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Background: Cerebral small vessel disease is the most common cause of lacunar strokes (LS). Understanding LS pathogenesis is vital for predicting disease severity, prognosis, and developing therapies. Objectives: To research molecular profiles that differentiate LS in deep brain structures from those in subcortical white matter. Design: Prospective case-control study involving 120 patients with imaging-confirmed LS and a 120 control group. Methods: We examined the relationship between Alzheimer's disease biomarkers [amyloid beta (Aß1-40, Aß1-42)], serum inflammatory marker (interleukin-6, IL-6), and endothelial dysfunction markers [soluble tumor necrosis factor-like weak inducer of apoptosis, and pentraxin-3 (sTWEAK, PTX3)] with respect to LS occurring in deep brain structures and subcortical white matter. In addition, we investigated links between LS, leukoaraiosis presence (white matter hyperintensities, WMHs), and functional outcomes at 3 months. Poor outcome was defined as a modified Rankin scale >2 at 3 months. Results: Significant differences were observed in levels of IL-6, PTX3, and sTWEAK between patients with deep lacunar infarcts and those with recent small subcortical infarcts (20.8 versus 15.6 pg/mL, p < 0.001; 7221.3 versus 4624.4 pg/mL, p < 0.0001; 2528.5 versus 1660.5 pg/mL, p = 0.001). Patients with poor outcomes at 3 months displayed notably higher concentrations of these biomarkers compared to those with good outcomes. By contrast, Aß1-40 and Aß1-42 were significantly lower in patients with deep LS (p < 0.0001). Aß1-42 levels were significantly higher in patients with LS in subcortical white matter who had poor outcomes. WMH severity only showed a significant association with deep LS and correlated with sTWEAK (p < 0.0001). Conclusion: The pathophysiological mechanisms of lacunar infarcts in deep brain structures seem different from those in the subcortical white matter. As a result, specific therapeutic and preventive strategies should be explored.
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Glutamate grabbers, such as glutamate oxaloacetate transaminase (GOT), have been proposed to prevent excitotoxicity secondary to high glutamate levels in stroke patients. However, the efficacy of blood glutamate grabbing by GOT could be dependent on the extent and severity of the disruption of the blood-brain barrier (BBB). Our purpose was to analyze the relationship between GOT and glutamate concentration with the patient's functional status differentially according to BBB serum markers (soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) and leukoaraiosis based on neuroimaging). This retrospective observational study includes 906 ischemic stroke patients. We studied the presence of leukoaraiosis and the serum levels of glutamate, GOT, and sTWEAK in blood samples. Functional outcome was assessed using the modified Rankin Scale (mRS) at 3 months. A significant negative correlation between GOT and glutamate levels at admission was shown in those patients with sTWEAK levels > 2900 pg/mL (Pearson's correlation coefficient: -0.249; p < 0.0001). This correlation was also observed in patients with and without leukoaraiosis (Pearson's correlation coefficients: -0.299; p < 0.001 vs. -0.116; p = 0.024). The logistic regression model confirmed the association of higher levels of GOT with lower odds of poor outcome at 3 months when sTWEAK levels were >2900 pg/mL (OR: 0.41; CI 95%: 0.28-0.68; p < 0.0001) or with leukoaraiosis (OR: 0.75; CI 95%: 0.69-0.82; p < 0.0001). GOT levels are associated with glutamate levels and functional outcomes at 3 months, but only in those patients with leukoaraiosis and elevated sTWEAK levels. Consequently, therapies targeting glutamate grabbing might be more effective in patients with BBB dysfunction.
