Research Progress on Biological Markers and Imaging Markers of Cognitive Impairment Associated with Carotid Artery Stenosis

Abstract

Objective: Carotid artery stenosis (CAS) is a major pathological substrate of ischemic cerebrovascular disease and has been increasingly recognized as an important contributor to the development and progression of vascular cognitive impairment. Through multiple interacting mechanisms, including chronic cerebral hypoperfusion, increased microembolic burden, inflammatory responses, and blood-brain barrier disruption, CAS may initiate or accelerate progressive cognitive decline, thereby adversely affecting long-term clinical outcomes and quality of life. Conventional cognitive assessment scales are limited by their inherent subjectivity and insufficient sensitivity to subtle early changes, highlighting the need for objective and quantifiable biomarkers for early risk identification, longitudinal disease monitoring, and therapeutic evaluation.

Methods: This review summarizes recent advances in biological biomarkers, including markers of inflammation and immune activation, lipid metabolism abnormalities, and vascular or neuronal injury, as well as multimodal imaging biomarkers encompassing brain structural alterations, white matter integrity, cerebral perfusion and metabolism, and functional connectivity networks.

Results: We highlight the potential applications of these biomarkers in risk stratification, personalized intervention strategies, and clinical decision-making for CAS-related cognitive decline, and outline future directions for research in this field.

Conclusion: This review provides a comprehensive reference for both clinical practice and future investigations into cognitive impairment associated with CAS.

Keywords

carotid artery stenosis / vascular cognitive impairment / biomarkers / imaging biomarkers / cerebral hypoperfusion

Carotid artery stenosis (CAS) is not only a major cause of ischemic stroke but also an independent risk factor for vascular cognitive impairment (VCI). Unlike the acute neurological injury resulting from overt stroke events, CAS more commonly contributes to progressive cognitive decline through chronic cerebral hypoperfusion, microembolic burden, blood-brain barrier (BBB) disruption, and neuroinflammatory responses. Importantly, these pathological changes may occur even during the asymptomatic stage, making early identification particularly challenging.

Although conventional cognitive assessment scales are widely used in clinical practice because of their convenience and accessibility, their diagnostic performance is influenced by educational background, patient cooperation, and testing conditions. Furthermore, these tools are often insufficiently sensitive to subtle cognitive changes and longitudinal disease progression. Therefore, the identification of objective, quantifiable, and pathophysiologically relevant biological and imaging biomarkers is essential for recognizing high-risk individuals, assessing disease severity, and predicting cognitive outcomes following carotid revascularization.

In this review, we summarize current evidence regarding biological and multimodal imaging biomarkers associated with cognitive impairment in patients with CAS. Particular emphasis is placed on biomarkers reflecting inflammatory responses, vascular and neuronal injury, cerebral structural alterations, hemodynamic disturbances, and functional network abnormalities. We also discuss their potential applications in risk stratification, disease monitoring, and personalized therapeutic decision-making.

Biological markers of cognitive impairment associated with CAS

Biological biomarkers provide objective information regarding the molecular and metabolic processes underlying disease pathophysiology and may facilitate the diagnosis, risk assessment, and prognosis of cognitive impairment associated with CAS.

Systemic inflammatory biomarkers

Chronic inflammation is a hallmark of atherosclerosis, the primary pathological process underlying CAS. Numerous studies have demonstrated a close association between elevated inflammatory activity and cognitive decline. C-reactive protein (CRP), a widely recognized marker of systemic inflammation, has been associated with cognitive impairment. However, elevated CRP levels may not necessarily predict future cognitive decline; rather, they may indicate an increased risk of progression from normal cognition to dementia[1].

Additionally, serum levels of homocysteine (Hcy), heat shock protein 70, and high-sensitivity C-reactive protein (hs-CRP) have been reported to correlate negatively with Montreal Cognitive Assessment (MoCA) scores[2]. Among inflammatory mediators, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) may contribute to cognitive impairment by disrupting BBB integrity, promoting neuronal apoptosis, and amplifying neuroinflammatory cascades[3,4]. Therefore, combined assessment of TNF-α and IL-6 may enhance the identification of individuals at elevated risk of cognitive impairment associated with CAS.

Nevertheless, although systemic inflammation is a recognized contributor to cognitive dysfunction, studies involving patients with asymptomatic carotid stenosis have demonstrated persistent deficits in learning, memory, motor performance, and processing speed even after adjustment for systemic inflammatory biomarkers, including IL-1β, IL-6, TNF-α, matrix metalloproteinases, and hs-CRP[5]. These findings suggest that systemic inflammation alone cannot fully explain cognitive impairment during the asymptomatic stage.

