Depressive and Anxiety Symptoms Predict Health-Related Quality of Life More Than Cognitive Impairment After Minor Stroke or Transient Ischemic Attack: A Hierarchical Regression Analysis

Depressive and Anxiety Symptoms Predict Health-Related Quality of Life More Than Cognitive Impairment After Minor Stroke or Transient Ischemic Attack: A Hierarchical Regression Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Depressive and Anxiety Symptoms Predict Health-Related Quality of Life More Than Cognitive Impairment After Minor Stroke or Transient Ischemic Attack: A Hierarchical Regression Analysis Maria Rocio Cordova Infante, José M Ramirez-Moreno This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8864143/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background and Purpose: Minor cerebrovascular events (TIA or minor ischemic stroke) are associated with substantial psychological morbidity, despite generally excellent functional recovery. This study investigated whether mood disturbances or cognitive impairment are the primary contributors to reduced quality of life in patients following minor cerebrovascular events. Methods: We conducted a prospective observational case–control study including 90 patients with acute TIA or minor ischemic stroke (NIHSS ≤ 4) confirmed by diffusion-weighted imaging, and 92 age-matched healthy controls. At 90 days post-event, participants underwent assessment with the Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, Montreal Cognitive Assessment, and the EQ-5D-5L quality-of-life utility index. Hierarchical multiple regression using standardized z-scores identified independent predictors of quality of life. Mediation analysis with 5,000-iteration bias-corrected bootstrap confidence intervals tested whether cognitive impairment mediated the relationship between mood symptoms and quality of life. Results: Compared with controls, cases showed markedly higher rates of clinical depression (82.2% vs. 18.5%), anxiety (81.1% vs. 21.7%), and cognitive impairment (66.7% vs. 13.0%; all p < 0.001). Hierarchical regression revealed that psychopathological variables (depression/anxiety) explained an additional 36.6% of the variance in quality of life (p < 0.001), whereas cognitive and neuroimaging variables contributed an additional 1.7% (ΔR²=0.017; incremental p = 0.523 ). Anxiety emerged as the strongest predictor at trend-level (β=−0.055; p = 0.064†), whereas cognitive impairment showed a negligible effect (β = − 0.001, p = 0.947). Mediation analysis demonstrated no significant indirect effects, suggesting that mood disturbances and cognitive impairment are independent, rather than sequential, post-event complications. Conclusions: Following TIA or minor ischemic stroke, depressive and anxiety symptoms are common, persist despite excellent neurological recovery, and exert a substantial negative impact on health-related quality of life. Anxiety appears to play a particularly prominent role in shaping patient-reported outcomes, underscoring the importance of routine mood screening and targeted management in this population. Transient ischemic attack minor ischemic stroke depression anxiety health-related quality of life hierarchical regression mediation analysis Figures Figure 1 Figure 2 Figure 3 INTRODUCTION Cerebrovascular disease remains one of the leading global causes of morbidity and disability, with an estimated 11.9 million incident cases each year.( 1 ) Although research has traditionally focused on moderate-to-severe stroke, transient ischemic attacks (TIAs) and minor ischemic strokes represent a substantial proportion of cerebrovascular events, accounting for up to 16% of first-ever cases in population-based cohorts.( 2 ) Historically considered to have minimal long-term consequences due to the absence of significant functional disability (modified Rankin Scale ≤ 2),( 3 , 4 ) these events are now recognized as potential triggers for persistent psychopathological symptoms and cognitive impairment, even in patients with excellent neurological recovery and no recurrent vascular events.( 5 , 6 ) Post-stroke depression is among the most prevalent neuropsychiatric complications in this population, affecting 11% to 42% of individuals after TIA or minor stroke depending on study design, timing, and patient characteristics.( 7 – 10 ) Anxiety is also common, reported in 12% to 30% of cases, and frequently co-occurs with depressive symptoms in a bidirectional pattern that amplifies emotional distress and functional difficulties.( 9 , 11 , 12 ) Importantly, these symptoms can arise even in the absence of detectable physical disability, implicating mechanisms beyond motor impairment, including neurobiological alterations, inflammatory pathways, and psychosocial stressors.( 13 , 14 ) Cognitive impairment is another frequently under-recognized sequela, reported in approximately 30–54% of TIA and minor stroke survivors ( 15 – 18 ) often coexisting with depressive and anxiety symptoms. Although cross-sectional studies ( 15 , 16 ) have been conducted, no previous study has directly evaluated whether cognitive impairment causally precedes mood alterations, contributes independently to emotional difficulties, or whether these complications emerge as parallel consequences of cerebrovascular injury. Mood disturbances have a substantial impact on health-related quality of life (HRQoL), functional independence, return to work, and rehabilitation engagement. ( 17 ) In patients with severe stroke, the HRQoL is primarily influenced by motor and functional limitations. However, the mechanisms underlying HRQoL reductions in minor cerebrovascular events, where physical disability is minimal, remain poorly characterized. Despite evidence linking depression, anxiety, and cognitive impairment to HRQoL after minor stroke, the relative contributions of these factors and potential pathways connecting them remain unclear. Mediation analysis offers a suitable approach to clarify whether ( 1 ) cognitive impairment leads to mood disturbances that subsequently reduce HRQoL, ( 2 ) cognitive impairment and mood disturbances exert independent effects, or ( 3 ) both mechanisms operate concurrently. The present study aimed to quantify the burden of psychopathological and cognitive complications following minor cerebrovascular events, identify the determinants of HRQoL, and examine whether mood symptoms mediate the relationship between cognitive impairment and HRQoL. Additionally, we assessed the utility of neuroimaging biomarkers as predictors of neuropsychiatric and cognitive outcomes in this population. METHODS Study Design and Participants We conducted a single-center, prospective, observational case–control study. Consecutive patients aged 18–70 years presenting with acute TIA or minor ischemic stroke (NIHSS ≤ 4) and confirmed by magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI) were enrolled. Exclusion criteria included prior dementia, significant pre-existing disability (pre-morbid modified Rankin Scale [mRS] > 1), and inability to communicate in Spanish. Controls were age-matched individuals with no history of cerebrovascular events, dementia, or major neurological disease. This study adhered to the STROBE reporting guidelines, and the protocol was approved by the Ethics Committee of the University Hospital of Badajoz (Spain). Written informed consent was obtained from all participants. Demographic characteristics, vascular risk factors, and neurological status—including NIHSS subscores for consciousness, language, and motor function, —were collected. The functional status at discharge was assessed using the mRS. Standardized physical measurements (blood pressure, height, weight, and body mass index) were obtained according to institutional protocols. Laboratory studies performed on admission included plasma glucose, urea, creatinine, estimated glomerular filtration rate, total cholesterol, HDL cholesterol, LDL cholesterol, and triglyceride levels. All clinical and psychopathological assessments were performed by trained evaluators who underwent standardized study-specific training to ensure inter-rater consistency. Neuroimaging Acquisition and Analysis All patients underwent brain MRI in the acute phase (mean 1.3 ± 0.8 days post-event) using a Philips Intera 1.5-Tesla scanner. The protocol included: DWI presence, number, and location of acute ischemic lesions Apparent diffusion coefficient (ADC) maps confirmation of acute ischemia FLAIR quantification of white matter hyperintensities using the Age-Related White Matter Changes (ARWMC) scale T2-weighted gradient echo presence, number, and location of cerebral microbleeds Neuroimaging analyses were performed by experienced neuroradiologists who were blinded to all clinical and psychopathological outcomes. Image quality was reviewed systematically, and cases with incomplete or non-diagnostic sequences were excluded from imaging-based analyses. Psychopathological, Cognitive, and HRQoL Assessment All assessments were conducted 90 ± 14 days after the index event by evaluators blinded to neuroimaging findings. Depression Hamilton Depression Rating Scale (HDRS-17); scores > 7 defined depressive symptoms. Anxiety Hamilton Anxiety Rating Scale (HAM-A); clinically relevant anxiety defined as HAM-A ≥ 7, consistent with prior work in post-stroke populations. Cognition Montreal Cognitive Assessment (MoCA; 30-point scale); scores < 26 defined cognitive impairment. The MoCA has been validated in Spanish-speaking patients with TIA/minor stroke. Health-related quality of life (HRQoL) EuroQol EQ-5D-5L utility index and visual analogue scale (EQ-VAS, 0–100). EQ-5D-5L utility values were derived using the Spanish value set. To minimize interviewer-related bias, all psychopathological scales were administered following a standardized structured protocol. Statistical Analysis Continuous variables are expressed as mean ± SD or median [IQR], and categorical variables as numbers (%). Between-group comparisons used independent-samples t tests or Mann–Whitney U tests, and χ² or Fisher’s exact tests were used for categorical variables. Effect sizes were expressed as Cohen’s d and odds ratios (ORs) with 95% confidence interval (CIs). Statistical significance was set at p < 0.05. Among the cases, bivariate associations were examined using Pearson or Spearman correlation coefficients, depending on the variable distribution and scale. Correlation strength was interpreted as weak (|r| 0.70). False-discovery-rate–adjusted q values are provided in Supplementary Tables. Regression Modeling Independent predictors of HRQoL (EQ-5D-5L utility index) were examined using hierarchical multiple linear regression. Three nested models were prespecified as follows: Sociodemographic/clinical age, sex, mRS, social risk Psychopathological HDRS-17, HAM-A Cognitive/neuroimaging MoCA, presence of DWI lesions, prior silent infarcts Continuous predictors were standardized (z-scores); binary variables were coded 0/1. Model fit was evaluated with R², adjusted R², ΔR², and incremental F tests. For each predictor, we report the standardized (β) and unstandardized (B) coefficients, SE, 95% CI, t , and p values. Model assumptions (linearity, homoscedasticity, normality of residuals, independence, and multicollinearity) were systematically checked. No violations that affected the inference were detected. Sensitivity analyses included HC3-robust standard errors and beta-regression to account for the bounded EQ-5D-5L distribution; findings were unchanged. Mediation Analysis Psychological mediation pathways were evaluated using non-parametric bootstrapped mediation. Two models were tested: a) MoCA → HDRS-17 → EQ-5D-5L and b) MoCA → HAM-A → EQ-5D-5L. All variables were standardized, and age and sex were included as covariates. Indirect effects were considered significant if the 95% bootstrap confidence interval (CI) excluded zero. Mediation analyses were conducted using PROCESS v3.5 (SPSS v29) with 5,000 bias-corrected accelerated bootstrap resamples; all other analyses were performed in R (v4.3.0). RESULTS Sample Characteristics