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Ácido Glutâmico , AVC Isquêmico , Humanos , Ácido Glutâmico/sangue , Feminino , Masculino , Idoso , AVC Isquêmico/sangue , Pessoa de Meia-Idade , Estudos Retrospectivos , Medicina de Precisão/métodos , Biomarcadores/sangue , Aspartato Aminotransferases/sangue , Leucoaraiose/sangue , Barreira Hematoencefálica/metabolismo , Citocina TWEAK/sangue , Idoso de 80 Anos ou mais , Isquemia Encefálica/sangueRESUMO
BACKGROUND: Successful recanalization does not lead to complete tissue reperfusion in a considerable percentage of ischemic stroke patients. This study aimed to identify biomarkers associated with futile recanalization. Leukoaraiosis predicts poor outcomes of this phenomenon. Soluble tumour necrosis factor-like weak inducer of apoptosis (sTWEAK), which is associated with leukoaraiosis degrees, could be a potential biomarker. METHODS: This study includes two cohorts of ischemic stroke patients in a multicentre retrospective observational study. Effective reperfusion, defined as a reduction of ≥8 points in the National Institutes of Health Stroke Scale (NIHSS) within the first 24 h, was used as a clinical marker of effective reperfusion. RESULTS: In the first cohort study, female sex, age, and high NIHSS at admission (44.7% vs. 81.1%, 71.3 ± 13.7 vs. 81.1 ± 6.7; 16 [13, 21] vs. 23 [17, 28] respectively; p < .0001) were confirmed as predictors of futile recanalization. ROC curve analysis showed that leukocyte levels (sensitivity of 99%, specificity of 55%) and sTWEAK level (sensitivity of 92%, specificity of 88%) can discriminate between poor and good outcomes. Both biomarkers simultaneously are higher associated with outcome after effective reperfusion (OR: 2.17; CI 95% 1.63-4.19; p < .0001) than individually (leukocytes OR: 1.38; CI 95% 1.00-1.64, p = .042; sTWEAK OR: 1.00; C I95% 1.00-1.01, p = .019). These results were validated using a second cohort, where leukocytes and sTWEAK showed a sensitivity of 100% and specificity of 66.7% and 75% respectively. CONCLUSIONS: Leukocyte and sTWEAK could be biomarkers of reperfusion failure and subsequent poor outcomes. Further studies will be necessary to explore its role in reperfusion processes.
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Biomarcadores , Citocina TWEAK , Futilidade Médica , Reperfusão , Humanos , Feminino , Masculino , Biomarcadores/sangue , Biomarcadores/metabolismo , Idoso , Estudos Retrospectivos , Pessoa de Meia-Idade , Citocina TWEAK/metabolismo , Idoso de 80 Anos ou mais , AVC Isquêmico , Leucoaraiose , Contagem de Leucócitos , Curva ROC , Estudos de CoortesRESUMO
AIM: To assess whether periodontitis is associated with cognitive decline and its progression as well as with certain blood-based markers of Alzheimer's disease. MATERIALS AND METHODS: Data from a 2-year follow-up prospective cohort study (n = 101) was analysed. Participants with a previous history of hypertension and aged ≥60 years were included in the analysis. All of them received a full-mouth periodontal examination and cognitive function assessments (Addenbrooke's Cognitive Examination (ACE) and Mini-Mental State Examination [MMSE]). Plasma levels of amyloid beta (Aß)1-40 , Aß1-42 , phosphorylated and total Tau (p-Tau and t-Tau) were determined at baseline, 12 and 24 months. RESULTS: Periodontitis was associated with poor cognitive performance (MMSE: ß = -1.5 [0.6]) and progression of cognitive impairment (hazard ratio [HR] = 1.8; 95% confidence interval: 1.0-3.1). Subjects with periodontitis showed greater baseline levels of p-Tau (1.6 [0.7] vs. 1.2 [0.2] pg/mL, p < .001) and Aß1-40 (242.1 [77.3] vs. 208.2 [73.8] pg/mL, p = .036) compared with those without periodontitis. Concentrations of the latter protein also increased over time only in the periodontitis group (p = .005). CONCLUSIONS: Periodontitis is associated with cognitive decline and its progression in elderly patients with a previous history of hypertension. Overexpression of p-Tau and Aß1-40 may play a role in this association.
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Doença de Alzheimer , Disfunção Cognitiva , Hipertensão , Periodontite , Idoso , Humanos , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/metabolismo , Estudos Prospectivos , Proteínas tau , Disfunção Cognitiva/complicações , Disfunção Cognitiva/diagnóstico , Biomarcadores , Hipertensão/complicações , Periodontite/complicações , Progressão da Doença , Fragmentos de PeptídeosRESUMO
Background: One of the main biological mechanisms behind the link between periodontitis and atherosclerotic vascular diseases is vascular endothelial dysfunction. Particularly, circulating endothelial progenitor cells (EPCs) have been considered a biomarker of altered vascular endothelial function. Objectives: The aim of this study was to investigate relationship between periodontal inflammation and increased number of circulating EPCs. Design: This is retrospective cohort study. Methods: In this study, 85 elderly patients with a previous history of hypertension were followed up to 12 months. A baseline full-mouth periodontal assessment was carried out, and the amount of periodontal tissue inflamed per subject was calculated as a proxy of periodontal inflammation [periodontal inflamed surface area (PISA)]. The number of circulating EPCs (CD34+/CD133+/KDR+) was determined by flow cytometry from peripheral blood samples collected at baseline and 12 months. Results: Mean concentrations of CD34+/CD133+/KDR+ progenitor cells were higher in periodontitis patients than in those without periodontitis at baseline [55.4, 95% confidence interval (CI) = 20.8 to 90.0 versus 27.2, 95% CI = 13.6 to 40.8, p = 0.008] and 12 months (114.6, 95% CI = 53.5 to 175.7 versus 19.1, 95% CI = 10.8 to 27.4, p = 0.003). A significant increase over the follow-up was noticed in the group of subjects with periodontitis (p = 0.049) but not in the nonperiodontitis group (p = 0.819). PISA was independently associated with CD34+/CD133+/KDR+ EPCs at baseline (B coefficient = 0.031, 95% CI = 0.005 to 0.058; p = 0.021). The relationship between PISA and CD34+/CD133+/KDR+ EPCs at 12 months was confounded by increased baseline body mass index (B coefficient = 0.064, 95% CI = -0.005 to 0.132; p = 0.066). Conclusion: Periodontal inflammation is associated with high number of CD34+/CD133+/KDR+ EPCs, thus supporting a potential link between periodontitis and endothelial dysfunction.