Neuroinflammation and the NLRP3 inflammasome

Compared with systemic inflammatory markers, neuroinflammation within the central nervous system may more directly reflect the pathological mechanisms underlying cognitive decline.

Experimental studies have demonstrated that CAS followed by reperfusion induces activation of the nuclear factor erythroid 2-related factor 2 signaling pathway, accompanied by suppression of neuroinflammatory and immune-cell signaling pathways[6]. Furthermore, interventions targeting the NLR family pyrin domain containing 3 (NLRP3) inflammasome have shown promising neuroprotective effects. Administration of NLRP3 inhibitors, such as AMS-17, significantly improved cognitive performance in mouse models of vascular dementia. These effects were associated with restoration of BBB integrity, promotion of remyelination, downregulation of NLRP3, apoptosis-associated speck-like protein containing a CARD, and cleaved caspase-1 expression in the brain, reduced circulating levels of TNF-α and IL-1β, and increased expression of the anti-inflammatory cytokine IL-4[7].

These findings suggest that molecules involved in the NLRP3 inflammasome pathway may serve not only as therapeutic targets but also as candidate biomarkers reflecting the degree of neuroinflammatory activation. Such biomarkers may facilitate mechanistic classification and therapeutic monitoring in CAS-related cognitive impairment.

Lipid-related biomarkers

Abnormal lipid metabolism is a major driver of atherosclerosis and may also contribute to cognitive dysfunction through amplification of inflammatory responses and disruption of the neurovascular unit.

Previous studies have reported that patients with asymptomatic CAS exhibit elevated apolipoprotein B/apolipoprotein A1 ratios, which are associated with thalamic atrophy and cognitive impairment[8]. In a bilateral CAS animal model, lipocalin-2 (LCN2) was identified as a key mediator of inflammatory signaling and cellular migration. Clinical investigations further demonstrated increased serum LCN2 levels in patients with VCI, with significant negative correlations observed between LCN2 concentrations and MoCA scores[9].

Collectively, these findings indicate that lipid-related biomarkers may not only reflect atherosclerotic burden but also indirectly signal structural and functional brain alterations. Consequently, they may provide valuable information when integrated into multimodal assessment frameworks.

Biomarkers of vascular injury and repair

Hcy plays a critical role in vascular injury through promotion of atherosclerosis, induction of oxidative stress, and direct neurotoxic effects.

Elevated plasma Hcy levels have consistently been associated with vascular dementia and cognitive decline[10], suggesting their potential utility as biomarkers for evaluating cognitive risk in patients with CAS[2]. However, Hcy concentrations are influenced by numerous factors, including dietary habits, renal function, and vitamin status. Therefore, future studies should determine the predictive value of Hcy across different degrees of stenosis, symptom profiles, and imaging phenotypes while rigorously controlling for potential confounders.

Neuronal injury biomarkers

Phosphorylated tau protein (p-tau217), a core component of neurofibrillary tangles, has emerged as one of the most promising biomarkers of neurodegeneration. Elevated plasma or cerebrospinal fluid levels of p-tau217 are indicative of neuronal injury and have traditionally been regarded as a hallmark of Alzheimer’s disease (AD).

Recent studies have demonstrated that patients with CAS also exhibit elevated p-tau217 levels, which are significantly associated with lower MoCA scores and poorer cognitive performance[11]. Specifically, increased p-tau217 concentrations correlate with deficits in processing speed and executive function[12]. These findings suggest that CAS may contribute to cognitive impairment through mechanisms overlapping with neurodegenerative disorders, including enhanced amyloid-β (Aβ) deposition and tau hyperphosphorylation.

Supporting this hypothesis, a recent experimental study demonstrated that sulforaphane improved VCI by suppressing short-term neuronal and white matter injury as well as reducing long-term accumulation of Aβ and p-tau217 induced by cerebrovascular pathology[13]. These observations further emphasize the importance of neuronal injury biomarkers in mechanistic stratification and the development of targeted therapeutic strategies.

Biomarkers of glial activation

Cerebral ischemia and hypoxia can induce astrocyte activation and stimulate the release of specific glial proteins. Glial fibrillary acidic protein (GFAP), an intermediate filament protein predominantly expressed in astrocytes, is widely recognized as a biomarker of astrocytic activation.

