Systemic Inflammation and White Matter Hyperintensities Associated with Cognitive Impairment in Intracranial Atherosclerotic Stenosis: A Retrospective Observational Study

Abstract

Background and Purpose

Cognitive impairment is a common clinical symptom in individuals with intracranial atherosclerotic stenosis (ICAS), but the underlying mechanisms have not been completely elucidated. This study aimed to identify factors associated with cognitive impairment in ICAS and explore their interrelationships.

Methods

A total of 129 consecutive patients with ICAS and 31 healthy controls were enrolled in this research. Among the patients with ICAS, 96 completed the Montreal Cognitive Assessment (MoCA), as did all healthy controls. Cognitive impairment was defined as MoCA <23, with scores ≥23 indicating normal function. Differences between these subgroups in peripheral blood inflammatory markers and neuroimaging features were assessed. Multivariate regression models identified independent predictors of cognitive impairment and evaluated their interrelationships.

Results

Patients with ICAS exhibited significantly lower MoCA scores than the controls (18.08 vs 25.10; P < 0.001). Within the ICAS cohort, individuals with cognitive impairment were older. They demonstrated greater systemic immune dysregulation, characterized by lower lymphocyte-to-monocyte ratio (LMR), higher white matter hyperintensities volume (WMHV), increased prevalence of plaque enhancement, and symptomatic ICAS (all P < 0.05). Multivariate analysis established LMR (OR: 0.65, 95% CI: 0.45–0.93) and lnWMHV (OR: 2.50, 95% CI: 1.54–4.06) as independent factors associated with cognitive impairment (both P < 0.05). LMR showed a positive linear correlation with MoCA scores, whereas lnWMHV displayed a negative correlation (both P < 0.05). Furthermore, moderate-to-severe WMH (overall, deep, or periventricular) was significantly associated with lower LMR (P < 0.05), suggesting an association between systemic inflammatory status and WMH in patients with ICAS.

Conclusion

Cognitive impairment in ICAS was associated with lower LMR and greater WMH burden, suggesting potential involvement of inflammatory dysregulation and white matter injury in cognitive dysfunction among patients with ICAS.

Introduction

Intracranial atherosclerotic stenosis (ICAS) is the most prevalent cause of ischemic stroke worldwide. ICAS accounts for 20–40 cases per 100,000 person-years globally and 33–50% of strokes/transient ischemic attacks in Asian populations.^1–3 ICAS not only leads to high disability and mortality rates, but also independently contributes to dementia and progressive cognitive impairment.^4,5 This significantly escalates the societal disease burden.

Cognitive impairment in patients with ICAS is associated with vascular risk factors (such as age, diabetes, and low-density lipoprotein level). However, cognitive impairment in ICAS may also be related to other factors.⁴ In recent years, inflammatory processes have been identified as key mechanisms contributing to cognitive impairment. On the one hand, as localized indices of neurovascular inflammation, WMH is substantially linked to overall cognitive decline, including executive function, memory, and attention.^6,7 Of these, a decrease in attention and executive ability could be attributed to the destruction of the integrity of white matter fiber tracts.^8,9 Moreover, the presence and severity of WMH are linked to a significantly higher risk of dementia and functional impairment, with periventricular WMH potentially raising the dementia risk by 1.51 times.^10,11 On the other hand, systemic inflammatory markers are involved in cognitive impairment. In patients with post-stroke cognitive impairment, the neutrophil/lymphocyte ratio (NLR) and C-reactive protein/lymphocyte ratio are significantly increased, while the lymphocyte/monocyte ratio (LMR) is decreased.¹² Studies have shown that inflammatory markers, such as interleukin (IL)-6, IL-1β, lipopolysaccharide-binding protein, and toll-like receptor 4, are markedly elevated in elderly individuals with cognitive impairment aged >60 years.¹³ Furthermore, research has shown that inflammatory markers, such as the Systemic Immune Inflammation Index (SII) and the Systemic Inflammatory Response Index (SIRI), are positively correlated with cognitive impairment, with SIRI being particularly notable.¹⁴

Inflammation plays a critical role in the formation and instability of ICAS.^1,2,15 Inflammatory components, including lipids and leukocytes, contribute to plaque progression and may precipitate clinical events.¹ The inflammatory infiltrate in ICAS can degrade interstitial collagen, causing plaque instability. Our prior work found that a low LMR in ICAS patients correlates with both plaque instability and a higher risk of stroke recurrence,¹⁵ but it remains unclear whether these inflammatory biomarkers relate to cognitive problems in ICAS patients. This knowledge gap could be clinically meaningful. Clarifying these associations may improve our understanding of cognitive impairment in ICAS. This study investigated neuropsychological deficits and their correlates in ICAS patients, as well as the associations of peripheral blood inflammatory markers and neuroimaging features with cognitive impairment.