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OBJECTIVE: To examine the relationship between periodontitis and subclinical intracranial atherosclerosis. The association of periodontitis with preclinical markers of atherosclerosis in other vascular territories was also explored. MATERIAL AND METHODS: This was a cross-sectional study where 97 elderly subjects with a previous history of hypertension received an ultrasonographic evaluation to assess subclinical atherosclerosis in different vascular territories: (1) cerebral [pulsatility (PI) and resistance index (RI) of the middle cerebral artery], (2) carotid [intima-media thickness (IMT)], and (3) peripheral [ankle-brachial index (ABI)]. Additionally, participants underwent a full-mouth periodontal assessment together with blood sample collection to determine levels of inflammatory biomarkers (leukocytes, fibrinogen, and erythrocyte sedimentation rate), lipid fractions (total cholesterol and high- and low-density lipoprotein), and glucose. RESULTS: Sixty-one individuals had periodontitis. Compared to subjects without periodontitis, those with periodontitis showed higher values of PI (1.24 ± 0.29 vs 1.01 ± 0.16), RI (0.70 ± 0.14 vs 0.60 ± 0.06), and IMT (0.94 ± 0.15 vs 0.79 ± 0.15) (all p < 0.001). No statistically significant differences were found neither for ABI or for other clinical and biochemical parameters. An independent association was found between periodontitis and increased intracranial atherosclerosis (ORadjusted = 10.16; 95% CI: 3.14-32.90, p < 0.001) and to a lesser extent with thicker carotid IMT (ORadjusted = 4.10; 95% CI: 1.61-10.48, p = 0.003). CONCLUSIONS: Periodontitis is associated with subclinical atherosclerosis in both intracranial and carotid arteries in elderly subjects with hypertension. CLINICAL RELEVANCE: The association of periodontitis with intracranial atherosclerosis implies that periodontitis patients might have greater chances to develop ischemic stroke in the future.
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Aterosclerose , Doenças das Artérias Carótidas , Hipertensão , Arteriosclerose Intracraniana , Periodontite , Humanos , Idoso , Espessura Intima-Media Carotídea , Estudos Transversais , Fatores de Risco , Aterosclerose/complicações , Periodontite/complicações , Hipertensão/complicações , Arteriosclerose Intracraniana/complicaçõesRESUMO
The circadian system regulates numerous physiological variables, including body temperature. Additionally, a circadian patter has been described in stroke onset. Considering this, we hypothesised that the chronobiology of temperature may have an impact on stroke onset and functional outcomes. We also studied the variation of blood biomarkers according to stroke onset time. This is a retrospective observational study. Of the patients included, 2763 had a stroke between midnight and 8:00 h; 1571 between 8:00-14:00 h; and 655 between 14:00 h and midnight. Axillary temperature was measured at admission. At this time, blood samples were collected for biomarker analysis (TNF-α, IL-1ß, IL-6, IL-10, and glutamate). Temperature was higher in patients admitted from 8:00 h to midnight (p < 0.0001). However, the percentage of poor outcome at 3 months was highest in patients from midnight to 8:00 h (57.7%, p < 0.001). The association between temperature and mortality was highest during night time (OR: 2.79; CI 95%: 2.36-3.28; p < 0.001). These patients exhibited high glutamate (220.2 ± 140.2 µM), IL-6 (32.8 ± 14.3 pg/mL) and low IL-10 (9.7 ± 14.3 pg/mL) levels. Therefore, temperature chronobiology could have a significant impact on stroke onset and functional outcome. Superficial body hyperthermia during sleep seems to be more dangerous than during wakefulness. Further studies will be necessary to confirm our data.