Previous studies have shown that elevated serum GFAP levels are independently associated with an increased risk of post-stroke cognitive impairment[14]. Because CAS is characterized by chronic cerebral hypoperfusion and ischemic injury, GFAP may serve as a useful indicator of glial reactivity and neurovascular unit dysfunction. Consequently, GFAP has considerable potential as a biomarker for assessing the severity of ischemic brain injury and predicting cognitive outcomes in patients with CAS.

Genetic biomarkers and susceptibility

Genetic factors may influence individual susceptibility to CAS and its associated cognitive impairment. Genetic polymorphisms can therefore provide complementary information for risk stratification and may contribute to the identification of high-risk populations before the onset of clinically detectable cognitive decline.

Apolipoprotein E

Apolipoprotein E (APOE) is a lipid transport protein involved in cholesterol and phospholipid metabolism and is widely distributed in plasma and various tissues. APOE plays a critical role in lipid homeostasis and has been strongly associated with both dyslipidemia and AD.

Among the three major APOE isoforms, the APOE ε4 allele is recognized as the most important genetic risk factor for cognitive impairment and dementia. Recent evidence suggests that APOE ε4 is an independent predictor of reduced cerebral blood flow in the anterior circulation. In individuals with asymptomatic CAS or occlusion, APOE ε4 carriage has been associated with a greater likelihood of cerebral hypoperfusion and memory impairment, indicating that APOE genotyping may facilitate early identification of high-risk individuals and improve disease severity assessment[15].

Mechanistically, APOE ε4 may promote cognitive decline through several pathways. First, it disrupts lipid homeostasis in macrophages and vascular smooth muscle cells, thereby enhancing systemic inflammation and accelerating atherosclerotic plaque formation. Second, APOE ε4 has been implicated in BBB dysfunction through its effects on endothelial cells and pericytes, contributing to increased BBB permeability and neurovascular injury[16].

Furthermore, compared with APOE ε4-negative individuals, APOE ε4 carriers exhibit impaired neurovascular coupling despite having higher resting cerebral blood flow and greater cerebrovascular reactivity to hypercapnia. These findings suggest that abnormalities in neurovascular coupling may precede measurable cognitive decline in aging APOE ε4 carriers[17].

Interestingly, not all APOE ε4 carriers develop cognitive impairment. However, among individuals with cognitive dysfunction, APOE ε4 carriers tend to have significantly shorter telomere lengths than cognitively normal carriers, suggesting a potential interaction between APOE genotype, cellular aging, and cognitive deterioration[18].

Taken together, APOE-related genetic variations provide important insights into individual heterogeneity in cognitive vulnerability and may serve as valuable biomarkers for early risk assessment in CAS-related cognitive impairment.

Advances in imaging biomarkers

Imaging techniques provide noninvasive approaches for evaluating the impact of CAS on brain structure, cerebral perfusion, and functional networks. Consequently, imaging biomarkers have become essential tools for identifying and monitoring cognitive impairment associated with CAS.

Structural and morphological brain changes

Gray matter and white matter atrophy

Patients with asymptomatic unilateral CAS, particularly those with severe stenosis, exhibit significant reductions in gray and white matter volumes in specific brain regions, including the parahippocampal gyrus, supplementary motor area, and insular cortex. These structural alterations have been associated with deficits in memory, language, executive function, and visuospatial abilities[19].

A mediation analysis further demonstrated that asymmetric atrophy of the posterior middle temporal cortex plays a critical role in the relationship between white matter hyperintensity (WMH) burden and verbal memory performance. Such hemispheric asymmetry may represent an important pathological substrate underlying accelerated brain aging and cognitive deterioration in patients with severe asymptomatic carotid stenosis and other forms of VCI[20].

Cortical thinning

Surface-based morphometric studies have revealed cortical thinning in multiple regions among patients with asymptomatic CAS, including the bilateral sensorimotor cortex, inferior frontal cortex, fusiform gyrus, and left lateral temporal cortex. These changes are significantly associated with verbal memory deficits and increased WMH burden[21].

Additionally, ipsilateral hemodynamic impairment caused by high-grade asymptomatic carotid stenosis, particularly prolonged time-to-peak perfusion, has been shown to predict ipsilateral cortical thinning[22]. Although some studies have failed to identify specific patterns of cortical thinning in patients without overt ischemic brain injury[23], accumulating evidence supports the concept that chronic hemodynamic compromise contributes to progressive cortical structural degeneration.

White matter integrity damage

White matter integrity is particularly vulnerable to chronic cerebral hypoperfusion and microvascular injury associated with CAS. Increasing evidence suggests that white matter abnormalities play a pivotal role in the development of cognitive impairment.