Materials and Methods

Study Population

This retrospective observational study was conducted in accordance with the REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) statement.¹⁶ Patients with ICAS treated at our institution between October 2018 and July 2024 were included. The enrollment of the patients required a definitive diagnosis through either digital subtraction angiography or magnetic resonance angiography (MRA).

For their inclusion, the patients were required to meet all of the following conditions: 1) age >18 years; 2) all subjects underwent magnetic resonance imaging, including T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), T2 fluid attenuated inversion recovery (T2 FLAIR), diffusion-weighted imaging (DWI), and high-resolution vessel wall imaging (HR-VWI); 3) patients with ICAS underwent neuropsychological assessment after admission and before the scheduled intervention, following the initial clinical evaluation, including the Montreal Cognitive Assessment (MoCA), Self-Rating Depression Scale (SDS), and Hamilton Anxiety Scale (HAMA). The patients who met any of the following criteria were excluded from the study: 1) non-atherosclerotic vasculopathies, including arterial dissection, intracranial aneurysm, or moyamoya disease; 2) prior cerebrovascular events, including a history of intracranial hemorrhage or intracranial arterial occlusion; 3) cardiovascular comorbidities: coronary artery disease and other significant cardiac pathologies; 4) systemic disorders, including malignancies, autoimmune diseases, persistent or chronic infections, hematologic conditions, and severe systemic illness. Concurrently, healthy controls were recruited from the community and confirmed to have no ICAS by MRA examination. The institutional review board at our center approved this study protocol.

Laboratory Assessment

Peripheral blood samples were obtained within 24 h of hospital admission and subjected to comprehensive analyses, including quantifiable parameters such as the lipid profiles (LDL-C and HDL-C), systemic inflammatory markers (high-sensitivity C-reactive protein; hs-CRP), and counts of various white blood cell types. The following three immunoinflammatory indices were derived computationally: i) NLR = neutrophil count/lymphocyte count; ii) LMR = lymphocyte count/monocyte count; iii) SII = platelet count × neutrophil count/lymphocyte count.

Imaging-Related Data and Related Analysis

Every ICAS patient underwent a cranial MR exam upon admission using a 3.0T-MR scanner equipped with a 32-channel head coil. The scanning procedures comprised T1WI, T2WI, T2 FLAIR, DWI, MRA, and HR-VWI scans. Detailed scanning parameters for these images are provided in the Supplementary Material 1.

The ICAS plaques were identified based on the presence of wall thickening on HR-VWI, both before and after contrast administration.¹⁷ Acute/subacute infarcts were precisely localized using DWI and FLAIR sequences. Thus, a plaque was classified as symptomatic if it met either of the following criteria: i) the sole lesion in the same side region of the ischemic stroke; ii) the narrowest plaque was identified when multiple plaques were present in the same area during an ischemic event. Transient ischemic attacks were not considered to be symptomatic. Consequently, plaques without any acute infarction in their parent arterial territory were designated as asymptomatic.¹⁸

Plaque enhancement was precisely characterized as enhanced visible signal intensity on T1 sequences occurring 5 min after the administration of gadolinium at a dose of 0.1 mmol/kg.¹⁹

WMH Volume Measurement

WMH appeared hyperintense on T2 FLAIR, isointense on DWI, hyperintense on T2WI, and isointense to mildly hypointense on T1WI. Fazekas and Schmidt’s visual rating scale was employed to determine the extent of WMH in both the deep WMH (DWMH) and periventricular WMH (PWMH). DWMH were evaluated with scores from 0 to 3, with 0 indicating no lesion, 1 indicating punctate foci, 2 indicating mild confluence, and 3 indicating confluent changes. The scoring for PWMH ranged from 0 to 3, with 0 indicating no changes, 1 indicating caps or a pencil-thin lining, 2 indicating a smooth halo, and 3 indicating irregular changes reaching into the DWM. DWMH/PWMH were assessed by two researchers who were not acquainted with the study or the clinical data. We categorized DWMH/PWMH into none-to-mild and moderate-to-severe based on Fazekas scores of 0–1 and 2–3.²⁰ Moderate-to-severe WMH was classified based on the presence of moderate-to-severe DWMH or PWMH; otherwise, it was classified as none-to-mild WMH.