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Temperatura Corporal , Ritmo Circadiano , Interleucina-10 , Acidente Vascular Cerebral , Humanos , Ritmo Circadiano/fisiologia , Glutamatos , Interleucina-6 , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/etiologia , BiomarcadoresRESUMO
INTRODUCTION AND OBJECTIVES: Recently, neurologists have begun to perform focused cardiac ultrasound for the detection of a cardiac source of embolism in stroke patients, requiring them to undergo a prior accredited training process. We designed a prospective study to analyze the incidence of heart disease detected by a focused cardiac ultrasound program within a stroke care network with cardiac imaging units and to identify the outcomes of detected structural heart disease at 1 year of follow-up. METHODS: We included patients admitted to a university hospital for ischemic stroke or a transient ischemic attack between 2017 and 2021 who were evaluated by focused cardiac ultrasound. We studied the presence of structural heart disease and cardioembolic sources. We analyzed cardiovascular events (CVE) during the first year of follow-up. RESULTS: Focused cardiac ultrasound was performed in 706 patients. Structural heart disease was detected in 52.1% and a cardioembolic source in 31.9%. Adverse CVE occurred in 5.49% of the patients in the first year of follow-up. The presence of de novo structural heart disease was independently associated with a higher probability of adverse CVE (HR, 1.72; 95%CI, 1.01- 2.91; P=.046). CONCLUSIONS: Focused cardiac ultrasound within a stroke care network with cardiac imaging units is an accessible technique with high diagnostic yield. Its use allows clinical and therapeutic actions in the prevention of stroke recurrences and other CVEs in this group of patients.
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Cardiopatias , Acidente Vascular Cerebral , Humanos , Estudos Prospectivos , Neurologistas , Ecocardiografia Transesofagiana , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Cardiopatias/diagnóstico , Cardiopatias/epidemiologia , Cardiopatias/complicaçõesRESUMO
BACKGROUND: Determining the cause of acute ischemic stroke is crucial for patient management, particularly for preventing future stroke. In recent years, carotid web (CW), a non-atherosclerotic disorder of the carotid wall, has been found to be an underestimated source of cerebral emboli. OBJECTIVE: The present study aimed to analyze the clinical, radiological, and pathological findings, along with the treatments performed in patients with CW and ipsilateral ischemic events. METHODS: Patients with anterior circulation ischemic stroke or transient ischemic attack and ipsilateral CW were prospectively included from January 2019 to December 2021. RESULTS: Nine patients were enrolled. The median age was 55 (43-62) years, with a female-to-male ratio of 3.5:1. Of the total, seven patients (78%) consulted for recurrent ipsilateral ischemic events. Despite medical treatment, 44% of the patients experienced new episodes. Computed tomographic angiography was suggestive of CW in all cases in which it was performed. The interval between the first ischemic event and diagnosis of CW was of 13 (6-68) months. After ruling out any other possible etiology, every patient underwent carotid revascularization, one underwent stenting and eight underwent carotidectomy. No severe or long-term complications were noted. Histological studies confirmed the diagnosis of CW. There were no recurrences after carotid revascularization during a follow-up of 24 (13-35) months. CONCLUSION: Knowledge of CW and differentiating it from atheroma plaques is essential, as medical management seems to be insufficient in many cases. Revascularization, which has been shown to be safe and effective, might be the best treatment modality.
