Stroke continues to be a predominant cause of death and long-term impairment globally, with ischemic stroke representing roughly 80-85% of all stroke instances [1]. Notwithstanding progress in comprehending classic risk variables including hypertension, diabetes mellitus, dyslipidemia, and smoking, a significant number of stroke instances arise in individuals devoid of conventional risk factors. [2]. This observation has prompted investigation of novel and emerging risk factors that may contribute to stroke pathogenesis. Homocysteine, a sulfur-containing amino acid resulting from methionine metabolism, has attracted significant interest as a potential independent risk factor for atherosclerotic vascular disease.[3]. Elevated plasma homocysteine levels, termed hyperhomocysteinemia, result from genetic polymorphisms affecting homocysteine metabolism (particularl methylenetetrahydrofolate reductase variants), nutritional deficiencies of folate, vitamin B12, or vitamin B6, renal dysfunction, certain medications, and lifestyle factors [4]. Normal fasting homocysteine concentrations typically range from 5-15 μmol/L, with hyperhomocysteinemia generally defined as levels exceeding 15 μmol/L [5]. The biological mechanisms linking hyperhomocysteinemia to vascular disease are multifaceted. Experimental studies have showed that elevated homocysteine promotes endothelial dysfunction through oxidative stress, reduces nitric oxide bioavailability, enhances smooth muscle cell proliferation, increases platelet aggregation, and activates procoagulant pathways [6, 7]. These pathophysiological processes create a prothrombotic and atherogenic milieu conducive to arterial thrombosis and stroke occurrence. Epidemiological evidence supporting the association between hyperhomocysteinemia and stroke has accumulated over the past three decades. A landmark meta-analysis by Homocysteine Studies Collaboration, encompassing data from multiple prospective studies, demonstrated that a 25% lower homocysteine level was associated with an 11% lower ischemic heart disease risk and 19% lower stroke risk [8]. Subsequent observational studies have reported varying strength of association, with some demonstrating robust relationships [9, 10] while others showed modest or inconsistent findings [11]. Recent research has extended beyond simple association to explore relationships between homocysteine levels and specific stroke characteristics. Several investigators have examined whether homocysteine correlates with stroke severity, with studies by Kim et al. and Yoldas et al. reporting positive associations between homocysteine concentrations and neurological deficit severity [12, 13]. Additionally, differential homocysteine levels across ischemic stroke subtypes have been investigated, with some evidence suggesting higher levels in large artery atherosclerosis compared to cardioembolic or lacunar strokes [14]. Despite this growing body of evidence, several controversies persist. Large randomized controlled trials of B-vitamin supplementation aimed at lowering homocysteine have yielded disappointing results regarding stroke prevention [15, 16], raising questions about the causal nature of the homocysteine-stroke association. Furthermore, ethnic and geographic variations in both baseline homocysteine levels and the strength of association with stroke necessitate region-specific studies. Data from diverse populations remain limited, and the clinical utility of homocysteine assessment in stroke risk stratification and management remains debated. In our population, comprehensive data regarding homocysteine levels in ischemic stroke patients, particularly in relation to stroke severity and subtypes, are lacking. Understanding these relationships has important implications for risk stratification, potential therapeutic interventions, and public health strategies targeting modifiable metabolic risk factors. Aim of the study: This case-control study aimed to: (1) measure and compare serum homocysteine levels between acute ischemic stroke patients and healthy controls; (2) assess the association between hyperhomocysteinemia and ischemic stroke; (3) evaluate the correlation between homocysteine levels and stroke severity as measured by NIHSS; and (4) compare homocysteine levels across different ischemic stroke subtypes classified by TOAST criteria.