The volume of WMH (WMHV) was measured using ITK-SNAP, a popular tool for segmenting 3D image data.²¹ FLAIR hyperintensity lesions were segmented and measured independently. WMHV was quantitatively analyzed by a neurologist with prior experience, who was blinded to the patient’s information; these findings were confirmed by a senior neurologist. ITK-SNAP automatically calculated WMHV, and the image evaluators could access other MRI sequences during the analysis. WMHV was natural logarithm-transformed (lnWMHV) before statistical analysis.²²

Assessments of Neuropsychological Functions

To assess the presence or absence of cognitive impairment, we utilized the validated Chinese version of the MoCA. Based on past research,²³ we classified the MoCA scores <23 as indicative of cognitive impairment (cognitive impairment group) and ≥23 as normal (normal cognitive group). Educational attainment was recorded for all participants and categorized as ≤ 12 years of education. In addition, the Chinese versions of the HAMA and SDS were administered to assess anxiety and depression. In this study, trained evaluators assessed cognitive, anxiety, and depressive status after admission and before the scheduled intervention.

Statistical Analyses

Initially, clinical, laboratory, neuroimaging, and cognitive data were systematically compared across ICAS patients and healthy controls. Next, ICAS patients were dichotomized by the cognitive status (MoCA < 23 vs ≥ 23) for subgroup comparisons. Subsequently, independent factors of cognitive impairment were identified through backward multivariate logistic regression in ICAS patients. Through correlation analyses, we determined the presence of a linear association between MoCA scores and independent factors for cognitive impairment in ICAS patients. Finally, Spearman correlation analysis was performed to evaluate the associations among cognitive scores, inflammatory biomarkers, neuroimaging parameters, and other continuous clinical variables. The results were visualized using a correlation heatmap and scatter plots with regression lines. Data distributions were visualized using half violin plots, with individual observations displayed as scatter points.

SPSS 29.0 software was used to conduct the statistical analyses. Continuous variables were presented as mean ± standard deviation or median (interquartile range), which were compared using Student’s t-test or the Mann–Whitney U-test. Categorical data were presented as counts (percentages), compared using Fisher’s exact or χ²-tests, with two-tailed P < 0.05 indicating statistical significance.

Results

Clinical Characteristics

A total of 129 patients with ICAS were included in the 6-year study based on the inclusion and exclusion criteria. Moreover, 31 healthy adults were included as the control group. The average age of the patients with ICAS was 59.90 ± 10.48 years, and 74 of them were men. The clinical traits of patients with ICAS and healthy adults are presented in Table 1. Of the patients with ICAS, 96 were assessed for MoCA, of whom 71 (74.0%) exhibited cognitive impairment and 25 displayed normal cognitive function. Statistical analyses revealed that hypertension, diabetes, and smoking were significantly associated with ICAS in the clinical data (Table 1).

Table 1.