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Estenose das Carótidas , Endarterectomia das Carótidas , Ataque Isquêmico Transitório , AVC Isquêmico , Placa Aterosclerótica , Acidente Vascular Cerebral , Estenose das Carótidas/complicações , Endarterectomia das Carótidas/efeitos adversos , Feminino , Humanos , Ataque Isquêmico Transitório/etiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/etiologia , Resultado do TratamentoRESUMO
BACKGROUND: Wake-up ischemic stroke (IS) has been usually excluded from acute stroke therapy options for being outside of the safe treatment window. We identified risk factors, and clinical or molecular biomarkers that could be therapeutic targets for wake-up stroke prevention, thus hopefully leading to a decrease in its mortality and disability in medium to long-term outcome. METHODS: 4251 ischemic stroke (IS) patients from a prospectively registered database were recruited; 3838 (90.3%) had known onset-symptom time, and 413 (9.7%) were wake-up strokes. The main endpoint was to analyze the association between different serum biomarkers with wake-up IS episodes and their progression. Leukocytes count, serum levels of C-reactive protein, fibrinogen, interleukin 6 (IL-6), and vitamin D were analyzed as inflammation biomarkers; N-terminal pro-B-type Natriuretic-Peptide and microalbuminuria, used as atrial/endothelial dysfunction biomarkers; finally, glutamate levels as excitotoxicity biomarker. In addition, demographic, clinical and neuroimaging variables associated with the time-evolution of wake-up IS patients and functional outcome at 3 months were evaluated. Good and poor functional outcome were defined as mRS ≤2 and mRS > 2 at 3 months, respectively. RESULTS: Wake-up IS showed a poorer outcome at 3-months than in patients with known on-set-symptom time (59.1% vs. 48.1%; p < 0.0001). Patients with wake-up IS had higher levels of inflammation biomarkers; IL-6 levels at admission (51.5 ± 15.1 vs. 27.8 ± 18.6 pg/ml; p < 0.0001), and low vitamin D levels at 24 h (5.6 ± 5.8 vs. 19.2 ± 9.4 ng/ml; p < 0.0001) are worthy of attention. In a logistic regression model adjusted for vitamin D, OR was 15.1; CI 95%: 8.6-26.3, p < 0.0001. However, we found no difference in vitamin D levels between patients with or without clinical-DWI mismatch (no: 18.95 ± 9.66; yes: 17.84 ± 11.77 ng/mL, p = 0.394). No difference in DWI volume at admission was found (49.3 ± 96.9 ml in wake-up IS patients vs. 51.7 ± 98.2 ml in awake IS patients; p = 0.895). CONCLUSIONS: Inflammatory biomarkers are the main factors that are strongly associated with wake-up IS episodes. Wake-up IS is associated with lower vitamin D levels. These data indicate that vitamin D deficiency could become a therapeutic target to reduce wake-up IS events.
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Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Biomarcadores , Isquemia Encefálica/complicações , Humanos , Inflamação/complicações , Interleucina-6 , Acidente Vascular Cerebral/complicações , Vitamina DRESUMO
Malignant infarction of the middle cerebral artery (m-MCA) is a complication of ischemic stroke. Since hyperthermia is a predictor of poor outcome, and antihyperthermic treatment is well tolerated, our main aim was to analyze whether the systemic temperature decrease within the first 24 h was associated with a better outcome. Furthermore, we studied potential biochemical and neuroimaging biomarkers. This is a retrospective observational analysis that included 119 patients. The temperature variations within the first 24 h were recorded. Biochemical laboratory parameters and neuroimaging variables were also analyzed. The temperature increase at the first 24 h (OR: 158.97; CI 95%: 7.29−3465.61; p < 0.001) was independently associated with a higher mortality. Moreover, antihyperthermic treatment (OR: 0.08; CI 95%: 0.02−0.38; p = 0.002) was significantly associated with a good outcome at 3 months. Importantly, antihyperthermic treatment was associated with higher survival at 3 months (78% vs. 50%, p = 0.003). Significant independently associations between the development of m-MCA and both microalbuminuria (OR: 1.01; CI 95%: 1.00−1.02; p = 0.005) and leukoaraiosis (OR: 3.07; CI 1.84−5.13−1.02; p < 0.0001) were observed. Thus, antihyperthermic treatment within the first 24 h was associated with both a better outcome and higher survival. An increased risk of developing m-MCA was associated with leukoaraiosis and an elevated level of microalbuminuria.
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Objective: This study aimed to explore the association between smoking habit and the serum levels of soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK), in relation with the functional outcome of patients with acute ischemic stroke undergoing reperfusion treatment. Methods: Observational and retrospective study of a series of patients with acute ischemic stroke subjected to reperfusion treatments. Clinical, analytical, and neuroimaging parameters were analyzed. The main endpoint was the functional outcome at 3 months, measured by the modified Ranking Scale (mRS). Logistic regression models were used to analyze the association between smoking and sTWEAK levels with functional outcome and leukoaraiosis. Results: The results showed that smoking habit was associated with a good functional outcome at 3 months in patients with stroke (OR: 3.52; 95% CI: 1.03-11.9; p = 0.044). However, this independent association was lost after adjusting by sTWEAK levels (OR 1.73; 95% CI: 0.86-13.28; p = 0.116). sTWEAK levels were significantly lower in smoker patients [4015.5 (973.66-7921.83) pg/ml vs. 5,628 (2,848-10,202) pg/ml, p < 0.0001], while sTWEAK levels were significantly higher in patients with poor functional outcomes at 3 months [10,284 (7,388-13.247) pg/ml vs. 3,405 (2,329-6,629) pg/ml, p < 0.0001]. Conclusion: The decrease in sTWEAK levels was associated with a good functional outcome in smoker patients with stroke undergoing reperfusion therapy.