A total of 182 participants were enrolled, including 90 patients with acute TIA or minor ischemic stroke (NIHSS ≤ 4) and 92 age-matched healthy controls. The case group had a significantly higher proportion of males (73.3% vs. 45.7%; χ² = 13.32; p < 0.001) and a greater prevalence of hypertension (58.9% vs. 37.0%; p = 0.003), diabetes mellitus (28.9% vs. 15.2%; p = 0.037), current smoking (63.3% vs. 38.0%; p < 0.001), and prior ischemic heart disease (13.3% vs. 1.1%; p = 0.004). Among cases, acute DWI lesions were present in 72.2% (n = 65), previous silent infarcts in 28.9% (n = 26), and cerebral microbleeds in 7.8% (n = 7). The baseline characteristics are summarized in Table 1 , with extended imaging descriptors in Table S1 (baseline block). Table 1 Baseline demographic characteristics, cardiovascular risk factors, and family history of cases and controls Variable Cases (n = 90) Controls (n = 92) p value Demographic characteristics Male sex, n (%) 66 (73.3) 42 (45.7) < 0.001 Age, years, mean ± SD 59.3 ± 8.2 58.6 ± 7.8 0.562 Urban residence, n (%) 43 (47.8) 57 (62.0) 0.055 Educational level, n (%) 0.005 ─ Literate without formal education 37 (41.1) 20 (21.7) ─ Primary or secondary education 50 (55.6) 61 (66.3) ─ University education 3 (3.3) 11 (12.0) Social situation, n (%) 0.037 ─ Good or acceptable 59 (65.6) 73 (79.3) ─ Social risk 31 (34.4) 19 (20.7) Cardiovascular risk factors Hypertension, n (%) 52 (57.8) 33 (35.9) 0.003 Dyslipidemia, n (%) 38 (42.2) 29 (31.5) 0.135 Diabetes mellitus, n (%) 26 (28.9) 15 (16.3) 0.042 Atrial fibrillation, n (%) 10 (11.1) 8 (8.7) 0.585 Prior ischemic heart disease, n (%) 11 (12.2) 1 (1.1) 0.002 Current tobacco use, n (%) 57 (64.0) 35 (38.0) < 0.001 Alcohol consumption, n (%) 50 (56.2) 39 (42.4) 0.064 Family history History of stroke, n (%) 25 (27.8) 27 (29.3) 0.815 History of ischemic heart disease, n (%) 29 (32.2) 30 (32.6) 0.956 Values are presented as mean ± standard deviation or number (percentage) . p values were calculated using Student’s t test for continuous variables and the χ² test or Fisher’s exact test for categorical variables, as appropriate. Statistical significance was set at p < 0.05. Psychopathological, Cognitive, and HRQoL Outcomes at 90 Days Depressive (HDRS-17 ≥ 7) and anxiety symptoms (HAM-A ≥ 7) were significantly more prevalent in cases than controls (depression: 82.2% vs 18.5%; χ² = 71.42; p < 0.001; anxiety: 81.1% vs. 21.7%; χ² = 61.82; p < 0.001). Patients also showed higher mean symptom scores (HDRS-17: 11.86 ± 5.84 vs 4.13 ± 4.35, p < 0.001, d = 1.50; HAM-A: 13.60 ± 7.57 vs. 4.64 ± 5.58, p < 0.001, d = 1.35). Cognitive impairment (MoCA < 26) was more frequent among cases (66.7% vs. 13.0%; χ² = 52.49; p < 0.001), with lower mean MoCA scores (24.08 ± 3.26 vs. 27.21 ± 2.36; p < 0.001, d = − 1.10). HRQoL (EQ-5D-5L utility) was markedly reduced in cases (0.847 ± 0.152) compared with controls (0.974 ± 0.076; p < 0.001, d = − 1.05). These contrasts are summarized in Fig. 1 and, in greater detail (including Cohen’s d , ORs, and 95% CIs), in Table S1 . The case–control prevalences are shown in Figure S1 , Panel A. Bivariate Associations Within cases, mood scores showed strong negative associations with HRQoL (HDRS-17 vs. EQ-5D-5L r = − 0.612, p < 0.001; HAM-A vs. EQ-5D-5L r = − 0.625, p < 0.001), and HDRS-17 correlated strongly with HAM-A ( r = 0.681, p < 0.001), whereas correlations between MoCA and HRQoL were negligible ( r = 0.092, p = 0.372). The complete correlation matrix (including correlation type and FDR-adjusted q values) is provided in Table S2 and is graphically displayed in Figure S1 , Panel B. Predictors of HRQoL: Hierarchical Regression Among cases with complete data (n = 89), Model 1 (age, sex, mRS and social risk) accounted for 6.1% of the HRQoL variance (F = 1.36; p = 0.256). Adding depressive and anxiety symptoms to Model 2 significantly increased the explained variance (ΔR² = 0.366; total R² = 0.427; F = 10.18; p < 0.001). Model 3, which added MoCA, DWI lesion status, and prior silent infarcts, contributed minimally (ΔR² = 0.017; R² = 0.444; F = 7.02; p < 0.001); the increment over Model 2 was not significant (ΔR² = 0.017; p = 0.523). Model-level metrics are presented in Table 2 and Table S4; full coefficients for Model 3 (β, B, SE, 95% CI, t , p ) in Table 3 and Table S5. Diagnostics (VIFs, residual analyses, and heteroscedasticity tests) and sensitivity analyses (HC3-robust estimates and beta-regression models) are provided in Tables S6–S7. Figure 2 illustrates the stepwise increase in R² (Panel A) and the standardized coefficients for the final model (Panel B). Table 2 Hierarchical Regression Model Comparison: Incremental Variance Explained in Quality of Life Prediction Model Predictors included R² Adjusted R² F statistic p value ΔR² Model 1 Age, sex, mRS, social risk 0.061 0.016 1.36 0.256 — Model 2 Model 1 + HDRS-17, HAM-A 0.427 0.385 10.18 < 0.001 0.366 Model 3 Model 2 + MoCA, DWI lesion burden, number of infarcts 0.444 0.381 7.02 < 0.001 0.017 R² indicates the proportion of variance that is explained by the model. ΔR² represents the incremental change in the explained variance relative to the previous model. mRS: modified Rankin Scale; HDRS-17: Hamilton Depression Rating Scale; HAM-A: Hamilton Anxiety Rating Scale; MoCA: Montreal Cognitive Assessment; DWI: diffusion-weighted imaging. Table 3 Standardized Regression Coefficients for Predictors of Quality of Life Predictor Standardized β SE 95% CI p value Anxiety (HAM-A) −0.055 0.029 −0.114 to 0.003 0.064† Social risk −0.048 0.029 −0.105 to 0.009 0.100 Depression (HDRS-17) −0.043 0.029 −0.102 to 0.016 0.147 DWI lesion burden 0.050 0.033 −0.016 to 0.116 0.133 Silent infarcts 0.015 0.030 −0.046 to 0.075 0.627 Age 0.006 0.014 −0.022 to 0.033 0.686 Sex −0.000 0.031 −0.062 to 0.061 0.990 mRS −0.001 0.021 −0.044 to 0.041 0.947 MoCA −0.001 0.014 −0.029 to 0.027 0.947 The values represent the standardized regression coefficients (β). 95% CI indicates the 95% confidence interval. †Trend toward statistical significance ( p < 0.10). HAM-A: Hamilton Anxiety Rating Scale; HDRS-17: Hamilton Depression Rating Scale; mRS: modified Rankin Scale; MoCA: Montreal Cognitive Assessment; DWI: diffusion-weighted imaging. Mediation Analysis In the depression model (Model A), MoCA was not associated with HRQoL (β = 0.056; p = 0.609) or depression severity (a-path β = −0.095; p = 0.381). Depression was associated with lower HRQoL (b-path β = −0.060; p = 0.034). The indirect effect was small and non-significant (β = −0.006; 95% BCa CI − 0.068 to 0.047). Similarly, in the anxiety model (Model B), MoCA was not associated with anxiety (a-path β = −0.127; p = 0.239), whereas anxiety predicted lower HRQoL (b-path β = −0.062; p = 0.041). The indirect effect was non-significant (β = 0.008; 95% BCa CI − 0.046 to 0.078). Path-level estimates (c, a, b, c′) and bootstrap intervals are detailed in Tables S3A–S3B; and the standardized path diagrams are show in Fig. 3 . Sex-stratified analysis. Sex-specific means for HDRS-17, HAM-A, MoCA, and EQ-5D-5L are presented in Figure S1 , Panel C; statistical tests and effect sizes are reported in Table S1 (sex-stratified block). This analysis complements the primary models and allows assessment of potential sex-related differences in clinical profiles. DISCUSSION This study highlights a notable paradox in the outcomes following TIA and minor ischemic stroke. Despite excellent functional recovery, with nearly 60% of patients achieving a mRS score of 0 ( 4 ), a substantial and clinically significant burden of psychopathological and cognitive complications remains.( ( 26 ) We observed a high prevalence of depression (82.2%) and anxiety (81.1%) symptoms, as well as cognitive impairment (66.7%), far exceeding rates in age-matched healthy controls (18.5%, 21.7%, and 13.0%, respectively), with effect sizes ranging from 1.10 to 1.50, indicating clinical significance far beyond statistical importance. These findings challenge the traditional labeling of TIA and minor stroke as “benign” and provide important context for interpreting post-event outcomes. The high prevalence of depressive (82.2%) and anxiety (81.1%) symptoms observed in our cohort aligns with studies that used symptom-based thresholds rather than diagnostic criteria, which typically yield higher estimates than interview-based diagnoses. Recent syntheses show that scale-based screening tends to identify a larger symptomatic burden than clinical interviews, underscoring that threshold selection materially influences prevalence estimates and clinical interpretation.( 33 ) Moreover, contemporary evidence indicates that stroke survivors have nearly threefold higher odds of depression than the general population, reinforcing that elevated symptom rates are epidemiologically plausible rather than artifacts of measurement.( 34 ) Our findings are also consistent with recent work highlighting lasting impairments after TIA or minor stroke—including depression, anxiety, fatigue, and cognitive change—which remain underrecognized and inconsistently treated. This evolving literature provides a broader context for our results, suggesting that substantial psychological morbidity persists despite minimal neurological deficits. ( 35 ) The prevalence of depressive symptoms in our cohort exceeds that reported in studies using comparable symptom-based assessments (~ 60%) ( 27 ) and is substantially higher than estimates from studies focusing on clinically diagnosed depression (11–41%), likely reflecting methodological differences in outcome definition.( 7 , 28 , 29 ) Notably, a high burden of depressive symptoms was observed independent of objective stroke severity (NIHSS ≤ 4), indicating that low stroke severity does not preclude psychological morbidity. Although the mean HRDS score (11.86 ± 5.84 in cases vs. 4.13 ± 4.35 in controls) fell within the mild depressive symptom range, the large effect size observed (Cohen's d = 1.50) supports the clinical relevance of these symptoms. Importantly, the use of higher diagnostic cut-offs in previous studies may have led to under-identification of patients with milder depressive symptoms, which can still impact function and HRQoL, without meeting criteria for clinically diagnosed depression. Similarly, the 81.1% prevalence of anxiety symptoms represents a substantial burden that has been infrequently quantified in minor stroke or TIA populations, where the reported prevalence ranges from 20–55%. ( 9 , 12 , 30 ) Anxiety has historically been under-investigated compared to depression or cognitive outcomes. These findings are consistent with neurobiological evidence that even minor ischemic events may trigger inflammatory cascades and neuroplastic changes that increase vulnerability to mood dysregulation. ( 13 ) The large independent effect sizes for both depression and anxiety indicate that post-stroke mood symptoms could represent relevant neuropsychiatric outcomes rather than merely secondary consequences of stroke. ( 35 ) Cognitive impairment (MoCA < 26) was detected in 66.7% of cases, a prevalence substantially exceeding that observed in control populations and at the upper end of the range reported in minor stroke or TIA populations (30–67%). ( 6 , 24 , 26 ) The lack of association between cognitive impairment and depression or anxiety in the mediation analysis (indirect effect p > 0.05) suggests that cognitive dysfunction represents an independent neurobiological consequence of cerebrovascular injury rather than a secondary manifestation of mood disturbance. This distinction raises the possibility that cognitive dysfunction and mood symptoms may arise through partially independent causal pathways, with implications for targeted cognitive and psychological interventions in patients with TIA. The absence of mediation by cognition in our models is compatible with recent longitudinal data showing that a single adjudicated, DWI-negative TIA is associated with subsequent cognitive decline independent of vascular and demographic factors, implying that cognitive and affective trajectories may be at least partially dissociable.