Characteristics of Patients with ICAS and Healthy Adults

	Patients with ICAS (n=129)	Healthy Controls (n=31)	P value
Age (yr)	59.90 ± 10.48	57.45 ± 14.50	0.283
Male	74 (57.36%)	16 (51.61%)	0.687
Education level ≤ 12 years	110 (85.3%)	23 (74.2%)	0.139
Hypertension	99 (76.74%)	12 (38.71%)	<0.001
Diabetes	55 (42.64%)	3 (9.68%)	<0.001
Smoking	41 (31.78%)	1 (3.23%)	<0.001
Drinking	24 (18.60%)	2 (6.45%)	0.112
WBC, ×109/L	6.99 (6.04–8.64)	5.90 (5.12–6.86)	< 0.001
LYM, ×109/L	2.00 ± 0.72	2.61 ± 0.87	< 0.001
NEUT, ×109/L	4.23 (3.36–5.57)	2.35 (1.95–3.68)	< 0.001
MONO, ×109/L	0.58 ± 0.23	0.46 ± 0.17	0.008
Platelets, ×109/L	258.58 ± 73.15	239.87 ± 50.70	0.180
CHOL	4.62 ± 1.22	4.25 ± 1.02	0.381
TG	1.40 (1.03–1.82)	1.20 (0.95–2.08)	0.864
HDL-C	1.10 ± 0.24	1.12 ± 0.15	0.744
LDL-C	2.97 ± 0.95	2.67 ± 0.79	0.355
ApoE	39.69 ± 13.02	45.12 ± 13.75	0.231
hs-CRP	2.01 (0.87–5.85)	0.36 (0.19–1.04)	0.006
NLR	2.24 (1.62–3.11)	0.87 (0.60–1.68)	< 0.001
LMR	3.80 ± 1.55	6.45 ± 3.13	< 0.001
SII	535.72 (404.04–914.16)	208.94 (135.00–374.85)	< 0.001
MoCA	18.08 ± 5.78	25.10 ± 3.68	< 0.001
HAMA	8.00 (4.00–12.00)	3.00 (3.00–5.00)	0.052
SDS	34.00 (29.00–40.00)	26.00 (26.00–29.00)	0.004

Note: Bold values indicate statistical significance (P < 0.05).

Abbreviations: LYM, lymphocyte counts; NEUT, neutrophil counts; MONO, monocyte counts; NLR, neutrophil to lymphocyte ratio; LMR, lymphocyte to monocyte ratio; SII, systemic immune inflammation index; MoCA, Montreal Cognitive Assessment.

Patients with ICAS Exhibited Cognitive Impairment and Abnormal Levels of Inflammatory Markers

Compared with healthy adults, the MoCA scores were significantly lower in the ICAS group, but the SDS scores were higher (MoCA, 18.08 vs 25.10, P < 0.001; SDS, 34.00 vs 26.00, P = 0.004; HAMA, 8.00 vs 3.00, P = 0.052). Patients exhibited elevated levels of white blood cells (WBC), neutrophils (NEUT), monocytes (MONO), hs-CRP, NLR, and SII (all P < 0.01) but reduced levels of lymphocytes (LYM) and LMR (both P < 0.001) compared with controls (Table 1).

Lower LMR, Plaque Enhancement, Symptomatic ICAS, and WMH Were Associated with Cognitive Impairment in Patients with ICAS

Patients with ICAS and cognitive impairment were older (P = 0.044), had a higher proportion of individuals with ≤12 years of education (P = 0.027), had lower LMR levels (P = 0.005), and showed a higher rate of plaque enhancement (P = 0.018) and symptomatic ICAS (P = 0.039) (Table 2). A substantial inter-rater agreement was observed in the assessment of DWMH/PWMH in 96 cases (κ values were 0.88 and 0.91, respectively). Moreover, cognitive impairment in patients with ICAS was associated with WMH, including WMH volume (3.71 vs 0.56, P < 0.001), lnWMHV (8.15 vs 6.34, P < 0.001), moderate-to-severe WMH (74.65% vs 28.00%, P < 0.001), moderate-to-severe DWMH (59.15% vs 24.00%, P = 0.002), and moderate-to-severe PWMH (70.42% vs 16.00%, P < 0.001). Compared with the cognitively normal group, the cognitive impairment group also showed elevated HAMA (P = 0.003) and SDS (P = 0.002) scores.

Table 2.