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OBJECTIVE: Leukoaraiosis (LA) refers to white matter lesions of undetermined etiology associated with the appearance and worsening of vascular pathologies. The aim is to confirm an increased frequency and intensity of LA in symptomatic patients with neurovascular pathology compared with asymptomatic subjects, and its association with circulating serum levels of soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK). METHODS: An observational study was conducted in which two groups of patients were compared. Group I (N = 242) comprised of asymptomatic subjects with arterial hypertension and/or diabetes or with a history of transient ischemic attacks, and Group II (N = 382) comprised patients with lacunar stroke or deep hemispheric intracerebral hemorrhage (ICH) of hypertensive origin. Serum levels of sTWEAK were analyzed and correlated with prevalence and intensity of LA according to the Fazekas scale. RESULTS: The prevalence of LA was higher in symptomatic (85.1%) versus asymptomatic patients (62.0%). Logistic regression model showed a significant relation of LA with neurovascular pathologies (OR: 2.69, IC 95%: 1.10-6.59, p = 0.003). When stratified according to the Fazekas scale, LA of grade II (OR: 3.53, IC 95%: 1.10-6.59, p = 0.003) and specially grade III (OR: 4.66, 95% CI: 1.09-19.84, p = 0.037) showed correlation with neurovascular pathologies. Increased sTWEAK levels were found in the symptomatic group in all LA grades (p < 0.0001), and associated with 5.06 times more risk of presenting clinical symptoms (OR: 5.06, 95% CI: 2.66-9.75, p < 0.0001). INTERPRETATION: LA showed a higher prevalence in patients with symptomatic lacunar stroke or deep hemispheric ICH. There is an association between sTWEAK levels and LA degree.
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Hemorragia Cerebral , Citocina TWEAK/sangue , Diabetes Mellitus , Hipertensão , Ataque Isquêmico Transitório , Leucoaraiose , Sistema de Registros , Acidente Vascular Cerebral Lacunar , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Hemorragia Cerebral/sangue , Hemorragia Cerebral/epidemiologia , Hemorragia Cerebral/patologia , Comorbidade , Diabetes Mellitus/sangue , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/patologia , Feminino , Humanos , Hipertensão/sangue , Hipertensão/epidemiologia , Hipertensão/patologia , Ataque Isquêmico Transitório/sangue , Ataque Isquêmico Transitório/epidemiologia , Ataque Isquêmico Transitório/patologia , Leucoaraiose/sangue , Leucoaraiose/epidemiologia , Leucoaraiose/patologia , Masculino , Pessoa de Meia-Idade , Prevalência , Acidente Vascular Cerebral Lacunar/sangue , Acidente Vascular Cerebral Lacunar/epidemiologia , Acidente Vascular Cerebral Lacunar/patologiaRESUMO
We research into the clinical, biochemical and neuroimaging factors associated with the outcome of stroke patients to generate a predictive model using machine learning techniques for prediction of mortality and morbidity 3-months after admission. The dataset consisted of patients with ischemic stroke (IS) and non-traumatic intracerebral hemorrhage (ICH) admitted to Stroke Unit of a European Tertiary Hospital prospectively registered. We identified the main variables for machine learning Random Forest (RF), generating a predictive model that can estimate patient mortality/morbidity according to the following groups: (1) IS + ICH, (2) IS, and (3) ICH. A total of 6022 patients were included: 4922 (mean age 71.9 ± 13.8 years) with IS and 1100 (mean age 73.3 ± 13.1 years) with ICH. NIHSS at 24, 48 h and axillary temperature at admission were the most important variables to consider for evolution of patients at 3-months. IS + ICH group was the most stable for mortality prediction [0.904 ± 0.025 of area under the receiver operating characteristics curve (AUC)]. IS group presented similar results, although variability between experiments was slightly higher (0.909 ± 0.032 of AUC). ICH group was the one in which RF had more problems to make adequate predictions (0.9837 vs. 0.7104 of AUC). There were no major differences between IS and IS + ICH groups according to morbidity prediction (0.738 and 0.755 of AUC) but, after checking normality with a Shapiro Wilk test with the null hypothesis that the data follow a normal distribution, it was rejected with W = 0.93546 (p-value < 2.2e-16). Conditions required for a parametric test do not hold, and we performed a paired Wilcoxon Test assuming the null hypothesis that all the groups have the same performance. The null hypothesis was rejected with a value < 2.2e-16, so there are statistical differences between IS and ICH groups. In conclusion, machine learning algorithms RF can be effectively used in stroke patients for long-term outcome prediction of mortality and morbidity.