This study was conducted in Department of General Medicine at Dr Moopens Medical College, Wayanad, Kerala which comprised 150 consecutive patients with acute ischemic stroke (cases) and 150 age- and sex-matched healthy individuals (controls). Sample size was calculated using a two-sample t-test formula with 90% power, 5% significance level, assuming a mean difference of 5 μmol/L in homocysteine levels with a pooled standard deviation of 8 μmol/L, yielding a minimum required sample of 138 per group. The sample was increased to 150 per group to account for potential exclusions. Inclusion and Exclusion Criteria Inclusion criteria for cases: (1) Age 18-80 years; (2) acute ischemic stroke verified by brain computed tomography (CT) or magnetic resonance imaging (MRI) within 48 hours of symptom onset; (3) first-ever stroke or prior stroke with complete recovery; and (4) presentation within 72 hours of symptom onset. Inclusion criteria for controls: (1) Age- and sex-matched healthy volunteers; (2) no history of stroke, transient ischemic attack, or other cerebrovascular disease; (3) no acute illness; and (4) willing to participate. Exclusion criteria for both groups: (1) Hemorrhagic stroke or stroke of undetermined type; (2) current vitamin B12, B6, or folic acid supplementation; (3) chronic kidney disease (estimated glomerular filtration rate <30 mL/min/1.73m²); (4) chronic liver disease; (5) malignancy; (6) thyroid disorders; (7) pregnancy or lactation; (8) autoimmune diseases; (9) recent surgery or major trauma within 3 months; and (10) medications known to affect homocysteine metabolism (methotrexate, phenytoin, theophylline). Clinical Assessment Detailed clinical history and demographic data were collected using structured proformas. For stroke patients, time of symptom onset, presenting symptoms, and neurological examination findings were documented. Vascular risk factors including hypertension, diabetes mellitus, dyslipidemia, smoking, alcohol consumption, and family history of vascular disease were recorded. Stroke severity was evaluated utilizing the National Institutes of Health Stroke Scale (NIHSS) within 24 hours after admission by qualified neurologists. NIHSS scores were classified as follows: mild stroke (NIHSS 1-4), moderate stroke (NIHSS 5-15), and severe stroke (NIHSS >15). The Glasgow Coma Scale (GCS) was recorded. Stroke subtypes were categorized based on the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria into five classifications: (1) large artery atherosclerosis, (2) cardioembolism, (3) small vessel occlusion (lacunar), (4) stroke of other determined etiology, and (5) stroke of undetermined etiology. Classification relied on clinical characteristics, neuroimaging, vascular imaging (including carotid Doppler, CT angiography, or MR angiography), and cardiac assessment (electrocardiography and echocardiography when warranted). Neuroimaging All stroke patients underwent brain imaging with non-contrast CT or MRI within 48 hours of symptom onset. Additional vascular imaging was performed based on clinical indication to identify large vessel stenosis or occlusion. Biochemical Analysis After 8-12 hours overnight fasting, venous blood samples (10 mL) were collected within 48-72 hours of stroke onset for cases, and at the time of enrollment for controls. Samples were collected in plain tubes, allowed to clot at room temperature for 30 minutes, and centrifuged at 3000 rpm for 15 minutes. Serum was separated and stored at -80°C until analysis. Serum total homocysteine levels were measured using chemiluminescence immunoassay (CLIA) method on ADVIA Centaur XP analyzer (Siemens Healthcare Diagnostics). The assay has a measurement range of 1-50 μmol/L with inter-assay and intra-assay coefficients of variation below 7%. Hyperhomocysteinemia was defined as serum homocysteine >15 μmol/L. Levels were further categorized as: normal (<15 μmol/L), moderate hyperhomocysteinemia (15-30 μmol/L), and severe hyperhomocysteinemia (>30 μmol/L). Additional biochemical parameters measured included fasting blood glucose, glycosylated hemoglobin (HbA1c), lipid profile (total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol), serum creatinine, blood urea nitrogen, liver enzymes, serum vitamin B12, and serum folate levels. All biochemical analyses were performed using standard automated methods. Statistical Analysis Statistical analysis was conducted utilizing SPSS version 28.0 (IBM Corp., Armonk, NY). The normality of continuous variables was evaluated by the Kolmogorov-Smirnov test and histogram analysis. Continuous variables were presented as mean ± standard deviation (SD) for normally distributed data or median (interquartile range) for non-normally distributed data. Categorical variables were expressed as frequencies and percentages. The independent t-test or Mann-Whitney U test was employed to compare continuous variables between cases and controls as warranted. One-way ANOVA or the Kruskal-Wallis test was utilized to compare continuous variables among several groups (stroke severity categories and subtypes), followed by post-hoc analyses (Tukey's or Dunn's test) for pairwise comparisons. The Chi-square test or Fisher's exact test was employed for categorical variables. Correlation analysis using Pearson or Spearman methods was conducted to evaluate the connections between homocysteine levels and stroke severity (NIHSS score) as well as other continuous variables. A multivariate logistic regression analysis was performed to determine independent predictors of ischemic stroke, controlling for age, sex, hypertension, diabetes, dyslipidemia, smoking, and other pertinent variables. Odds ratios (OR) accompanied with 95% confidence intervals (CI) were computed. An examination of the receiver operating characteristic (ROC) curve was conducted to evaluate the discriminative capacity of homocysteine for ischemic stroke. A two-tailed p-value of less than 0.05 was deemed statistically significant.