Factors Associated with Cognitive Impairment in Patients with ICAS

	Cognitive Impairment Group (n=71)	Cognitively Normal Group (n=25)	P value
Age (yr)	60.37 ± 10.59	55.40 ± 10.09	0.044
Male	38 (53.52%)	15 (60.00%)	0.644
Education level ≤ 12 years	64 (90.14%)	18 (72.00%)	0.027
Hypertension	57 (80.28%)	16 (64.00%)	0.111
Diabetes	33 (46.48%)	8 (32.00%)	0.246
Smoking	21 (29.58%)	10 (40.00%)	0.456
Drinking	15 (21.13%)	3 (12.00%)	0.386
WBC, ×109/L	6.80 (5.87–8.28)	6.40 (5.41–8.97)	0.890
LYM, ×109/L	1.96 ± 0.72	2.25 ± 0.71	0.082
NEUT, ×109/L	3.96 (3.27–5.61)	3.90 (3.13–5.07)	0.596
MONO, ×109/L	0.56 ± 0.21	0.52 ± 0.23	0.339
Platelets, ×109/L	251.39 ± 58.37	247.24 ± 76.16	0.779
ApoE	36.92 ± 10.94	41.30 ± 13.72	0.361
NLR	2.25 (1.56–3.37)	1.83 (1.53–2.34)	0.126
LMR	3.74 ± 1.52	4.85 ± 1.70	0.005
SII	537.35 (405.06–929.35)	451.08 (364.00–541.30)	0.073
hs-CRP	2.01 (0.67–6.46)	1.87 (1.21–5.05)	0.950
CHOL	4.29 (3.47–5.16)	5.02 (4.25–5.85)	0.053
TG	1.43 (1.03–1.84)	1.51 (1.29–2.23)	0.222
HDL-C	1.09 (0.90–1.25)	1.07 (0.98–1.24)	0.623
LDL-C	2.75 (2.15–3.51)	3.13 (2.58–3.93)	0.078
Symptom	43 (60.56%)	9 (36.00%)	0.039
Plaque enhancement	46 (64.79%)	9 (36.00%)	0.018
Overall WMH	69 (97.18%)	21 (84.00%)	0.038
Moderate-to-severe Overall WMH	53 (74.65%)	7 (28.00%)	< 0.001
Moderate-to-severe DWMH	42 (59.15%)	6 (24.00%)	0.002
Moderate-to-severe PWMH	50 (70.42%)	4 (16.00%)	< 0.001
WMH volume, cm3	3.71 (1.49–11.19)	0.56 (0.26–1.57)	< 0.001
lnWMHV	8.15 ± 1.40	6.34 ± 1.21	< 0.001
HAMA score	8.00 (6.00–13.50)	4.00 (3.00–8.50)	0.003
SDS score	36.00 (30.00–44.00)	29.50 (26.00–35.00)	0.002

Note: Bold values indicate statistical significance (P < 0.05).

Abbreviations: LYM, lymphocyte counts; NEUT, neutrophil counts; MONO, monocyte counts; NLR, neutrophil to lymphocyte ratio; LMR, lymphocyte to monocyte ratio; SII, systemic immune inflammation index; CHOL, Cholesterol; TG, Triglyceride; HDL-C, High density lipoprotein cholesterol; LDL-C, Low-Density Lipoprotein Cholesterol; WMH volume, White Matter Hyperintensities volume; HAMA, Hamilton Anxiety Scale; SDS, self-rating depression scale.

LMR and lnWMHV Were Independently Associated with Cognitive Impairment in Patients with ICAS and Were Linearly Correlated with MoCA

Backward multiple logistic regression analysis revealed that LMR (OR: 0.65, 95% CI: 0.45–0.93, P = 0.018) and lnWMHV (OR: 2.50, 95% CI: 1.54–4.06, P < 0.001) were independently associated with cognitive impairment (Figure 1).

Figure 1.

Multiple logistic regression analysis of factors associated with cognitive impairment in patients with ICAS. Black squares represent odds ratio (OR) estimates, and horizontal black lines represent 95% confidence intervals (CIs). Bold values indicate statistically significant associations (P < 0.05). LMR, lymphocyte-to-monocyte ratio; lnWMHV, natural logarithm-transformed white matter hyperintensity volume.

Furthermore, linear correlation analysis demonstrated a positive association between LMR and MoCA scores (R = 0.228, P = 0.026), whereas lnWMHV was inversely correlated with MoCA scores (R = −0.567, P < 0.001) (Figures 2A and B). In addition, Spearman correlation analysis was performed to evaluate the overall relationships among cognitive scores, inflammatory biomarkers, neuroimaging parameters, and clinical variables. The correlation patterns are presented in Supplementary Figure 1.

Figure 2.

A positive linear association was detected between LMR and MoCA scores (A), whereas lnWMHV showed a negative linear association with MoCA scores in ICAS patients (B).

Lower LMR and MoCA Scores Were Linked to Moderate-to-Severe WMH in Patients with ICAS

MoCA scores were significantly lower in patients with ICAS and moderate-to-severe WMH (16.00 vs 22.50, P < 0.001), DWMH (16.00 vs 20.00, P = 0.001), and PWMH (16.00 vs 22.50, P < 0.001) (Figure 3A–C). LMR levels were also significantly lower in patients with ICAS and moderate-to-severe WMH (3.47 vs 4.68, P = 0.008), DWMH (3.47 vs 4.60, P = 0.003), and PWMH (3.47 vs 4.60, P = 0.029) (Figure 3D–F).