( 36 ) This supports our interpretation that mood and cognitive complications can arise through parallel pathways, each warranting specific monitoring and intervention.( 35 ) Although DWI lesions were present in 72.2% of cases and prior silent infarcts in 28.9%, these neuroimaging findings contributed minimally to HRQoL outcomes, suggesting that structural abnormalities do not necessarily predict symptom burden or functional impact and may be driven by neurobiological mechanisms. A key finding of this study is the predominant contribution of psychopathological symptoms, particularly anxiety and depression, to HRQoL, accounting for 36.6% of the incremental variance, compared with the 1.5% explained by cognitive and neuroimaging variables. Once psychopathological variables were accounted for, cognitive impairment and neuroimaging markers provided minimal additional predictive value for HRQoL outcomes (ΔR² = 0.015, p = 0.523), suggesting that their association with reduced HRQoL is largely mediated or confounded by mood symptoms. These findings indicate that in this patient population, psychological factors are more strongly associated with patient-reported health status and functional well-being than traditional neurological or imaging-based measures. Additionally, anxiety emerged as the strongest independent predictor of reduced HRQoL (β = -0.0595, p = 0.044), surpassing the effect of depression and identifying a potentially modifiable contributor to patient-reported HRQoL outcomes, being consistent with previous studies in stroke populations.( 31 ) Mediation analyses further indicated that anxiety and depression influence HRQoL through independent, parallel pathways rather than sequential mechanisms, extending previous work on post-stroke psychopathology. Multiple interacting neuropsychobiological mechanisms after stroke have been implicated in post-stroke anxiety, as well as depression. These include dysregulation of the hypothalamic–pituitary–adrenal axis, impaired neuroplasticity due to endothelial dysfunction and reduced cerebral blood flow, and heightened inflammatory responses characterized by elevated proinflammatory cytokines. In addition, ischemic lesions may cause functional disconnection of prefrontal–limbic networks involved in mood regulation, contributing to heterogeneous anxiety presentations after stroke.( 13 , 14 , 32 ) Together, these findings suggest limitations in models that conceptualize post-stroke psychological and cognitive sequelae as consequences of cognitive injury and support a framework in which anxiety, depression, and cognitive impairment are viewed as parallel complications. A key unmeasured factor in our analysis is fatigue, which has emerged as a frequent and impactful sequela after TIA/minor stroke and is repeatedly identified as a determinant of HRQoL. Future studies should incorporate validated fatigue measures to clarify potential confounding or mediating roles between mood symptoms and HRQoL and to refine prognostic models beyond psychopathology and cognition. ( 35 ) Clinically, these data reinforce the need for routine mood screening early after TIA/minor stroke and during follow-up, using brief validated tools and establishing referral pathways to evidence-based interventions (e.g., psychological therapies, pharmacotherapy) shown to improve depressive outcomes in post-stroke populations.( 33 , 37 ) Given the outsized contribution of anxiety and depression to HRQoL, integrating structured screening and treatment into stroke pathways may yield disproportionate gains in patient-reported outcomes relative to strategies focused solely on neurological impairment.( 33 , 37 ) Several important limitations that warrant consideration when interpreting findings. First, our case-control design precludes definitive causal inference regarding the temporal relationship between mood and HRQoL. Prospective longitudinal studies tracking mood trajectories would elucidate temporal sequences and allow for stronger causal claims. Additionally, assessment occurred at a single timepoint (90 days post-event), the longitudinal evolution of mood and HRQoL over longer recovery periods remains unknown. Second, the measurement and population considerations may limit generalizability of the findings. Psychological measures relied on self-report instruments that were potentially subject to recall and social desirability bias. Medication use (antidepressants, anxiolytics and other psychotropic medications) was not tracked, representing an important unmeasured confounder. Our sample was recruited from a university hospital and was predominantly male (72.8%), potentially limiting its applicability to community populations or healthcare systems with different demographic compositions. Third, statistical and analytical considerations merit further attention. The hierarchical regression model included nine predictors and 89 participants, maintaining the recommended 10:1 participant-to-predictor ratio and achieving adequate post-hoc statistical power (1-β = 0.84); nevertheless, larger multicenter samples would improve generalizability and allow subgroup analyses. Finally, while mediation analyses indicated independent contributions of mood and cognition to HRQoL, the absence of statistically significant mediation does not definitively prove independence; unmeasured cognitive domains or alternative pathways may also contribute. Conclusions This study shows that TIA and minor ischemic stroke (NIHSS ≤ 4) are associated with a substantial burden of depression and anxiety symptoms, as well as cognitive impairment, which persists despite excellent neurological recovery and is strongly linked to reduced HRQoL. Mood symptoms, particularly anxiety, were more strongly associated with patient-reported outcomes than cognitive impairment or neuroimaging findings. The relative independence of mood and cognitive complications suggests distinct underlying mechanisms and challenges paradigms that focus primarily on neurological recovery when interpreting post-event outcomes. These findings further indicate that HRQoL may be more closely linked to psychological symptoms than to cognitive recovery alone, underscoring the importance of considering mood when evaluating post-event outcomes, which should be the subject of future studies research. Abbreviations TIA: transient ischemic attack mRS: modified Rankin Scale HRQoL: health-related quality of life DWI: diffusion-weighted imaging NIHSS: National Institutes of Health Stroke Scale HDRS-17: Hamilton Depression Rating Scale HAM-A: Hamilton Anxiety Rating Scale MoCA: Montreal Cognitive Assessment Declarations Funding: None. Disclosures: All authors reported no conflicts of interest related to this work. Ethics Approval and Consent to Participate: The study was approved by the Ethics Committee of the University Hospital of Badajoz, Spain. Written informed consent was obtained from all the participants. Data Availability: The data that support the findings of this study are available from the corresponding author upon reasonable request. Author Contribution Both authors contributed equally to the conception and design of the study, data collection, analysis and interpretation of the results, as well as the drafting and critical revision of the manuscript. Both authors approved the final version and agree to be accountable for all aspects of the work. Data Availability The data that support the findings of this study are available from the corresponding author upon reasonable request. References Feigin VL, Stark BA, Johnson CO, Roth GA, Bisignano C, Abady GG, et al. 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Hackett ML, Köhler S, O’Brien JT, Mead GE. Neuropsychiatric outcomes of stroke. Lancet Neurol. 2014;13(5):525–34. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23(1):56–62. Aben I, Verhey F, Lousberg R, Lodder J, Honig A. Validity of the Beck Depression Inventory, Hospital Anxiety and Depression Scale, SCL–90, and Hamilton Depression Rating Scale as screening instruments for depression in stroke patients. Psychosomatics. 2002;43(5):386–93. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 1959;32(1):50–5. Xiao M, Huang G, Feng L, Luan X, Wang Q, Ren W, et al. Impact of sleep quality on post–stroke anxiety in stroke patients. Brain Behav. 2020;10(12):e01813. Zhu BL, Hu AY, Huang GQ, Qiu HH, Hong XC, Hu PL, et al. Association between obesity and post–stroke anxiety in patients with acute ischemic stroke. Front Nutr. 2021;8:749958. Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, et al. The Montreal Cognitive Assessment (MoCA): a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695–9. Ramírez–Moreno JM, Bartolomé Alberca S, Muñoz Vega P, Guerrero Barona EJ. Detección del deterioro cognitivo con la Evaluación Cognitiva de Montreal en pacientes españoles con ictus minor o ataque isquémico transitorio. Neurología. 2022;37(1):38–44. Herdman M, Gudex C, Lloyd A, Janssen MF, Kind P, Parkin D, et al. Development and preliminary testing of the new five–level version of EQ–5D (EQ–5D–5L). Qual Life Res. 2011;20(10):1727–36. Moran GM, Fletcher B, Feltham MG, Calvert M, Sackley C, Marshall T. Fatigue, psychological and cognitive impairment following transient ischaemic attack and minor stroke: a systematic review. Eur J Neurol. 2014;21(10):1258–67. Xiao W, Liu Y, Huang J, Huang Lan, Bian Y, Zou G. Analysis of factors associated with depressive symptoms in stroke patients based on a national cross–sectional study. Sci Rep. 2024;14(1):9268. Altieri M, Maestrini I, Mercurio A, Troisi P, Sgarlata E, Rea V, et al. Depression after minor stroke: prevalence and predictors. Eur J Neurol. 2012;19(3):517–21. McColl AJ, Luengo–Fernandez R, Vaughan–Fowler ER, Downer MB, Pendlebury ST, Binney LE, et al. Prevalence, predictors, and prognosis of depression after transient ischemic attack: a population–based study. Stroke. 2026;57(1):125–33. Vitturi BK, Mitre LP, Kim AIH, Gagliardi RJ. Prevalence and predictors of fatigue and neuropsychiatric symptoms in patients with minor ischemic stroke. J Stroke Cerebrovasc Dis. 2021;30(9):105964. Randolph S, Lee Y, Nicholas ML, Connor LT. The mediating effect of anxiety on the association between residual neurological impairment and post–stroke participation among persons with and without post–stroke depression. Neuropsychol Rehabil. 2024;34(2):181–95. Li W, Xiao WM, Chen YK, Qu JF, Liu YL, Fang XW, et al. Anxiety in patients with acute ischemic stroke: risk factors and effects on functional status. Front Psychiatry. 2019;10:257. Liu L, Xu M, Marshall IJ, Wolfe CDA, Wang Y, O’Connell MDL. Prevalence and natural history of depression after stroke: a systematic review and meta-analysis. PLoS Med. 2023;20(3):e1004200. Naghedi A, Delgado-Mederos R, Vives-Bauza C. Stroke survivors have almost three times higher risk of depression: a systematic review and meta-analysis. J Clin Med. 2025;14(23):8410. Ebbesen BH, Modrau B, Kontou E, et al. Lasting impairments following transient ischemic attack and minor stroke: a systematic review protocol. Front Neurol. 2023;14:1177309. Del Bene VA, Howard G, Gropen TI et al. Cognitive decline after first-time transient ischemic attack. JAMA Neurol. 2025;82(4). Available at: https://jamanetwork.com/journals/jamaneurology/fullarticle/2830012 . Accessed January 29, 2026. Sonoda K, Wakabayashi M. Interventions for treatment of poststroke depression. Am Fam Physician. 2023;108(5): Online. Available at: https://www.aafp.org/pubs/afp/issues/2023/1100/mbtn-poststroke-depression.html . Accessed January 29, 2026. Additional Declarations No competing interests reported. Supplementary Files TableS1MoodSymptomsDriveHRQoLAfterMinorStroke.docx TableS2MoodSymptomsDriveHRQoLAfterMinorStroke.docx TableS3MoodSymptomsDriveHRQoLAfterMinorStroke.docx STROBEChecklistPAPER3QoL.pdf FigureS1MoodSymptomsDriveHRQoLAfterMinorStroke.png Figure S1. Prevalence, correlations, and sex‑stratified outcomes at 90 days after TIA/minor stroke. Ldegend: Three‑panel summary. Panel A (Prevalence): Cases vs. controls—depressive symptoms (HDRS‑17 ≥ 7), 82.2% vs. 18.5%; anxiety symptoms (HAM‑A ≥ 7), 81.1% vs. 21.7%; cognitive impairment (MoCA < 26), 66.7% vs. 13.0%. Panel B (Correlation heatmap, cases n=90): strong associations between mood and HRQoL (HDRS‑17 vs. EQ‑5D‑5L r = −0.612***; HAM‑A vs. EQ‑5D‑5L r = −0.625***), strong HDRS‑17–HAM‑A correlation ( r = 0.681***), and negligible MoCA–EQ‑5D‑5L correlation ( r = 0.092, NS). Color scale: red = negative, blue = positive, white = null. Panel C (Sex‑stratified outcomes): mean scores by sex among cases (see Table S1 for tests and exact p values). Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8864143","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":593446561,"identity":"c2e97ec7-9633-45b5-a75a-2b21ef888382","order_by":0,"name":"Maria Rocio Cordova Infante","email":"","orcid":"","institution":"Hospital Universitario de Valme","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Rocio Cordova","lastName":"Infante","suffix":""},{"id":593446562,"identity":"5a0380d5-c28c-468a-8459-e47cf1e4b584","order_by":1,"name":"José M Ramirez-Moreno","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAtUlEQVRIiWNgGAWjYBACxgYILUe6FmPSbUtsIFop8+zDTzdXVNSlb7jdfEyCoaKOCIf1pZndPHOGLXfDnWPJBgxnDhOhpYfB7GZjG0/uhhs5hg8Y2w4Qo4X9283GfxLpBjfyPxxg/EeMw3p4gLY0GCQY3MhhfMDYwEyUlrKbDccSDGfeSDM2SDhGhF8Me9i33WyoqZPnu5H8TOJDDREOM2xA5iUQ1sDAIE+MolEwCkbBKBjhAACsmjsWO1g2ewAAAABJRU5ErkJggg==","orcid":"","institution":"University of Extremadura","correspondingAuthor":true,"prefix":"","firstName":"José","middleName":"M","lastName":"Ramirez-Moreno","suffix":""}],"badges":[],"createdAt":"2026-02-12 16:23:40","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8864143/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8864143/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102998189,"identity":"ac79924b-ec34-4ecd-9a45-253ef13de217","added_by":"auto","created_at":"2026-02-19 12:39:14","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":299821,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of Depressive Symptoms, Anxiety, Cognition, and Quality of Life Between ATI/Minor Stroke Patients and Healthy Controls\u003c/p\u003e\n\u003cp\u003eLegend:\u003c/p\u003e\n\u003cp\u003eComparison of depressive symptoms (HDRS-17), anxiety (HAM‑A), cognitive performance (MoCA), and quality of life (EQ‑5D‑5L) between ATI/minor stroke patients (n = 90) and healthy controls (n = 92). Boxes represent median and interquartile range; whiskers indicate minimum and maximum values, excluding outliers. Group comparisons were performed using independent-samples tests as appropriate. \u003cem\u003ep\u003c/em\u003e\u003cstrong\u003e \u0026lt; 0.001.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure1MoodSymptomsDriveHRQoLAfterMinorStroke.png","url":"https://assets-eu.researchsquare.com/files/rs-8864143/v1/e9e8846ff17915a299b08466.png"},{"id":102998098,"identity":"41e31fee-a725-4b6f-a455-830e3f85225a","added_by":"auto","created_at":"2026-02-19 12:39:07","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":190075,"visible":true,"origin":"","legend":"\u003cp\u003eHierarchical Regression Analysis: Model Progression and Predictor Contribution\u003c/p\u003e\n\u003cp\u003eLegend:\u003c/p\u003e\n\u003cp\u003eHierarchical regression model performance and standardized coefficients. Panel A shows the variance explained (R²) for each incremental model and the corresponding change in explained variance (ΔR²). Panel B displays the standardized regression coefficients (β) and 95% confidence intervals for the predictors in the final model. Red markers denote trend-level effects (0.05 ≤ \u003cem\u003ep\u003c/em\u003e\u0026lt; 0.10). HAM‑A: Hamilton Anxiety Rating Scale; HDRS-17: Hamilton Depression Rating Scale; mRS: modified Rankin Scale; MoCA: Montreal Cognitive Assessment; DWI: diffusion-weighted imaging.\u003c/p\u003e","description":"","filename":"Figure2MoodSymptomsDriveHRQoLAfterMinorStroke.png","url":"https://assets-eu.researchsquare.com/files/rs-8864143/v1/bec8033561a5a5c2f6217294.png"},{"id":102998231,"identity":"2b127dd0-16fa-4786-8952-b78c3ce5580b","added_by":"auto","created_at":"2026-02-19 12:39:14","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":879229,"visible":true,"origin":"","legend":"\u003cp\u003eMediation Analysis: Indirect Effects of Depression and Anxiety on the Cognition–Health-Related Quality of Life Relationship.\u003c/p\u003e\n\u003cp\u003eLegend:\u003c/p\u003e\n\u003cp\u003eModel A (MoCA → HDRS‑17 → EQ‑5D‑5L): a‑path β = −0.095, p = 0.381; b‑path β = −0.060, p = 0.034; indirect effect β ≈ +0.006 (95% BCa CI −0.068 to 0.047), not significant; direct effect c′ (MoCA → HRQoL) β = 0.056, p = 0.609.\u003c/p\u003e\n\u003cp\u003eModel B (MoCA → HAM‑A → EQ‑5D‑5L): a‑path β = −0.127, p = 0.239; b‑path β = −0.062, p = 0.041; indirect effect β = 0.008 (95% BCa CI −0.046 to 0.078), not significant; direct effect c′ β = 0.056, p = 0.609.\u003c/p\u003e\n\u003cp\u003eAll coefficients are standardized (z‑scored variables). Red arrows denote significant paths (p \u0026lt; 0.05); blue/gray arrows denote non‑significant paths. These models show no significant indirect effects, indicating that mood symptoms and cognitive impairment are parallel, independent complications after TIA/minor stroke.\u003c/p\u003e","description":"","filename":"Figure3MoodSymptomsDriveHRQoLAfterMinorStroke.png","url":"https://assets-eu.researchsquare.com/files/rs-8864143/v1/98cd1854eae52cdbf07eb23a.png"},{"id":103051702,"identity":"cde95a89-9b6a-4340-baa1-0b0cf6f1983c","added_by":"auto","created_at":"2026-02-20 08:02:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2087666,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8864143/v1/164af73c-37ab-4bbe-a0d9-2c8fc756270b.pdf"},{"id":102998254,"identity":"8a62a2fb-a1fd-4c7c-a3d9-becd0415d58b","added_by":"auto","created_at":"2026-02-19 12:39:19","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":16794,"visible":true,"origin":"","legend":"","description":"","filename":"TableS1MoodSymptomsDriveHRQoLAfterMinorStroke.docx","url":"https://assets-eu.researchsquare.com/files/rs-8864143/v1/10e677d1ffad6e19ce1d5424.docx"},{"id":102998126,"identity":"4840b73d-249d-41c5-a584-13fb10f5196e","added_by":"auto","created_at":"2026-02-19 12:39:13","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":16393,"visible":true,"origin":"","legend":"","description":"","filename":"TableS2MoodSymptomsDriveHRQoLAfterMinorStroke.docx","url":"https://assets-eu.researchsquare.com/files/rs-8864143/v1/f85559ae0c0b12c0a0fdb7cf.docx"},{"id":102998237,"identity":"12a948fd-6d3a-49bf-a8a9-da7c23c61f74","added_by":"auto","created_at":"2026-02-19 12:39:14","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":17405,"visible":true,"origin":"","legend":"","description":"","filename":"TableS3MoodSymptomsDriveHRQoLAfterMinorStroke.docx","url":"https://assets-eu.researchsquare.com/files/rs-8864143/v1/eee5e2942634a387da2cbb4c.docx"},{"id":103049381,"identity":"fb22812f-121d-4002-b6a2-0f08657e9655","added_by":"auto","created_at":"2026-02-20 07:40:30","extension":"pdf","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":159618,"visible":true,"origin":"","legend":"","description":"","filename":"STROBEChecklistPAPER3QoL.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8864143/v1/fc3dcebffa3ee4df303a17f9.pdf"},{"id":102998252,"identity":"e8cfe150-9509-4108-8cfa-0a3d326cb4a8","added_by":"auto","created_at":"2026-02-19 12:39:19","extension":"png","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":195770,"visible":true,"origin":"","legend":"\u003cp\u003eFigure S1. Prevalence, correlations, and sex‑stratified outcomes at 90 days after TIA/minor stroke.\u003c/p\u003e\n\u003cp\u003eLdegend:\u003c/p\u003e\n\u003cp\u003eThree‑panel summary. Panel A (Prevalence): Cases vs. controls—depressive symptoms (HDRS‑17 ≥ 7), 82.2% vs. 18.5%; anxiety symptoms (HAM‑A ≥ 7), 81.1% vs. 21.7%; cognitive impairment (MoCA \u0026lt; 26), 66.7% vs. 13.0%. Panel B (Correlation heatmap, cases n=90): strong associations between mood and HRQoL (HDRS‑17 vs. EQ‑5D‑5L \u003cem\u003er\u003c/em\u003e = −0.612***; HAM‑A vs. EQ‑5D‑5L \u003cem\u003er\u003c/em\u003e = −0.625***), strong HDRS‑17–HAM‑A correlation (\u003cem\u003er\u003c/em\u003e = 0.681***), and negligible MoCA–EQ‑5D‑5L correlation (\u003cem\u003er\u003c/em\u003e = 0.092, NS). Color scale: red = negative, blue = positive, white = null. Panel C (Sex‑stratified outcomes): mean scores by sex among cases (see Table S1 for tests and exact \u003cem\u003ep\u003c/em\u003e values).\u003c/p\u003e","description":"","filename":"FigureS1MoodSymptomsDriveHRQoLAfterMinorStroke.png","url":"https://assets-eu.researchsquare.com/files/rs-8864143/v1/5049c5bb38af030d66e1657f.png"}],"financialInterests":"No competing interests reported.","formattedTitle":"Depressive and Anxiety Symptoms Predict Health-Related Quality of Life More Than Cognitive Impairment After Minor Stroke or Transient Ischemic Attack: A Hierarchical Regression Analysis","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eCerebrovascular disease remains one of the leading global causes of morbidity and disability, with an estimated 11.9\u0026nbsp;million incident cases each year.(\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e) Although research has traditionally focused on moderate-to-severe stroke, transient ischemic attacks (TIAs) and minor ischemic strokes represent a substantial proportion of cerebrovascular events, accounting for up to 16% of first-ever cases in population-based cohorts.(\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e) Historically considered to have minimal long-term consequences due to the absence of significant functional disability (modified Rankin Scale ≤ 2),(\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e) these events are now recognized as potential triggers for persistent psychopathological symptoms and cognitive impairment, even in patients with excellent neurological recovery and no recurrent vascular events.(\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e \u003cp\u003ePost-stroke depression is among the most prevalent neuropsychiatric complications in this population, affecting 11% to 42% of individuals after TIA or minor stroke depending on study design, timing, and patient characteristics.(\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e–\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e) Anxiety is also common, reported in 12% to 30% of cases, and frequently co-occurs with depressive symptoms in a bidirectional pattern that amplifies emotional distress and functional difficulties.(\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e) Importantly, these symptoms can arise even in the absence of detectable physical disability, implicating mechanisms beyond motor impairment, including neurobiological alterations, inflammatory pathways, and psychosocial stressors.(\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eCognitive impairment is another frequently under-recognized sequela, reported in approximately 30–54% of TIA and minor stroke survivors (\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e–\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e) often coexisting with depressive and anxiety symptoms. Although cross-sectional studies (\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e) have been conducted, no previous study has directly evaluated whether cognitive impairment causally precedes mood alterations, contributes independently to emotional difficulties, or whether these complications emerge as parallel consequences of cerebrovascular injury.\u003c/p\u003e \u003cp\u003eMood disturbances have a substantial impact on health-related quality of life (HRQoL), functional independence, return to work, and rehabilitation engagement. (\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e) In patients with severe stroke, the HRQoL is primarily influenced by motor and functional limitations. However, the mechanisms underlying HRQoL reductions in minor cerebrovascular events, where physical disability is minimal, remain poorly characterized.