Baseline Characteristics Table 1 presents the baseline demographic and clinical characteristics of study participants. There were no significant differences between stroke patients and controls regarding age (58.4 ± 11.6 vs. 57.8 ± 11.2 years, p=0.652) and sex distribution (62.0% vs. 62.7% males, p=0.902), confirming appropriate matching. However, stroke patients had significantly higher prevalence of vascular risk factors including hypertension (68.0% vs. 32.7%, p<0.001), diabetes mellitus (46.7% vs. 18.0%, p<0.001), dyslipidemia (54.0% vs. 28.7%, p<0.001), current smoking (42.7% vs. 24.0%, p=0.001), and family history of vascular disease (38.0% vs. 22.0%, p=0.003). Mean BMI was higher in stroke patients (26.8 ± 4.2 vs. 24.6 ± 3.4 kg/m², p<0.001). Among stroke patients, 32.7% had mild stroke (NIHSS 1-4), 48.0% had moderate stroke (NIHSS 5-15), and 19.3% had severe stroke (NIHSS >15). According to TOAST classification, large artery atherosclerosis was the most common subtype (38.7%), followed by small vessel occlusion (28.0%), cardioembolism (20.7%), undetermined etiology (10.0%), and other determined etiology (2.6%). Table 1. Baseline Demographic and Clinical Characteristics Characteristic Stroke Patients (n=150) Controls (n=150) p-value Age (years) 58.4 ± 11.6 57.8 ± 11.2 0.652 Male, n (%) 93 (62.0) 94 (62.7) 0.902 Female, n (%) 57 (38.0) 56 (37.3) BMI (kg/m²) 26.8 ± 4.2 24.6 ± 3.4 <0.001 Hypertension, n (%) 102 (68.0) 49 (32.7) <0.001 Diabetes mellitus, n (%) 70 (46.7) 27 (18.0) <0.001 Dyslipidemia, n (%) 81 (54.0) 43 (28.7) <0.001 Current smoking, n (%) 64 (42.7) 36 (24.0) 0.001 Alcohol consumption, n (%) 48 (32.0) 38 (25.3) 0.214 Family history of vascular disease, n (%) 57 (38.0) 33 (22.0) 0.003 NIHSS Score Category Mild (1-4), n (%) 49 (32.7) - Moderate (5-15), n (%) 72 (48.0) - Severe (>15), n (%) 29 (19.3) - TOAST Classification Large artery atherosclerosis, n (%) 58 (38.7) - Cardioembolism, n (%) 31 (20.7) - Small vessel occlusion, n (%) 42 (28.0) - Other determined etiology, n (%) 4 (2.6) - Undetermined etiology, n (%) 15 (10.0) - Serum Homocysteine Levels and Biochemical Parameters Table 2 demonstrates significant differences in serum homocysteine levels and other biochemical parameters between groups. Mean serum homocysteine was markedly elevated in stroke patients compared to controls (18.6 ± 7.4 μmol/L vs. 10.2 ± 3.1 μmol/L, p<0.001). Hyperhomocysteinemia (>15 μmol/L) was present in 64.7% of stroke cases versus 16.7% of controls (p<0.001). Moderate hyperhomocysteinemia (15-30 μmol/L) occurred in 54.0% of stroke patients compared to 15.3% of controls, while severe hyperhomocysteinemia (>30 μmol/L) was observed in 10.7% versus 1.4% respectively. Stroke patients had significantly higher fasting glucose, HbA1c, total cholesterol, LDL-cholesterol, and triglycerides, with lower HDL-cholesterol levels. Vitamin B12 levels were lower in stroke patients (286.4 ± 112.6 vs. 342.8 ± 124.2 pg/mL, p<0.001), as were serum folate levels (6.8 ± 2.4 vs. 8.4 ± 2.6 ng/mL, p<0.001). Table 2. Comparison of Serum Homocysteine and Biochemical Parameters Parameter Stroke Patients (n=150) Controls (n=150) p-value Serum homocysteine (μmol/L) 18.6 ± 7.4 10.2 ± 3.1 <0.001 Homocysteine Categories, n (%) Normal (<15 μmol/L) 53 (35.3) 125 (83.3) <0.001 Moderate elevation (15-30 μmol/L) 81 (54.0) 23 (15.3) Severe elevation (>30 μmol/L) 16 (10.7) 2 (1.4) Hyperhomocysteinemia (>15 μmol/L), n (%) 97 (64.7) 25 (16.7) <0.001 Fasting glucose (mg/dL) 118.6 ± 42.4 94.2 ± 16.8 <0.001 HbA1c (%) 6.4 ± 1.4 5.6 ± 0.6 <0.001 Total cholesterol (mg/dL) 198.6 ± 46.2 176.4 ± 38.4 <0.001 Triglycerides (mg/dL) 168.4 ± 58.6 138.2 ± 42.8 <0.001 HDL-cholesterol (mg/dL) 42.6 ± 10.8 48.4 ± 12.2 <0.001 LDL-cholesterol (mg/dL) 122.4 ± 38.6 106.8 ± 32.4 <0.001 Serum creatinine (mg/dL) 1.1 ± 0.3 0.9 ± 0.2 <0.001 Vitamin B12 (pg/mL) 286.4 ± 112.6 342.8 ± 124.2 <0.001 Serum folate (ng/mL) 6.8 ± 2.4 8.4 ± 2.6 <0.001 Homocysteine Levels by Stroke Severity and Subtypes Table 3 presents homocysteine levels stratified by stroke severity and TOAST subtypes, along with correlation analysis and