Figure 3.

The MoCA score were significantly lower in ICAS patients with moderate-to-severe WMH (A), DWMH (B), PWMH (C), and LMR were also significantly lower in ICAS patients with moderate-to-severe WMH (D), DWMH (E), and PWMH (F). *P < 0.05; **P < 0.01; #P < 0.001.

Discussion

In this retrospective study, we investigated the associations between systemic inflammation, WMH, and cognitive impairment in patients with ICAS. Lower LMR and greater lnWMHV were independently associated with cognitive impairment and correlated with MoCA scores. In addition, greater WMH severity was associated with reduced LMR, suggesting a potential relationship between systemic inflammatory status and white matter injury in ICAS.

The cognitive status of patients with ICAS has become a focal research point. A population-based longitudinal study showed that the incidence of cognitive impairment was significantly higher in patients with cervicocerebral stenosis.²⁴ Moreover, a combination of cross-sectional, prospective cohort, and autopsy data established that ICAS was an independent predictor of cognitive impairment in various populations. The level of stenosis and the involvement of multiple vessels worsened the severity of the impairment.²⁵ This study found that patients with ICAS exhibited a decline in cognitive function compared with healthy adults, a finding consistent with previous studies.

Earlier investigations have documented that levels of inflammatory markers in the bloodstream are associated with cognitive decline.^26,27 In a large Chinese community-based cohort, higher NLR, an indicator of systemic inflammatory imbalance, was independently associated with cognitive impairment, with individuals in the highest NLR quartile showing an increased risk of cognitive impairment compared with those in the lowest quartile (OR: 1.51, 95% CI: 1.16–1.95).²⁸ However, few studies have examined the relationship between circulating inflammation and cognitive impairment in patients with ICAS. Our team’s previous research identified that LMR was an independent risk factor for symptomatic ICAS and plaque enhancement, suggesting that LMR may reflect ICAS plaque instability.^15,29 In the present study, lower LMR was independently associated with cognitive impairment in patients with ICAS (OR: 0.65, 95% CI: 0.45–0.93), and LMR showed a positive linear association with MoCA scores, suggesting that systemic immune dysregulation may be associated with cognitive dysfunction in ICAS.

Prior studies have established a robust association between cognitive impairment and WMH. Longitudinal studies and meta-analyses have consistently demonstrated that increased WMHV is associated with accelerated cognitive deterioration and an elevated risk of dementia across diverse populations.^30–32 Supporting this association, a meta-analysis of ischemic stroke cohorts reported that moderate-to-severe WMH was associated with an increased risk of cognitive impairment (RR: 2.29, 95% CI: 1.48–3.54), while another meta-analysis of 36 prospective studies demonstrated that WMH was associated with increased risks of cognitive impairment and dementia, with PWMH conferring approximately a 1.51-fold higher risk of dementia.^10,11 Consistent with previous findings, our study observed that patients with cognitive impairment exhibited substantially greater WMH burden, including higher WMHV (3.71 vs 0.56) and increased prevalence of moderate-to-severe PWMH (70.42% vs 16.00%), further supporting the association between WMH burden and cognitive dysfunction. Previous studies have suggested that WMH involves local neuroinflammatory processes, including astrocyte activation and microglial proliferation.⁷ In our study, the association between greater WMH severity and reduced LMR further suggests a potential link between systemic inflammatory dysregulation and white matter changes in patients with ICAS, although the underlying mechanisms require further investigation.

In addition, this study identified a significant correlation between WMH and systemic inflammatory biomarker LMR in patients with ICAS. Previous studies have also suggested that systemic inflammation is associated with WMH burden. In individuals without dementia, inflammatory biomarkers were associated with greater white matter lesion burden and cognitive decline.³³ Moreover, SERPINA3, an inflammatory biomarker, showed a linear dose–response relationship with WMH burden in patients with ischemic stroke.³⁴ Community-based studies further demonstrated that endothelial inflammatory markers, such as VCAM-1, were positively associated with WMH progression.³⁵ Similarly, systemic inflammatory markers were associated with WMH volume and white matter microstructural injury in large population-based cohorts.^36,37 Consistent with these findings, our study demonstrated that lower LMR was associated with more severe WMH, including overall WMH, DWMH, and PWMH, suggesting that systemic immune dysregulation may contribute to white matter injury in patients with ICAS.