\u003c/p\u003e \u003cp\u003eDespite evidence linking depression, anxiety, and cognitive impairment to HRQoL after minor stroke, the relative contributions of these factors and potential pathways connecting them remain unclear. Mediation analysis offers a suitable approach to clarify whether (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e) cognitive impairment leads to mood disturbances that subsequently reduce HRQoL, (\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e) cognitive impairment and mood disturbances exert independent effects, or (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e) both mechanisms operate concurrently.\u003c/p\u003e \u003cp\u003eThe present study aimed to quantify the burden of psychopathological and cognitive complications following minor cerebrovascular events, identify the determinants of HRQoL, and examine whether mood symptoms mediate the relationship between cognitive impairment and HRQoL. Additionally, we assessed the utility of neuroimaging biomarkers as predictors of neuropsychiatric and cognitive outcomes in this population.\u003c/p\u003e "},{"header":"METHODS","content":"\u003cp\u003eStudy Design and Participants\u003c/p\u003e\u003cp\u003eWe conducted a single-center, prospective, observational case–control study. Consecutive patients aged 18–70 years presenting with acute TIA or minor ischemic stroke (NIHSS ≤ 4) and confirmed by magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI) were enrolled.\u003c/p\u003e\u003cp\u003eExclusion criteria included prior dementia, significant pre-existing disability (pre-morbid modified Rankin Scale [mRS] \u0026gt; 1), and inability to communicate in Spanish. Controls were age-matched individuals with no history of cerebrovascular events, dementia, or major neurological disease.\u003c/p\u003e\u003cp\u003e This study adhered to the STROBE reporting guidelines, and the protocol was approved by the Ethics Committee of the University Hospital of Badajoz (Spain). Written informed consent was obtained from all participants.\u003c/p\u003e\u003cp\u003eDemographic characteristics, vascular risk factors, and neurological status—including NIHSS subscores for consciousness, language, and motor function, —were collected. The functional status at discharge was assessed using the mRS. Standardized physical measurements (blood pressure, height, weight, and body mass index) were obtained according to institutional protocols. Laboratory studies performed on admission included plasma glucose, urea, creatinine, estimated glomerular filtration rate, total cholesterol, HDL cholesterol, LDL cholesterol, and triglyceride levels.\u003c/p\u003e\u003cp\u003eAll clinical and psychopathological assessments were performed by trained evaluators who underwent standardized study-specific training to ensure inter-rater consistency.\u003c/p\u003e\u003cp\u003eNeuroimaging Acquisition and Analysis\u003c/p\u003e\u003cp\u003eAll patients underwent brain MRI in the acute phase (mean 1.3 ± 0.8 days post-event) using a Philips Intera 1.5-Tesla scanner. The protocol included:\u003c/p\u003e\u003cp\u003e \u003cstrong\u003eDWI\u003c/strong\u003e \u003c/p\u003e\u003cp\u003epresence, number, and location of acute ischemic lesions\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e \u003cstrong\u003eApparent diffusion coefficient (ADC) maps\u003c/strong\u003e \u003c/p\u003e\u003cp\u003econfirmation of acute ischemia\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e \u003cstrong\u003eFLAIR\u003c/strong\u003e \u003c/p\u003e\u003cp\u003equantification of white matter hyperintensities using the Age-Related White Matter Changes (ARWMC) scale\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e \u003cstrong\u003eT2-weighted gradient echo\u003c/strong\u003e \u003c/p\u003e\u003cp\u003epresence, number, and location of cerebral microbleeds\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eNeuroimaging analyses were performed by experienced neuroradiologists who were blinded to all clinical and psychopathological outcomes. Image quality was reviewed systematically, and cases with incomplete or non-diagnostic sequences were excluded from imaging-based analyses.\u003c/p\u003e\u003cp\u003ePsychopathological, Cognitive, and HRQoL Assessment\u003c/p\u003e\u003cp\u003eAll assessments were conducted 90 ± 14 days after the index event by evaluators blinded to neuroimaging findings.\u003c/p\u003e\u003cp\u003e \u003cstrong\u003eDepression\u003c/strong\u003e \u003c/p\u003e\u003cp\u003eHamilton Depression Rating Scale (HDRS-17); scores \u0026gt; 7 defined depressive symptoms.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e \u003cstrong\u003eAnxiety\u003c/strong\u003e \u003c/p\u003e\u003cp\u003eHamilton Anxiety Rating Scale (HAM-A); clinically relevant anxiety defined as HAM-A ≥ 7, consistent with prior work in post-stroke populations.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e \u003cstrong\u003eCognition\u003c/strong\u003e \u003c/p\u003e\u003cp\u003eMontreal Cognitive Assessment (MoCA; 30-point scale); scores \u0026lt; 26 defined cognitive impairment. The MoCA has been validated in Spanish-speaking patients with TIA/minor stroke.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e \u003cstrong\u003eHealth-related quality of life (HRQoL)\u003c/strong\u003e \u003c/p\u003e\u003cp\u003eEuroQol EQ-5D-5L utility index and visual analogue scale (EQ-VAS, 0–100). EQ-5D-5L utility values were derived using the Spanish value set.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eTo minimize interviewer-related bias, all psychopathological scales were administered following a standardized structured protocol.\u003c/p\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eContinuous variables are expressed as mean ± SD or median [IQR], and categorical variables as numbers (%). Between-group comparisons used independent-samples \u003cem\u003et\u003c/em\u003e tests or Mann–Whitney U tests, and χ² or Fisher’s exact tests were used for categorical variables. Effect sizes were expressed as Cohen’s \u003cem\u003ed\u003c/em\u003e and odds ratios (ORs) with 95% confidence interval (CIs). Statistical significance was set at p \u0026lt; 0.05.\u003c/p\u003e\u003cp\u003eAmong the cases, bivariate associations were examined using Pearson or Spearman correlation coefficients, depending on the variable distribution and scale. Correlation strength was interpreted as weak (|r| \u0026lt;0.30), moderate (0.30–0.70), or strong (\u0026gt; 0.70). False-discovery-rate–adjusted \u003cem\u003eq\u003c/em\u003e values are provided in Supplementary Tables.\u003c/p\u003e\u003cp\u003eRegression Modeling\u003c/p\u003e\u003cp\u003eIndependent predictors of HRQoL (EQ-5D-5L utility index) were examined using hierarchical multiple linear regression. Three nested models were prespecified as follows:\u003c/p\u003e\u003cp\u003e \u003cstrong\u003eSociodemographic/clinical\u003c/strong\u003e \u003c/p\u003e\u003cp\u003eage, sex, mRS, social risk\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e \u003cstrong\u003ePsychopathological\u003c/strong\u003e \u003c/p\u003e\u003cp\u003eHDRS-17, HAM-A\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e \u003cstrong\u003eCognitive/neuroimaging\u003c/strong\u003e \u003c/p\u003e\u003cp\u003eMoCA, presence of DWI lesions, prior silent infarcts\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eContinuous predictors were standardized (z-scores); binary variables were coded 0/1. Model fit was evaluated with R², adjusted R², ΔR², and incremental \u003cem\u003eF\u003c/em\u003e tests. For each predictor, we report the standardized (β) and unstandardized (B) coefficients, SE, 95% CI, \u003cem\u003et\u003c/em\u003e, and \u003cem\u003ep\u003c/em\u003e values.\u003c/p\u003e\u003cp\u003eModel assumptions (linearity, homoscedasticity, normality of residuals, independence, and multicollinearity) were systematically checked. No violations that affected the inference were detected. Sensitivity analyses included HC3-robust standard errors and beta-regression to account for the bounded EQ-5D-5L distribution; findings were unchanged.\u003c/p\u003e\u003cp\u003eMediation Analysis\u003c/p\u003e\u003cp\u003ePsychological mediation pathways were evaluated using non-parametric bootstrapped mediation. Two models were tested: a) MoCA → HDRS-17 → EQ-5D-5L and b) MoCA → HAM-A → EQ-5D-5L.\u003c/p\u003e\u003cp\u003eAll variables were standardized, and age and sex were included as covariates. Indirect effects were considered significant if the 95% bootstrap confidence interval (CI) excluded zero.\u003c/p\u003e\u003cp\u003eMediation analyses were conducted using PROCESS v3.5 (SPSS v29) with 5,000 bias-corrected accelerated bootstrap resamples; all other analyses were performed in R (v4.3.0).\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eSample Characteristics\u003c/p\u003e\n\u003cp\u003eA total of 182 participants were enrolled, including 90 patients with acute TIA or minor ischemic stroke (NIHSS\u0026thinsp;\u0026le;\u0026thinsp;4) and 92 age-matched healthy controls. The case group had a significantly higher proportion of males (73.3% vs. 45.7%; \u0026chi;\u0026sup2; = 13.32; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and a greater prevalence of hypertension (58.9% vs. 37.0%; p\u0026thinsp;=\u0026thinsp;0.003), diabetes mellitus (28.9% vs. 15.2%; p\u0026thinsp;=\u0026thinsp;0.037), current smoking (63.3% vs. 38.0%; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and prior ischemic heart disease (13.3% vs. 1.1%; p\u0026thinsp;=\u0026thinsp;0.004). Among cases, acute DWI lesions were present in 72.2% (n\u0026thinsp;=\u0026thinsp;65), previous silent infarcts in 28.9% (n\u0026thinsp;=\u0026thinsp;26), and cerebral microbleeds in 7.8% (n\u0026thinsp;=\u0026thinsp;7). The baseline characteristics are summarized in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, with extended imaging descriptors in Table \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003e (baseline block).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eBaseline demographic characteristics, cardiovascular risk factors, and family history of cases and controls\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eVariable\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCases (n\u0026thinsp;=\u0026thinsp;90)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eControls (n\u0026thinsp;=\u0026thinsp;92)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDemographic characteristics\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"3\" align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMale sex, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e66 (73.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e42 (45.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge, years, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e59.3\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e58.6\u0026thinsp;\u0026plusmn;\u0026thinsp;7.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.562\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUrban residence, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e43 (47.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e57 (62.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.055\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEducational level, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.005\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e─ Literate without formal education\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e37 (41.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20 (21.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e─ Primary or secondary education\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50 (55.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e61 (66.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e─ University education\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (3.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (12.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSocial situation, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.037\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e─ Good or acceptable\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e59 (65.