multivariate regression results. Serum homocysteine showed a strong positive correlation with NIHSS score (r = 0.482, p<0.001), indicating higher homocysteine levels in more severe strokes. Mean homocysteine levels were 14.2 ± 4.8 μmol/L in mild stroke, 19.4 ± 6.2 μmol/L in moderate stroke, and 24.8 ± 8.6 μmol/L in severe stroke (p<0.001 for trend). Post-hoc analysis revealed significant differences between all severity categories. Significant variations in homocysteine levels were observed across TOAST subtypes (p=0.002). Large artery atherosclerosis demonstrated the highest mean homocysteine (21.4 ± 8.2 μmol/L), followed by small vessel occlusion (18.2 ± 6.4 μmol/L), undetermined etiology (17.8 ± 7.6 μmol/L), cardioembolism (15.6 ± 6.2 μmol/L), and other determined etiology (14.2 ± 5.8 μmol/L). Multivariate logistic regression analysis, adjusting for age, sex, hypertension, diabetes, dyslipidemia, smoking, BMI, vitamin B12, and folate levels, demonstrated that hyperhomocysteinemia (>15 μmol/L) was independently associated with ischemic stroke (adjusted OR = 6.84, 95% CI: 3.92-11.94, p<0.001). When analyzed as a continuous variable, each 5 μmol/L increase in homocysteine conferred a 1.72-fold increased risk of ischemic stroke (95% CI: 1.42-2.08, p<0.001). ROC curve analysis revealed an area under the curve (AUC) of 0.812 (95% CI: 0.768-0.856) for homocysteine in discriminating stroke cases from controls, with an optimal cutoff of 13.5 μmol/L yielding 74.7% sensitivity and 76.0% specificity. Table 3. Homocysteine Levels by Stroke Characteristics and Regression Analysis A. Homocysteine by Stroke Severity (NIHSS) n Homocysteine (μmol/L) p-value Mild stroke (NIHSS 1-4) 49 14.2 ± 4.8 <0.001* Moderate stroke (NIHSS 5-15) 72 19.4 ± 6.2 Severe stroke (NIHSS >15) 29 24.8 ± 8.6 Correlation with NIHSS score r = 0.482 <0.001 B. Homocysteine by TOAST Classification n Homocysteine (μmol/L) p-value Large artery atherosclerosis 58 21.4 ± 8.2 0.002* Cardioembolism 31 15.6 ± 6.2 Small vessel occlusion 42 18.2 ± 6.4 Other determined etiology 4 14.2 ± 5.8 Undetermined etiology 15 17.8 ± 7.6 C. Multivariate Logistic Regression for Ischemic Stroke Variable Adjusted OR (95% CI) p-value Hyperhomocysteinemia (>15 μmol/L) 6.84 (3.92-11.94) <0.001 Homocysteine (per 5 μmol/L increase) 1.72 (1.42-2.08) <0.001 Hypertension 3.24 (1.86-5.64) <0.001 Diabetes mellitus 2.68 (1.48-4.86) 0.001 Dyslipidemia 2.12 (1.22-3.68) 0.008 Current smoking 2.04 (1.16-3.59) 0.013 Low vitamin B12 (<200 pg/mL) 2.48 (1.24-4.96) 0.010 Low folate (<5 ng/mL) 1.98 (1.08-3.63) 0.027 D. ROC Curve Analysis Area under curve (AUC) 0.812 (95% CI: 0.768-0.856) <0.001 Optimal cutoff 13.5 μmol/L Sensitivity 74.7% Specificity 76.0% *p-value for overall comparison across groups

This case-control study demonstrates a strong and independent association between elevated serum homocysteine levels and acute ischemic stroke. Our findings reveal that stroke patients have nearly twice the mean homocysteine concentration compared to healthy controls, with hyperhomocysteinemia present in nearly two-thirds of stroke cases. Furthermore, homocysteine levels correlate significantly with stroke severity and vary across ischemic stroke subtypes, with highest levels observed in large artery atherosclerosis. The mean homocysteine level of 18.6 μmol/L observed in our stroke population is consistent with previous reports from similar cohorts [17, 18]. The 64.7% prevalence of hyperhomocysteinemia in our stroke patients aligns with findings from Eikelboom et al., who reported hyperhomocysteinemia in approximately 60% of stroke patients in a meta-analysis of observational studies [19]. Our results extend these observations by demonstrating that hyperhomocysteinemia confers a nearly seven-fold increased odds of ischemic stroke after adjusting for traditional vascular risk factors, indicating an independent pathogenic role. The biological mechanisms underlying the homocysteine-stroke association are well-established. Elevated homocysteine induces endothelial dysfunction through multiple pathways, including increased production