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Algoritmos , Hemorragia Cerebral/mortalidade , Acidente Vascular Cerebral Hemorrágico/mortalidade , Hospitalização/estatística & dados numéricos , AVC Isquêmico/mortalidade , Índice de Gravidade de Doença , Idoso , Hemorragia Cerebral/patologia , Hemorragia Cerebral/terapia , Feminino , Seguimentos , Acidente Vascular Cerebral Hemorrágico/patologia , Acidente Vascular Cerebral Hemorrágico/terapia , Humanos , AVC Isquêmico/patologia , AVC Isquêmico/terapia , Aprendizado de Máquina , Masculino , Prognóstico , Estudos Prospectivos , Curva ROC , Taxa de SobrevidaRESUMO
Aim: The purpose of this study was to investigate clinical and neuroimaging factors associated with stroke recurrence in reperfused ischemic stroke patients, as well as the influence of specific biomarkers of inflammation and endothelial dysfunction. Methods: We conducted a retrospective analysis on a prospectively registered database. Of the 875 patients eligible for this study (53.9% males; mean age 69.6 ± 11.8 years vs. 46.1% females; mean age 74.9 ± 12.6 years), 710 underwent systemic thrombolysis, 87 thrombectomy and in 78, systemic or intra-arterial thrombolysis together with thrombectomy was applied. Plasma levels of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα) were analyzed as markers of inflammation, and soluble tumor necrosis factor-like inducer of apoptosis (sTWEAK) as an endothelial dysfunction marker. The main outcome variables of the study were the presence and severity of leukoaraiosis (LA) and stroke recurrence. Results: The average follow-up time of the study was 25 ± 13 months, during which 127 patients (14.5%) showed stroke recurrence. The presence and severity of LA was more severe in the second stroke episode (Grade III of the Fazekas 28.3 vs. 52.8%; p < 0.0001). IL-6 levels at the first admission and before reperfusion treatment in patients with and without subsequent recurrence were similar (9.9 ± 10.4 vs. 9.1 ± 7.0 pg/mL, p = 0.439), but different for TNFα (14.7 ± 5.6 vs. 15.9 ± 5.7 pg/mL, p = 0.031) and sTWEAK (5,970.8 ± 4,330.4 vs. 8,660.7 ± 5,119.0 pg/mL, p < 0.0001). sTWEAK values ≥7,000 pg/mL determined in the first stroke were independently associated to recurrence (OR 2.79; CI 95%: 1.87-4.16, p < 0.0001). Conclusions: The severity and the progression of LA are the main neuroimaging factors associated with stroke recurrence. Likewise, sTWEAK levels were independently associated to stroke recurrence, so further studies are necessary to investigate sTWEAK as a therapeutic target.
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OBJECTIVE: To study the association between early growth of haematoma with biomarkers of endothelial dysfunction such as leukoaraiosis (LA) and the soluble tumour necrosis factor-like weak inducer of apoptosis (sTWEAK) in patients with intracerebral haemorrhage (ICH). METHODS: This is a retrospective observational study of patients with nontraumatic ICH. Clinical and biochemical parameters were analysed. sTWEAK levels were measured by ELISA. LA was analysed in the hemisphere without haemorrhage to avoid interference with the acute injury. The main endpoint was the haematoma growth evaluated by the difference in volume between the second and the initial neuroimage. Poor functional outcome, defined as a modified Rankin Scale >2 at 3 months, was considered as secondary endpoint. Receiver operating characteristic curve analysis was performed to stablish the best cut-off for sTWEAK levels associated with haematoma growth. RESULTS: We included 653 patients with ICH in our analysis (71.1±11.9 years, 44% women). Haematoma growth was observed in 188 patients (28.8%). sTWEAK levels ≥5600 pg/mL predicted ICH growth with a sensitivity of 84% and a specificity of 87%. sTWEAK levels ≥5600 pg/mL and the presence of LA were associated with haematoma growth (OR: 42.46; (CI 95% 22.67 to 79.52) and OR: 2.73 (CI 95% 1.39 to 5.34), respectively). Also, the presence of LA (OR: 4.31 (CI 95% 2.89 to 6.42)) and the interaction between ICH growth and sTWEAK (OR: 2.23 (CI 95% 1.40 to 3.55)) were associated with poor functional outcome at 3 months. CONCLUSION: sTWEAKs, together with the presence and grade of LA, are biomarkers able to predict ICH growth and poor functional outcome in patients with ICH.