WMHs and leukoaraiosis

WMHs, also referred to as leukoaraiosis, are among the most common neuroimaging manifestations in patients with CAS. Both WMHs and cerebral infarctions are closely associated with cognitive impairment, and their prevalence increases with the severity of CAS[24].

Interestingly, the effects of CAS on cognition appear to differ according to the affected hemisphere. Huang et al.[24] demonstrated that left-sided CAS indirectly influences nearly all cognitive domains through ipsilateral periventricular white matter lesions, whereas right-sided CAS primarily affects nonverbal cognitive functions, including visual memory and processing speed, through ipsilateral cerebral infarctions.

These findings suggest that white matter injury serves as an important mediator linking CAS to cognitive dysfunction and may represent a valuable imaging biomarker for disease severity and cognitive prognosis.

Diffusion tensor imaging biomarkers

Diffusion tensor imaging (DTI) is a magnetic resonance imaging technique that evaluates the directionality and magnitude of water diffusion within biological tissues, thereby providing quantitative information regarding white matter microstructural integrity.

A tract-based spatial statistics study demonstrated that patients with vulnerable carotid plaques exhibited significantly reduced fractional anisotropy (FA) and increased radial diffusivity (RD) in multiple white matter tracts, including the anterior thalamic radiation, corticospinal tract, cingulum bundle, splenium of the corpus callosum, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, and uncinate fasciculus[25]. These findings indicate that DTI-based analyses can detect microstructural white matter damage before the appearance of overt clinical symptoms.

Similarly, studies involving patients with VCI have consistently demonstrated reduced FA and increased mean diffusivity, axial diffusivity, and RD across extensive white matter regions. Importantly, these DTI parameters show significant correlations with MoCA scores, indicating a close relationship between white matter integrity and cognitive performance[25].

In patients with CAS, global mean FA values have also been shown to correlate significantly with attention and verbal memory performance. Lower FA values are generally associated with poorer cognitive outcomes[26].

Taken together, DTI-derived parameters provide sensitive indicators of white matter microstructural damage and may serve as promising imaging biomarkers for predicting cognitive decline in CAS.

Cerebral perfusion and metabolic abnormalities

Chronic cerebral hypoperfusion

One of the most important mechanisms linking CAS to cognitive impairment is chronic cerebral hypoperfusion. Progressive narrowing of the carotid artery restricts cerebral blood supply, leading to insufficient oxygen and nutrient delivery to vulnerable brain regions.

Particularly, hypoperfusion within the middle cerebral artery (MCA) territory appears to play a critical role in cognitive deterioration. Recent studies have shown that reduced MCA blood flow mediates approximately 40% of the effect of arterial stenosis on WMH burden[27]. These findings suggest that restoring cerebral perfusion may represent an effective strategy for preventing white matter injury and cognitive decline.

Evidence from both animal models and clinical studies has consistently demonstrated reductions in cerebral blood flow following CAS[28]. Furthermore, a longitudinal cohort study found that regional cerebral hypoperfusion could be detected before the onset of clinically apparent cognitive impairment, suggesting that perfusion abnormalities may serve as early predictors of cognitive decline[29].

Carotid revascularization procedures, including carotid endarterectomy and carotid artery stenting, can improve cerebral perfusion by restoring blood flow to functionally important brain regions. Prospective studies have demonstrated significant increases in both ipsilateral and global cerebral blood flow after revascularization, particularly among patients with stenosis exceeding 90%. Notably, improvements in cerebral perfusion have been positively correlated with enhanced attentional performance[30].

These findings support the use of cerebral perfusion measurements as potential biomarkers for disease monitoring and therapeutic evaluation.

Altered cerebral energy metabolism

In addition to perfusion abnormalities, severe CAS or occlusion can impair cerebral energy metabolism. Reduced oxygen delivery limits oxidative metabolism, resulting in decreased metabolic efficiency and impaired neuronal function.

Advanced imaging studies have demonstrated that cerebral oxygen metabolism is significantly compromised in patients with high-grade carotid stenosis or occlusion. Importantly, carotid revascularization has been shown to restore global cerebral energy metabolism, suggesting that metabolic impairment may be at least partially reversible[6,31].

Positron emission tomography studies have further revealed that long-term resveratrol supplementation can increase cerebral blood flow in specific brain regions, including the frontal cortex and thalamus, among patients with asymptomatic CAS or occlusion. These hemodynamic improvements were accompanied by measurable cognitive benefits[32].