of reactive oxygen species, reduced nitric oxide bioavailability, and direct cytotoxic effects on endothelial cells [20]. These processes promote atherogenesis by enhancing smooth muscle cell proliferation, increasing LDL oxidation, and stimulating inflammatory responses [21]. Additionally, homocysteine activates prothrombotic mechanisms by increasing tissue factor expression, enhancing platelet reactivity, activating factor V and factor XII, and inhibiting anticoagulant proteins such as thrombomodulin and protein C [22]. Our finding of a strong positive correlation between homocysteine levels and stroke severity (r = 0.482) is particularly noteworthy. Patients with severe stroke (NIHSS >15) had mean homocysteine levels 75% higher than those with mild stroke. This observation is consistent with studies by Parnetti et al. and Yoldas et al., who reported similar correlations between homocysteine and neurological deficit severity [13, 23]. The mechanisms linking higher homocysteine to greater stroke severity may involve more extensive thrombosis, enhanced inflammatory responses, or greater baseline vascular vulnerability. Alternatively, severe stroke itself, through metabolic stress and altered nutritional status, might acutely elevate homocysteine levels, although the bidirectional nature of this relationship requires longitudinal investigation. The significant variation in homocysteine levels across TOAST subtypes, with highest concentrations in large artery atherosclerosis (21.4 μmol/L), supports the mechanistic role of homocysteine in promoting atherosclerosis [24]. This finding aligns with Khan et al., who demonstrated that hyperhomocysteinemia was more prevalent in atherothrombotic stroke compared to cardioembolic stroke [14]. The chronic pro-atherogenic effects of elevated homocysteine make it biologically plausible that this metabolic abnormality would preferentially associate with atherosclerotic stroke mechanisms rather than cardioembolic sources. The lower vitamin B12 and folate levels observed in our stroke patients are significant, as these vitamins serve as essential cofactors in homocysteine metabolism [25]. Folate is required for remethylation of homocysteine to methionine via methylenetetrahydrofolate reductase (MTHFR), while vitamin B12 serves as a cofactor for methionine synthase [26]. Deficiency of these vitamins impairs homocysteine clearance, leading to accumulation. Our multivariate analysis confirmed that low vitamin B12 and folate levels independently associated with stroke risk, suggesting that nutritional optimization could represent a therapeutic target. The clinical implications of our findings merit consideration. The high discriminatory ability of homocysteine (AUC = 0.812) suggests potential utility as a biomarker for stroke risk assessment. However, before recommending routine homocysteine screening, several considerations are warranted. First, the causal nature of the homocysteine-stroke relationship remains controversial despite strong observational evidence. Large randomized controlled trials of homocysteine-lowering therapy through B-vitamin supplementation have yielded inconsistent results regarding stroke prevention [27, 28]. The HOPE-2 trial showed that folic acid supplementation reduced stroke risk by 25% in patients with vascular disease [29], while the VITATOPS trial showed no significant benefit [30]. A meta-analysis by Wang et al. suggested that folic acid supplementation reduced stroke risk by 18%, with greater effects in populations with lower baseline folate status and without mandatory folic acid fortification [31]. These findings suggest that the preventive benefit of homocysteine lowering may be context-dependent, influenced by baseline nutritional status, genetic factors, and population characteristics. The lack of consistent benefit from homocysteine-lowering interventions has raised questions about whether hyperhomocysteinemia is a causal risk factor or merely a marker of other pathogenic processes. Mendelian randomization studies examining genetic variants affecting homocysteine levels