A significant relationship was also observed between cognitive impairment and local inflammation (plaque enhancement on HR-VWI) in this study. Vulnerable plaques were identified based on the imaging marker of plaque enhancement.^19,38 Pathological investigations have revealed that gadolinium enhancement of atherosclerotic plaques is independently related to both macrophage area and microvessel density, indicating that local inflammation is responsible for plaque enhancement on HR-VWI.³⁹ Moreover, our earlier study found that LMR was independently associated with ICAS plaque enhancement.^15,29

Patients with ICAS have a higher likelihood of experiencing anxiety and depression. Moreover, during the initial phases of Alzheimer’s disease, anxiety and depression often accompany cognitive decline owing to challenges in coping.⁴⁰ In this study, patients with ICAS who exhibited cognitive impairment had higher SDS and HAMA scores than those who were cognitively normal. Inflammation might be a shared factor in this phenomenon as it has been linked to the pathophysiology of depression.⁴¹

In summary, lower LMR and greater WMH burden were associated with cognitive impairment in patients with ICAS. The observed associations among systemic inflammatory status, WMH burden, and cognitive impairment suggest potential interrelationships that warrant further investigation.

Nonetheless, this study has several limitations. First, its single-center retrospective design and moderate sample size might have introduced selection bias, although statistical adjustments were performed to reduce potential confounding effects. Second, cognitive assessments during hospitalization might have been affected by acute stroke-related factors, and potential residual effects of education on MoCA performance cannot be completely excluded. Third, although multiple inflammatory biomarkers were evaluated, the biological mechanisms linking systemic inflammation, WMH burden, and cognitive impairment remain unclear. Future mechanistic and longitudinal studies are warranted to further clarify these associations. Fourth, machine learning approaches were not applied due to the limited sample size and lack of an independent validation cohort. Future studies with larger multicenter datasets are needed to develop and validate machine learning-based models for cognitive impairment risk prediction in patients with ICAS. Finally, because our cohort exclusively included Chinese participants, further multiethnic validation is warranted to determine the generalizability of our findings.

Conclusion

Cognitive impairment in ICAS is associated with WMH and systemic immune dysregulation, represented by lower LMR. The association between LMR and WMH suggests a potential relationship between peripheral immune status and white matter changes. Further prospective studies with larger cohorts are required to validate these findings and clarify the underlying mechanisms linking systemic inflammation, WMH burden, and cognitive impairment in ICAS.

Funding Statement

This study was supported by the National Administration of Traditional Chinese Medicine Foundation of China (No. CXZH202404015) and Sun Yat-Sen Eighth Affiliated Hospital Clinical Research Program (PY-2025-5).

Data Sharing Statement

The data and materials supporting the results and analyses presented in this study are available from the corresponding author upon reasonable request, subject to applicable ethical and privacy requirements.

Ethics Statement

This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Sun Yat-Sen Memorial Hospital (Ethics approval ID: SYSKY-2025-642-01). The patients/participants provided their written informed consent to participate in this study.

Author Contributions

Zhong-Run Huang: Conceptualization, Data curation, Methodology, Formal analysis, and Writing – original draft. Hui-Tong Pan: Data curation, Methodology, Investigation, Writing – original draft. Chi-Chen Liu: Data curation, Formal analysis, Visualization, Writing – original draft. Sheng-Wen Wang: Methodology, Resources, Visualization, Writing – original draft. Xin Guo: Investigation, Project administration, Writing – review & editing. Yi-Ao Liu: Validation, Resources, Writing – review & editing. Li-Xin Huang: Resources, Software, Writing – review & editing. Shao-Yi Fan: Software, Validation, Writing –review & editing. Xiao-Bing Wu: Conceptualization, Project administration, Supervision, Writing – review & editing. Mei-Guang Zheng: Conceptualization, Project administration, Supervision, Writing – review & editing. Bin Luo: Conceptualization, Methodology, Validation, Funding acquisition, Supervision, Writing – review & editing. All authors gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare no conflicts of interest.