Therefore, metabolic imaging biomarkers may provide complementary information regarding neuronal viability, treatment response, and long-term cognitive outcomes.

Functional connectivity alterations

Disruption of resting-state functional connectivity

Resting-state functional magnetic resonance imaging has emerged as a powerful tool for investigating large-scale brain networks involved in cognition.

Patients with severe asymptomatic CAS exhibit widespread disruptions in functional connectivity involving the dorsal attention network, frontoparietal network, sensorimotor network, and default mode network (DMN)[33]. Such abnormalities are often accompanied by deficits in working memory, verbal fluency, and executive functioning.

Structural and functional imaging studies have demonstrated reduced gray matter volume, decreased cortical thickness, and impaired connectivity between several cognition-related brain regions. Specifically, decreased connectivity has been observed between the left superior temporal gyrus and precuneus, the middle temporal gyrus and superior temporal gyrus, the insula and middle temporal gyrus, as well as between the middle and superior frontal gyri[34]. These alterations correlate significantly with cognitive performance.

Additional studies have identified reduced activity within the left middle occipital gyrus and weakened connectivity between this region and the frontoparietal network in patients with asymptomatic CAS[35]. Collectively, these findings suggest that functional network disruption represents an important neural substrate underlying cognitive impairment.

Functional connectivity as a predictive and therapeutic biomarker

Beyond its diagnostic value, functional connectivity may serve as a predictive marker and therapeutic target.

The strength of connectivity within specific networks, particularly the dorsal attention network, has been shown to correlate with attentional performance[33]. Furthermore, carotid revascularization can partially reverse network dysfunction.

Following carotid revascularization, increased connectivity within the DMN has been observed in patients with cognitive impairment, and the magnitude of connectivity enhancement is positively associated with improvements in cognitive scores. A pilot study reported significant increases in functional connectivity between the left lateral parietal cortex and the right cingulate cortex, lingual gyrus, and precuneus three weeks after revascularization. Importantly, enhanced connectivity between the left lateral parietal cortex and precuneus was significantly associated with improved MoCA scores[36].

Similarly, studies of symptomatic chronic internal carotid artery occlusion have demonstrated that disrupted functional connectivity contributes to cognitive decline and that endovascular recanalization can restore connectivity within key cognitive networks. Improvements in network connectivity were positively correlated with cognitive recovery[37].

These findings highlight the potential of functional connectivity biomarkers for early diagnosis, prognosis prediction, treatment monitoring, and mechanistic research in CAS-related cognitive impairment.

Conclusions and future perspectives

Cognitive impairment associated with CAS arises from complex interactions among vascular dysfunction, chronic inflammation, cerebral hypoperfusion, BBB disruption, and neurodegenerative processes. Because no single biomarker can comprehensively capture the multifactorial pathophysiology of this condition, multimodal assessment strategies are increasingly recognized as the most promising approach for improving diagnosis and risk stratification.

Among biological biomarkers, systemic inflammatory markers, neuroinflammatory mediators related to the NLRP3 inflammasome pathway, lipid-associated biomarkers, and neuronal injury markers such as p-tau217 have demonstrated significant associations with cognitive dysfunction. However, their clinical utility remains limited by insufficient standardization, uncertain diagnostic thresholds, and variability in sensitivity and specificity.

Neuroimaging biomarkers provide complementary insights into the structural, hemodynamic, metabolic, and functional consequences of CAS. Structural MRI can identify cortical atrophy and white matter injury, DTI enables quantification of microstructural white matter damage, cerebral perfusion and metabolic imaging reveal hemodynamic compromise, and resting-state functional MRI characterizes alterations in large-scale cognitive networks. Together, these modalities offer a comprehensive framework for evaluating cognitive risk.

Future research should focus on several key areas. First, the causal relationships and mediating effects among biological and imaging biomarkers require further clarification. Second, multimodal predictive models integrating molecular, genetic, structural, and functional biomarkers should be developed to improve individualized risk stratification. Third, the utility of biomarkers in guiding personalized therapeutic decision-making and monitoring treatment responses warrants further investigation. Finally, large-scale prospective studies with long-term follow-up are needed to validate the prognostic value of these biomarkers for cognitive outcomes and to facilitate their translation into clinical practice.

In conclusion, the integration of biological and imaging biomarkers holds considerable promise for advancing the early detection, mechanistic understanding, risk assessment, and precision management of cognitive impairment associated with CAS.

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The Author(s) 2026. This article is published by Higher Education Press at journal.hep.com.cn.