have yielded mixed results [32], although some support a causal relationship specifically for stroke [33]. These observations suggest that while elevated homocysteine may contribute to stroke pathogenesis, other factors associated with hyperhomocysteinemia (such as nutritional deficiencies, lifestyle factors, or genetic polymorphisms) may also play important roles. Our study has several strengths. The comprehensive assessment of homocysteine in relation to stroke severity and subtypes provides detailed characterization beyond simple case-control comparison. Rigorous adjustment for multiple confounders strengthens evidence for independent association. The use of validated stroke severity (NIHSS) and classification (TOAST) systems enhances reproducibility. Measurement of vitamin cofactors provides insights into mechanisms underlying hyperhomocysteinemia. However, limitations should be acknowledged. The case-control design limits inference regarding temporality and causation. Homocysteine measurement at a single time point after stroke onset may not reflect pre-stroke baseline levels, as acute illness and metabolic stress could influence concentrations. Lack of genetic analysis (particularly MTHFR polymorphisms) limits mechanistic insights. The study did not assess detailed dietary intake, which influences both homocysteine levels and stroke risk. Follow-up data on functional outcomes and recurrent vascular events were not collected, limiting assessment of prognostic value. The single-center design and specific population may limit generalizability. Future research should include prospective cohort studies measuring homocysteine before stroke occurrence, genetic studies examining MTHFR polymorphisms and their interaction with nutritional factors, intervention trials in populations with high hyperhomocysteinemia prevalence and low baseline folate status, investigation of homocysteine's prognostic value for functional outcomes and recurrent events, and mechanistic studies exploring specific pathways linking homocysteine to different stroke subtypes.

This study demonstrates that elevated serum homocysteine levels are significantly and independently associated with acute ischemic stroke, with nearly seven-fold increased odds after controlling for traditional vascular risk factors. Stroke patients exhibit substantially higher homocysteine concentrations compared to healthy controls, with hyperhomocysteinemia present in approximately two-thirds of cases. Importantly, homocysteine levels correlate positively with stroke severity, with patients experiencing severe strokes demonstrating the highest concentrations. Significant variation across stroke subtypes, with peak levels in large artery atherosclerosis, supports the mechanistic role of homocysteine in promoting atherothrombotic processes. These findings underscore hyperhomocysteinemia as a significant metabolic abnormality in ischemic stroke patients and highlight its potential utility as a biomarker for risk stratification. The strong associations with both stroke occurrence and severity suggest clinical relevance beyond statistical significance. Given that hyperhomocysteinemia is potentially modifiable through nutritional supplementation with B vitamins, these results support consideration of homocysteine assessment in comprehensive stroke evaluation, particularly in populations with high prevalence of nutritional deficiencies. However, translation to clinical practice requires caution pending definitive evidence from intervention trials demonstrating that homocysteine lowering reduces stroke incidence or improves outcomes. Future research should focus on identifying populations most likely to benefit from homocysteine-lowering strategies and elucidating the complex interplay between genetic factors, nutritional status, and vascular risk. Understanding these relationships may facilitate development of personalized prevention approaches targeting this modifiable metabolic risk factor to reduce the substantial global burden of ischemic stroke.

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