primarily secreted by plasma cells. As a central element of humoral immunity, globulin collaborates with albumin to preserve plasma oncotic pressure, thereby preventing tissue edema. Additionally, it plays an essential role in complement activation and inflammatory processes. Under conditions of trauma, inflammation, or systemic stress, serum albumin levels are typically diminished. A reduction in albumin concentration (<35 g/L) reflects impaired hepatic synthetic capacity and compromised nutritional status. Consequently, several studies have proposed that serum albumin may serve as a potential biomarker for assessing systemic inflammatory states (15, 18).

Clinical observational studies have demonstrated that persistent hypoalbuminemia is associated with adverse outcomes in patients with sepsis, whereas normalization of serum albumin levels may indicate clinical improvement (19). Accumulating evidence indicates that serum albumin levels significantly influence clinical outcomes in individuals with ischemic stroke (20). A nationwide registry study involving 13,618 patients revealed that elevated admission albumin levels were independently linked to improved functional recovery and reduced mortality, with consistent associations observed at both 3-month and 1-year follow-up periods (21). Similarly, a meta-analysis encompassing 23,597 patients confirmed that low admission albumin levels were significantly correlated with increased long-term mortality following stroke (22). Nonetheless, the therapeutic use of albumin infusion during the acute phase of ischemic stroke remains controversial. Some studies suggest that such treatment may elevate the risk of pulmonary edema and intracranial hemorrhage (23), although these effects appear to be influenced by the dosage and timing of administration.

AGR represents a novel biomarker reflecting both nutritional status and immune function, which has demonstrated significant clinical relevance in the pathogenesis and progression of various diseases. Compared to individual measurements of albumin or globulin levels, AGR exhibits superior prognostic performance, likely due to its integrated assessment of both nutritional and inflammatory components that influence disease outcomes. Currently, AGR is recognized as a valuable prognostic indicator in multiple malignancies. A meta-analysis summarizing 18 studies on solid tumors over the past decade reported that AGR was significantly associated with at least one prognostic outcome in each cancer type examined, supporting its role as a cost-effective and clinically meaningful predictive marker (12). When AGR is less than 1.1, it is associated with a shorter overall survival period in patients with renal cell carcinoma (24). Moreover, emerging evidence suggests that AGR serves as an effective diagnostic biomarker for periprosthetic joint infection following prosthetic implantation (25). In critically ill ICU patients, reduced AGR levels are independently associated with increased risks of pneumonia and 28-day mortality (26). A cross-sectional study involving 8,381 participants revealed that long-term regular aerobic exercise (≥2 sessions per week for more than 1 year) significantly elevates AGR levels, potentially contributing to the inhibition of atherosclerotic progression. Furthermore, higher AGR values were correlated with reduced systemic inflammation (27). Han et al. (14) reported a significant association between AGR and common carotid artery intima-media thickness among ischemic stroke patients, suggesting a potential role of AGR in modulating atherosclerosis progression. Specifically, elevated AGR levels were associated with a 59% reduction in the risk of abnormal intima-media thickness. However, the mere presence of atherosclerosis does not necessarily lead to hemodynamically significant stenosis, as this progression depends on plaque characteristics, spatial distribution, and vascular compensatory mechanisms. In the present study, we provide the first evidence demonstrating a direct negative correlation between AGR levels and the presence of cerebral atherosclerotic stenosis, encompassing both anterior and posterior circulation as well as intracranial and extracranial involvement. These findings suggest that individuals with low AGR may benefit from earlier vascular evaluation and intensified therapeutic interventions to prevent irreversible stenotic changes.

It is well known that being overweight and obese are risk factors for atherosclerosis. The immune response in atherosclerosis involves various immune cells, along with their associated cytokines and adhesion molecules. Cholesterol in the brain accounts for approximately 25% of the body’s total cholesterol, with the majority located in the myelin sheath (28). Cholesterol is also a key component of synaptic vesicles, playing essential roles in maintaining cell membrane integrity, myelin formation, synaptic development, neural repair and remodeling, and signaling pathways critical to neurodevelopment (29). However, when cholesterol becomes overloaded, it can aggregate into crystals that activate the NLRP3 inflammasome, a crucial driver of atherosclerosis (30, 31). Elevated circulating cholesterol levels could influence T-cell activation and reprogramming, promoting the differentiation of CD4 + T cells toward an inflammatory Th1 phenotype, as observed in mouse models (32). For individuals with a BMI indicating overweight status, early implementation of weight management strategies and active weight reduction interventions have been demonstrated to significantly lower the risk of ischemic stroke (6). Notably, an elevated BMI during adolescence in males has been linked to an increased risk of early-onset atrial fibrillation, which in turn is associated with worse long-term outcomes following ischemic stroke (7).