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e73 (79.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e─ Social risk\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e31 (34.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19 (20.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCardiovascular risk factors\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"3\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHypertension, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e52 (57.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33 (35.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.003\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDyslipidemia, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e38 (42.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e29 (31.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.135\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDiabetes mellitus, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26 (28.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (16.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.042\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAtrial fibrillation, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (11.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (8.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.585\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePrior ischemic heart disease, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (12.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (1.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.002\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCurrent tobacco use, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e57 (64.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e35 (38.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAlcohol consumption, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50 (56.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e39 (42.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.064\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eFamily history\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"3\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHistory of stroke, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25 (27.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27 (29.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.815\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHistory of ischemic heart disease, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e29 (32.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30 (32.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.956\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\"\u003eValues are presented as \u003cem\u003emean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation\u003c/em\u003e or \u003cem\u003enumber (percentage)\u003c/em\u003e. \u003cem\u003ep\u003c/em\u003e values were calculated using Student\u0026rsquo;s \u003cem\u003et\u003c/em\u003e test for continuous variables and the \u0026chi;\u0026sup2; test or Fisher\u0026rsquo;s exact test for categorical variables, as appropriate. Statistical significance was set at \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003ePsychopathological, Cognitive, and HRQoL Outcomes at 90 Days\u003c/p\u003e\n\u003cp\u003eDepressive (HDRS-17\u0026thinsp;\u0026ge;\u0026thinsp;7) and anxiety symptoms (HAM-A\u0026thinsp;\u0026ge;\u0026thinsp;7) were significantly more prevalent in cases than controls (depression: 82.2% vs 18.5%; \u0026chi;\u0026sup2; = 71.42; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; anxiety: 81.1% vs. 21.7%; \u0026chi;\u0026sup2; = 61.82; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Patients also showed higher mean symptom scores (HDRS-17: 11.86\u0026thinsp;\u0026plusmn;\u0026thinsp;5.84 vs 4.13\u0026thinsp;\u0026plusmn;\u0026thinsp;4.35, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003ed\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.50; HAM-A: 13.60\u0026thinsp;\u0026plusmn;\u0026thinsp;7.57 vs. 4.64\u0026thinsp;\u0026plusmn;\u0026thinsp;5.58, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003ed\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.35). Cognitive impairment (MoCA\u0026thinsp;\u0026lt;\u0026thinsp;26) was more frequent among cases (66.7% vs. 13.0%; \u0026chi;\u0026sup2; = 52.49; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), with lower mean MoCA scores (24.08\u0026thinsp;\u0026plusmn;\u0026thinsp;3.26 vs. 27.21\u0026thinsp;\u0026plusmn;\u0026thinsp;2.36; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003ed\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;1.10). HRQoL (EQ-5D-5L utility) was markedly reduced in cases (0.847\u0026thinsp;\u0026plusmn;\u0026thinsp;0.152) compared with controls (0.974\u0026thinsp;\u0026plusmn;\u0026thinsp;0.076; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003ed\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;1.05). These contrasts are summarized in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e and, in greater detail (including Cohen\u0026rsquo;s \u003cem\u003ed\u003c/em\u003e, ORs, and 95% CIs), in Table \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003e. The case\u0026ndash;control prevalences are shown in Figure \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003e, Panel A.\u003c/p\u003e\n\u003cp\u003eBivariate Associations\u003c/p\u003e\n\u003cp\u003eWithin cases, mood scores showed strong negative associations with HRQoL (HDRS-17 vs. EQ-5D-5L \u003cem\u003er\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;0.612, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; HAM-A vs. EQ-5D-5L \u003cem\u003er\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;0.625, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and HDRS-17 correlated strongly with HAM-A (\u003cem\u003er\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.681, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), whereas correlations between MoCA and HRQoL were negligible (\u003cem\u003er\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.092, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.372). The complete correlation matrix (including correlation type and FDR-adjusted \u003cem\u003eq\u003c/em\u003e values) is provided in Table S2 and is graphically displayed in Figure \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003e, Panel B.\u003c/p\u003e\n\u003cp\u003ePredictors of HRQoL: Hierarchical Regression\u003c/p\u003e\n\u003cp\u003eAmong cases with complete data (n\u0026thinsp;=\u0026thinsp;89), Model 1 (age, sex, mRS and social risk) accounted for 6.1% of the HRQoL variance (F\u0026thinsp;=\u0026thinsp;1.36; p\u0026thinsp;=\u0026thinsp;0.256). Adding depressive and anxiety symptoms to Model 2 significantly increased the explained variance (\u0026Delta;R\u0026sup2; = 0.366; total R\u0026sup2; = 0.427; F\u0026thinsp;=\u0026thinsp;10.18; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Model 3, which added MoCA, DWI lesion status, and prior silent infarcts, contributed minimally (\u0026Delta;R\u0026sup2; = 0.017; R\u0026sup2; = 0.444; F\u0026thinsp;=\u0026thinsp;7.02; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001); the increment over Model 2 was not significant (\u0026Delta;R\u0026sup2; = 0.017; p\u0026thinsp;=\u0026thinsp;0.523). Model-level metrics are presented in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e and Table S4; full coefficients for Model 3 (\u0026beta;, B, SE, 95% CI, \u003cem\u003et\u003c/em\u003e, \u003cem\u003ep\u003c/em\u003e) in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e and Table S5. Diagnostics (VIFs, residual analyses, and heteroscedasticity tests) and sensitivity analyses (HC3-robust estimates and beta-regression models) are provided in Tables S6\u0026ndash;S7. Figure\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e illustrates the stepwise increase in R\u0026sup2; (Panel A) and the standardized coefficients for the final model (Panel B).\u0026nbsp;\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eHierarchical Regression Model Comparison: Incremental Variance Explained in Quality of Life Prediction\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eModel\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ePredictors included\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eR\u0026sup2;\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAdjusted R\u0026sup2;\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eF\u003c/em\u003e statistic\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u0026Delta;R\u0026sup2;\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eModel 1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge, sex, mRS, social risk\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.061\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.016\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.36\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.256\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026mdash;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eModel 2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eModel 1\u0026thinsp;+\u0026thinsp;HDRS-17, HAM-A\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.427\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.385\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e10.18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.366\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eModel 3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eModel 2\u0026thinsp;+\u0026thinsp;MoCA, DWI lesion burden, number of infarcts\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.444\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.381\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e7.02\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.017\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"7\"\u003eR\u0026sup2; indicates the proportion of variance that is explained by the model. \u0026Delta;R\u0026sup2; represents the incremental change in the explained variance relative to the previous model. mRS: modified Rankin Scale; HDRS-17: Hamilton Depression Rating Scale; HAM-A: Hamilton Anxiety Rating Scale; MoCA: Montreal Cognitive Assessment; DWI: diffusion-weighted imaging.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"char\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab5\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eStandardized Regression Coefficients for Predictors of Quality of Life\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ePredictor\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eStandardized \u0026beta;\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSE\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e95% CI\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAnxiety (HAM-A)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026minus;0.055\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.029\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026minus;0.114 to 0.003\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.064\u0026dagger;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSocial risk\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026minus;0.048\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.029\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026minus;0.105 to 0.009\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.100\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDepression (HDRS-17)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026minus;0.043\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.029\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026minus;0.102 to 0.016\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.147\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDWI lesion burden\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.050\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.033\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026minus;0.016 to 0.116\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.133\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSilent infarcts\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.015\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.030\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026minus;0.046 to 0.075\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.627\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.006\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.014\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026minus;0.022 to 0.033\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.686\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSex\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026minus;0.000\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.031\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026minus;0.062 to 0.061\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.990\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emRS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026minus;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.021\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026minus;0.044 to 0.041\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.947\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMoCA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026minus;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.014\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026minus;0.029 to 0.027\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.947\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003eThe values represent the standardized regression coefficients (\u0026beta;). 95% CI indicates the 95% confidence interval.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003e\u0026dagger;Trend toward statistical significance (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.10). HAM-A: Hamilton Anxiety Rating Scale; HDRS-17: Hamilton Depression Rating Scale; mRS: modified Rankin Scale; MoCA: Montreal Cognitive Assessment; DWI: diffusion-weighted imaging.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cp\u003eMediation Analysis\u003c/p\u003e\n\u003cp\u003eIn the depression model (Model A), MoCA was not associated with HRQoL (\u0026beta;\u0026thinsp;=\u0026thinsp;0.056; p\u0026thinsp;=\u0026thinsp;0.609) or depression severity (a-path \u0026beta; = \u0026minus;0.095; p\u0026thinsp;=\u0026thinsp;0.381). Depression was associated with lower HRQoL (b-path \u0026beta; = \u0026minus;0.060; p\u0026thinsp;=\u0026thinsp;0.034). The indirect effect was small and non-significant (\u0026beta; = \u0026minus;0.006; 95% BCa CI\u0026thinsp;\u0026minus;\u0026thinsp;0.068 to 0.047). Similarly, in the anxiety model (Model B), MoCA was not associated with anxiety (a-path \u0026beta; = \u0026minus;0.127; p\u0026thinsp;=\u0026thinsp;0.239), whereas anxiety predicted lower HRQoL (b-path \u0026beta; = \u0026minus;0.062; p\u0026thinsp;=\u0026thinsp;0.041). The indirect effect was non-significant (\u0026beta;\u0026thinsp;=\u0026thinsp;0.008; 95% BCa CI\u0026thinsp;\u0026minus;\u0026thinsp;0.046 to 0.078). Path-level estimates (c, a, b, c\u0026prime;) and bootstrap intervals are detailed in Tables S3A\u0026ndash;S3B; and the standardized path diagrams are show in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003eSex-stratified analysis.\u003c/p\u003e\n\u003cp\u003eSex-specific means for HDRS-17, HAM-A, MoCA, and EQ-5D-5L are presented in Figure \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003e, Panel C; statistical tests and effect sizes are reported in Table \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003e (sex-stratified block). This analysis complements the primary models and allows assessment of potential sex-related differences in clinical profiles.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis study highlights a notable paradox in the outcomes following TIA and minor ischemic stroke. Despite excellent functional recovery, with nearly 60% of patients achieving a mRS score of 0 (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e), a substantial and clinically significant burden of psychopathological and cognitive complications remains.( (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) We observed a high prevalence of depression (82.2%) and anxiety (81.1%) symptoms, as well as cognitive impairment (66.7%), far exceeding rates in age-matched healthy controls (18.5%, 21.7%, and 13.0%, respectively), with effect sizes ranging from 1.10 to 1.50, indicating clinical significance far beyond statistical importance. These findings challenge the traditional labeling of TIA and minor stroke as \u0026ldquo;benign\u0026rdquo; and provide important context for interpreting post-event outcomes.\u003c/p\u003e \u003cp\u003eThe high prevalence of depressive (82.2%) and anxiety (81.1%) symptoms observed in our cohort aligns with studies that used symptom-based thresholds rather than diagnostic criteria, which typically yield higher estimates than interview-based diagnoses. Recent syntheses show that scale-based screening tends to identify a larger symptomatic burden than clinical interviews, underscoring that threshold selection materially influences prevalence estimates and clinical interpretation.(\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e) Moreover, contemporary evidence indicates that stroke survivors have nearly threefold higher odds of depression than the general population, reinforcing that elevated symptom rates are epidemiologically plausible rather than artifacts of measurement.(\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eOur findings are also consistent with recent work highlighting lasting impairments after TIA or minor stroke\u0026mdash;including depression, anxiety, fatigue, and cognitive change\u0026mdash;which remain underrecognized and inconsistently treated. This evolving literature provides a broader context for our results, suggesting that substantial psychological morbidity persists despite minimal neurological deficits. (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eThe prevalence of depressive symptoms in our cohort exceeds that reported in studies using comparable symptom-based assessments (~\u0026thinsp;60%) (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e) and is substantially higher than estimates from studies focusing on clinically diagnosed depression (11\u0026ndash;41%), likely reflecting methodological differences in outcome definition.(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e) Notably, a high burden of depressive symptoms was observed independent of objective stroke severity (NIHSS\u0026thinsp;\u0026le;\u0026thinsp;4), indicating that low stroke severity does not preclude psychological morbidity. Although the mean HRDS score (11.86\u0026thinsp;\u0026plusmn;\u0026thinsp;5.84 in cases vs. 4.13\u0026thinsp;\u0026plusmn;\u0026thinsp;4.35 in controls) fell within the mild depressive symptom range, the large effect size observed (Cohen's d\u0026thinsp;=\u0026thinsp;1.50) supports the clinical relevance of these symptoms. Importantly, the use of higher diagnostic cut-offs in previous studies may have led to under-identification of patients with milder depressive symptoms, which can still impact function and HRQoL, without meeting criteria for clinically diagnosed depression.\u003c/p\u003e \u003cp\u003eSimilarly, the 81.1% prevalence of anxiety symptoms represents a substantial burden that has been infrequently quantified in minor stroke or TIA populations, where the reported prevalence ranges from 20\u0026ndash;55%. (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e) Anxiety has historically been under-investigated compared to depression or cognitive outcomes. These findings are consistent with neurobiological evidence that even minor ischemic events may trigger inflammatory cascades and neuroplastic changes that increase vulnerability to mood dysregulation. (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) The large independent effect sizes for both depression and anxiety indicate that post-stroke mood symptoms could represent relevant neuropsychiatric outcomes rather than merely secondary consequences of stroke. (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eCognitive impairment (MoCA\u0026thinsp;\u0026lt;\u0026thinsp;26) was detected in 66.7% of cases, a prevalence substantially exceeding that observed in control populations and at the upper end of the range reported in minor stroke or TIA populations (30\u0026ndash;67%). (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) The lack of association between cognitive impairment and depression or anxiety in the mediation analysis (indirect effect p\u0026thinsp;\u0026gt;\u0026thinsp;0.05) suggests that cognitive dysfunction represents an independent neurobiological consequence of cerebrovascular injury rather than a secondary manifestation of mood disturbance. This distinction raises the possibility that cognitive dysfunction and mood symptoms may arise through partially independent causal pathways, with implications for targeted cognitive and psychological interventions in patients with TIA.\u003c/p\u003e \u003cp\u003eThe absence of mediation by cognition in our models is compatible with recent longitudinal data showing that a single adjudicated, DWI-negative TIA is associated with subsequent cognitive decline independent of vascular and demographic factors, implying that cognitive and affective trajectories may be at least partially dissociable.(\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e) This supports our interpretation that mood and cognitive complications can arise through parallel pathways, each warranting specific monitoring and intervention.(\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eAlthough DWI lesions were present in 72.2% of cases and prior silent infarcts in 28.9%, these neuroimaging findings contributed minimally to HRQoL outcomes, suggesting that structural abnormalities do not necessarily predict symptom burden or functional impact and may be driven by neurobiological mechanisms.\u003c/p\u003e \u003cp\u003eA key finding of this study is the predominant contribution of psychopathological symptoms, particularly anxiety and depression, to HRQoL, accounting for 36.6% of the incremental variance, compared with the 1.5% explained by cognitive and neuroimaging variables. Once psychopathological variables were accounted for, cognitive impairment and neuroimaging markers provided minimal additional predictive value for HRQoL outcomes (ΔR\u0026sup2; = 0.015, p\u0026thinsp;=\u0026thinsp;0.523), suggesting that their association with reduced HRQoL is largely mediated or confounded by mood symptoms. These findings indicate that in this patient population, psychological factors are more strongly associated with patient-reported health status and functional well-being than traditional neurological or imaging-based measures.\u003c/p\u003e \u003cp\u003eAdditionally, anxiety emerged as the strongest independent predictor of reduced HRQoL (β = -0.0595, p\u0026thinsp;=\u0026thinsp;0.044), surpassing the effect of depression and identifying a potentially modifiable contributor to patient-reported HRQoL outcomes, being consistent with previous studies in stroke populations.(\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e) Mediation analyses further indicated that anxiety and depression influence HRQoL through independent, parallel pathways rather than sequential mechanisms, extending previous work on post-stroke psychopathology.\u003c/p\u003e \u003cp\u003eMultiple interacting neuropsychobiological mechanisms after stroke have been implicated in post-stroke anxiety, as well as depression. These include dysregulation of the hypothalamic\u0026ndash;pituitary\u0026ndash;adrenal axis, impaired neuroplasticity due to endothelial dysfunction and reduced cerebral blood flow, and heightened inflammatory responses characterized by elevated proinflammatory cytokines. In addition, ischemic lesions may cause functional disconnection of prefrontal\u0026ndash;limbic networks involved in mood regulation, contributing to heterogeneous anxiety presentations after stroke.