Emerging evidence also suggests that BMI may influence stroke incidence through interactive effects with the triglyceride-glucose index (TyG), highlighting the complex interplay between metabolic dysregulation and cerebrovascular events (33). Importantly, our findings reveal that the association between AGR and atherosclerotic vascular stenosis remains robust and consistently independent of confounding variables such as body mass index, age, or gender. This observation underscores the potential role of AGR as a stable and reliable biomarker across diverse patient subgroups. These results further imply that, while traditional risk factor modification remains crucial, clinicians should also monitor albumin and globulin levels in young individuals with normal body weight. Maintaining adequate intake of high-quality proteins to prevent hypoproteinemia may serve as a complementary strategy for reducing the risk of adverse clinical outcomes.

Furthermore, our study revealed a linear association between AGR levels and the presence of posterior circulation stenosis as well as intracranial vascular stenosis. This intriguing discrepancy may be attributed to a confluence of anatomical, hemodynamic, and pathological factors. Firstly, from an anatomical perspective, this phenomenon may be attributed to anatomical and physiological differences between intracranial and extracranial arteries, particularly in terms of nutrient vessel density and antioxidant capacity, which limit lipid deposition and render intracranial arteries more vulnerable to inflammatory insults, and intracranial arteries reside within the confined space of the skull and lack an external elastic lamina and vasa vasorum, rendering them more vulnerable to systemic metabolic and inflammatory insults reflected by AGR, compared to the more resilient extracranial arteries (34). Secondly, hemodynamic characteristics differ significantly; the posterior circulation, with its more tortuous anatomy and unique flow patterns (e.g., in the vertebrobasilar system), might experience altered shear stress that modulates the localization and progression of inflammation-driven atherosclerosis, to which AGR is intrinsically linked (13, 27). Lastly, posterior and anterior circulation arteries originate from distinct embryonic vascular systems, leading to inherent structural disparities in their vessel walls and more tortuous anatomical pathways in the posterior circulation (35). These morphological features directly influence cerebral hemodynamics (36) and may render posterior circulation vessels more sensitive to systemic nutritional status and localized arterial wall inflammation. High-Resolution Vessel Wall Imaging has further demonstrated marked differences in plaque morphology between anterior and posterior circulation arteries. Specifically, posterior circulation plaques exhibit larger surface areas and stronger contrast enhancement, likely due to increased inflammatory activity and neovascularization, thereby elevating the risk of plaque rupture (37). Compared with anterior circulation stroke, posterior circulation involvement is typically associated with more severe clinical presentations, worse functional outcomes, and higher mortality rates. The novel association between AGR and posterior circulation stenosis identified in this study may serve as a cost-effective and accessible parameter associated with the presence of posterior circulation stenosis. When integrated with conventional risk factors, AGR may aid in identifying asymptomatic high-risk individuals, thereby contributing to our understanding of the disease etiology and informing hypotheses for future interventional studies.

With the rapid advancement of multi-omics technologies, high-throughput analytical tools, and artificial intelligence, research into stroke biomarkers is transitioning from single-molecule approaches toward multidimensional and dynamic integration models. This paradigm shift presents both new opportunities and challenges for the precision diagnosis and tailored management of stroke. However, several limitations must be acknowledged. First, as a single-center investigation, our findings may be subject to selection bias and may not fully represent broader patient populations. Second, the current observational design does not allow for causal inference regarding the relationship between AGR and cerebral vascular stenosis. Further mechanistic studies and large-scale, multicenter prospective trials are warranted to validate these findings and assess their clinical utility. While our findings suggest the potential value of AGR in risk assessment, it is crucial to interpret these results within the context of our study population—individuals who have already experienced an acute ischemic stroke. Therefore, our results primarily illuminate the role of AGR in the pathophysiology of established cerebral atherosclerosis rather than its predictive power for first-ever events in asymptomatic individuals. The promising clinical outlook of using AGR for identifying asymptomatic high-risk individuals remains a hypothesis that must be rigorously validated in future large-scale, prospective cohort studies conducted in community-based populations.

This study demonstrates a significant association between AGR levels and the presence of posterior circulation stenosis as well as intracranial vascular stenosis. As a readily accessible and cost-effective biomarker, AGR holds potential for the early identification of cerebral atherosclerotic stenosis. Incorporating AGR into clinical practice may facilitate timely risk factor management and contribute to more informed decision-making in the diagnosis and treatment of stroke.