(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e) Together, these findings suggest limitations in models that conceptualize post-stroke psychological and cognitive sequelae as consequences of cognitive injury and support a framework in which anxiety, depression, and cognitive impairment are viewed as parallel complications.\u003c/p\u003e \u003cp\u003eA key unmeasured factor in our analysis is fatigue, which has emerged as a frequent and impactful sequela after TIA/minor stroke and is repeatedly identified as a determinant of HRQoL. Future studies should incorporate validated fatigue measures to clarify potential confounding or mediating roles between mood symptoms and HRQoL and to refine prognostic models beyond psychopathology and cognition. (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eClinically, these data reinforce the need for routine mood screening early after TIA/minor stroke and during follow-up, using brief validated tools and establishing referral pathways to evidence-based interventions (e.g., psychological therapies, pharmacotherapy) shown to improve depressive outcomes in post-stroke populations.(\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e) Given the outsized contribution of anxiety and depression to HRQoL, integrating structured screening and treatment into stroke pathways may yield disproportionate gains in patient-reported outcomes relative to strategies focused solely on neurological impairment.(\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eSeveral important limitations that warrant consideration when interpreting findings. First, our case-control design precludes definitive causal inference regarding the temporal relationship between mood and HRQoL. Prospective longitudinal studies tracking mood trajectories would elucidate temporal sequences and allow for stronger causal claims. Additionally, assessment occurred at a single timepoint (90 days post-event), the longitudinal evolution of mood and HRQoL over longer recovery periods remains unknown. Second, the measurement and population considerations may limit generalizability of the findings. Psychological measures relied on self-report instruments that were potentially subject to recall and social desirability bias. Medication use (antidepressants, anxiolytics and other psychotropic medications) was not tracked, representing an important unmeasured confounder. Our sample was recruited from a university hospital and was predominantly male (72.8%), potentially limiting its applicability to community populations or healthcare systems with different demographic compositions. Third, statistical and analytical considerations merit further attention. The hierarchical regression model included nine predictors and 89 participants, maintaining the recommended 10:1 participant-to-predictor ratio and achieving adequate post-hoc statistical power (1-β\u0026thinsp;=\u0026thinsp;0.84); nevertheless, larger multicenter samples would improve generalizability and allow subgroup analyses. Finally, while mediation analyses indicated independent contributions of mood and cognition to HRQoL, the absence of statistically significant mediation does not definitively prove independence; unmeasured cognitive domains or alternative pathways may also contribute.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis study shows that TIA and minor ischemic stroke (NIHSS\u0026thinsp;\u0026le;\u0026thinsp;4) are associated with a substantial burden of depression and anxiety symptoms, as well as cognitive impairment, which persists despite excellent neurological recovery and is strongly linked to reduced HRQoL. Mood symptoms, particularly anxiety, were more strongly associated with patient-reported outcomes than cognitive impairment or neuroimaging findings. The relative independence of mood and cognitive complications suggests distinct underlying mechanisms and challenges paradigms that focus primarily on neurological recovery when interpreting post-event outcomes. These findings further indicate that HRQoL may be more closely linked to psychological symptoms than to cognitive recovery alone, underscoring the importance of considering mood when evaluating post-event outcomes, which should be the subject of future studies research.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eTIA:\u0026nbsp;transient ischemic attack\u003c/p\u003e\n\u003cp\u003emRS: modified Rankin Scale\u003c/p\u003e\n\u003cp\u003eHRQoL: health-related quality of life\u003c/p\u003e\n\u003cp\u003eDWI: diffusion-weighted imaging\u003c/p\u003e\n\u003cp\u003eNIHSS: National Institutes of Health Stroke Scale\u003c/p\u003e\n\u003cp\u003eHDRS-17: Hamilton Depression Rating Scale\u003c/p\u003e\n\u003cp\u003eHAM-A: Hamilton Anxiety Rating Scale\u003c/p\u003e\n\u003cp\u003eMoCA: Montreal Cognitive Assessment\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eNone.\u003c/p\u003e \u003cp\u003eDisclosures:\u003c/p\u003e \u003cp\u003eAll authors reported no conflicts of interest related to this work.\u003c/p\u003e \u003cp\u003eEthics Approval and Consent to Participate:\u003c/p\u003e \u003cp\u003e The study was approved by the Ethics Committee of the University Hospital of Badajoz, Spain. Written informed consent was obtained from all the participants.\u003c/p\u003e \u003cp\u003eData Availability:\u003c/p\u003e \u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eBoth authors contributed equally to the conception and design of the study, data collection, analysis and interpretation of the results, as well as the drafting and critical revision of the manuscript. Both authors approved the final version and agree to be accountable for all aspects of the work.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eFeigin VL, Stark BA, Johnson CO, Roth GA, Bisignano C, Abady GG, et al. Global, regional, and national burden of stroke and its risk factors, 1990\u0026ndash;2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol. 2021;20(10):795\u0026ndash;820.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eD\u0026iacute;az\u0026ndash;Guzm\u0026aacute;n J, Egido JA, Gabriel\u0026ndash;S\u0026aacute;nchez R, Barber\u0026aacute;\u0026ndash;Comes G, Fuentes\u0026ndash;Gimeno B. Fern\u0026aacute;ndez\u0026ndash;P\u0026eacute;rez C. Stroke and transient ischemic attack incidence rate in Spain: The IBERICTUS study. Cerebrovasc Dis. 2012;34(4):272\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmarenco P. Transient ischemic attack. N Engl J Med. 2020;382(20):1933\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHobeanu C, Lavall\u0026eacute;e PC, Charles H, Labreuche J, Albers GW, Caplan LR, et al. 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Sci Rep. 2019;9(1):1\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShi Y, Xiang Y, Yang Y, Zhang N, Wang S, Ungvari GS, et al. Depression after minor stroke: prevalence and predictors. J Psychosom Res. 2015;79(2):143.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBroomfield NM, Quinn TJ, Abdul\u0026ndash;Rahim AH, Walters MR, Evans JJ. Depression and anxiety symptoms post\u0026ndash;stroke/TIA: prevalence and associations in cross\u0026ndash;sectional data from a regional stroke registry. BMC Neurol. 2014;14:198.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHackett ML, Pickles K, Part I. Frequency of depression after stroke: An updated systematic review and meta\u0026ndash;analysis of observational studies. Int J Stroke. 2014;9(8):1017\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaaijwee NAMM, Tendolkar I, Rutten\u0026ndash;Jacobs LCA, Arntz RM, Schaapsmeerders P, Dorresteijn LD, et al. 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Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.aafp.org/pubs/afp/issues/2023/1100/mbtn-poststroke-depression.html\u003c/span\u003e\u003cspan address=\"https://www.aafp.org/pubs/afp/issues/2023/1100/mbtn-poststroke-depression.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed January 29, 2026.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Transient ischemic attack, minor ischemic stroke, depression, anxiety, health-related quality of life, hierarchical regression, mediation analysis","lastPublishedDoi":"10.21203/rs.3.rs-8864143/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8864143/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground and Purpose:\u003c/h2\u003e \u003cp\u003eMinor cerebrovascular events (TIA or minor ischemic stroke) are associated with substantial psychological morbidity, despite generally excellent functional recovery. This study investigated whether mood disturbances or cognitive impairment are the primary contributors to reduced quality of life in patients following minor cerebrovascular events.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003eWe conducted a prospective observational case\u0026ndash;control study including 90 patients with acute TIA or minor ischemic stroke (NIHSS\u0026thinsp;\u0026le;\u0026thinsp;4) confirmed by diffusion-weighted imaging, and 92 age-matched healthy controls. At 90 days post-event, participants underwent assessment with the Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, Montreal Cognitive Assessment, and the EQ-5D-5L quality-of-life utility index. Hierarchical multiple regression using standardized z-scores identified independent predictors of quality of life. Mediation analysis with 5,000-iteration bias-corrected bootstrap confidence intervals tested whether cognitive impairment mediated the relationship between mood symptoms and quality of life.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003eCompared with controls, cases showed markedly higher rates of clinical depression (82.2% vs. 18.5%), anxiety (81.1% vs. 21.7%), and cognitive impairment (66.7% vs. 13.0%; all p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Hierarchical regression revealed that psychopathological variables (depression/anxiety) explained an additional 36.6% of the variance in quality of life (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), whereas cognitive and neuroimaging variables contributed an additional 1.7% (ΔR\u0026sup2;=0.017; incremental p\u0026thinsp;=\u0026thinsp;0.523\u003cb\u003e).\u003c/b\u003e Anxiety emerged as the strongest predictor at trend-level (β=\u0026minus;0.055; p\u0026thinsp;=\u0026thinsp;0.064\u0026dagger;), whereas cognitive impairment showed a negligible effect (β = \u0026minus;\u0026thinsp;0.001, p\u0026thinsp;=\u0026thinsp;0.947). Mediation analysis demonstrated no significant indirect effects, suggesting that mood disturbances and cognitive impairment are independent, rather than sequential, post-event complications.\u003c/p\u003e\u003ch2\u003eConclusions:\u003c/h2\u003e \u003cp\u003eFollowing TIA or minor ischemic stroke, depressive and anxiety symptoms are common, persist despite excellent neurological recovery, and exert a substantial negative impact on health-related quality of life. Anxiety appears to play a particularly prominent role in shaping patient-reported outcomes, underscoring the importance of routine mood screening and targeted management in this population.\u003c/p\u003e","manuscriptTitle":"Depressive and Anxiety Symptoms Predict Health-Related Quality of Life More Than Cognitive Impairment After Minor Stroke or Transient Ischemic Attack: A Hierarchical Regression Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-19 12:38:27","doi":"10.21203/rs.3.rs-8864143/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"11d5cd16-3a78-48a4-9890-f3153d3a188e","owner":[],"postedDate":"February 19th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-20T07:48:34+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-19 12:38:27","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8864143","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8864143","identity":"rs-8864143","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}