Assuntos
Leucoaraiose , Biomarcadores , Hemorragia Cerebral/diagnóstico , Feminino , Hematoma/complicações , Hematoma/patologia , Humanos , Leucoaraiose/diagnóstico por imagem , Masculino , Estudos RetrospectivosRESUMO
OBJECTIVE: To investigate whether elevated serum levels of sTWEAK (soluble tumor necrosis factor-like inducer of apoptosis) might be involved in a higher frequency of symptomatic hemorrhagic transformation (HT) through the presence of leukoaraiosis (LA) in patients with acute ischemic stroke (IS) undergoing reperfusion therapies. METHODS: This is a retrospective observational study. The primary endpoint was to study the sTWEAK-LA-HT relationship by comparing results with biomarkers associated to HT and evaluating functional outcome at 3-months. Clinical factors, neuroimaging variables and biomarkers associated to inflammation, endothelial/atrial dysfunction or blood-brain barrier damage were also investigated. RESULTS: We enrolled 875 patients (mean age 72.3 ± 12.2 years; 46.0% women); 710 individuals underwent intravenous thrombolysis, 87 endovascular therapy and 78 both. HT incidence was 32%; LA presence was 75.4%. Patients with poor functional outcome at 3-months showed higher sTWEAK levels at admission (9844.2 [7460.4-12,542.0] vs. 2717.3 [1489.7-5852.3] pg/mL, P < 0.0001). By means of logistic regression models, PDGF-CC and sTWEAK were associated with mechanisms linked simultaneously to HT and LA. Serum sTWEAK levels at admission ≥6700 pg/mL were associated with an odds ratio of 13 for poor outcome at 3-months (OR: 13.6; CI 95%: 8.2-22.6, P < 0.0001). CONCLUSIONS: Higher sTWEAK levels are independently associated with HT and poor functional outcome in patients with IS undergoing reperfusion therapies through the presence of LA. sTWEAK could become a therapeutic target to reduce HT incidence in patients with IS.
Assuntos
Hemorragia Cerebral/sangue , Citocina TWEAK/sangue , AVC Isquêmico/sangue , Leucoaraiose/patologia , Avaliação de Resultados em Cuidados de Saúde , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Hemorragia Cerebral/epidemiologia , Hemorragia Cerebral/terapia , Comorbidade , Feminino , Seguimentos , Humanos , AVC Isquêmico/epidemiologia , AVC Isquêmico/terapia , Leucoaraiose/diagnóstico por imagem , Leucoaraiose/epidemiologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Reperfusão/estatística & dados numéricos , Estudos RetrospectivosRESUMO
Although hyperthermia is associated with poor outcomes in ischaemic stroke (IS), some studies indicate that high body temperature may benefit reperfusion therapies. We assessed the association of temperature with effective reperfusion (defined as a reduction of ≥8 points in the National Institute of Health Stroke Scale (NIHSS) within the first 24 h) and poor outcome (modified Rankin Scale (mRS) > 2) in 875 retrospectively-included IS patients. We also studied the influence of temperature on thrombolytic (cellular fibronectin (cFn); matrix metalloproteinase 9 (MMP-9)) and inflammatory biomarkers (tumour necrosis factor-alpha (TNF-α), interleukin 6 (IL-6)) and their relationship with effective reperfusion. Our results showed that a higher temperature at 24 but not 6 h after stroke was associated with failed reperfusion (OR: 0.373, p = 0.001), poor outcome (OR: 2.190, p = 0.005) and higher IL-6 levels (OR: 0.958, p < 0.0001). Temperature at 6 h was associated with higher MMP-9 levels (R = 0.697; p < 0.0001) and effective reperfusion, although this last association disappeared after adjusting for confounding factors (OR: 1.178, p = 0.166). Our results suggest that body temperature > 37.5 °C at 24 h, but not at 6 h after stroke, is correlated with reperfusion failure, poor clinical outcome, and infarct size. Mild hyperthermia (36.5-37.5 °C) in the first 6 h window might benefit drug reperfusion therapies by promoting clot lysis.
RESUMO
BACKGROUND: Recent preclinical studies have shown that regulatory T cells (Treg) play a key role in the immune response after ischemic stroke (IS). However, the role of Treg in human acute IS has been poorly investigated. Our aim was to study the relationship between circulating Treg and outcome in human IS patients. METHODS: A total of 204 IS patients and 22 control subjects were recruited. The main study variable was good functional outcome at 3 months (modified Rankin scale ≤2) considering infarct volume, Early Neurological Deterioration (END) and risk of infections as secondary variables. The percentage of circulating Treg was measured at admission, 48, 72 h and at day 7 after stroke onset. RESULTS: Circulating Treg levels were higher in IS patients compared to control subjects. Treg at 48 h were independently associated with good functional outcome (OR, 3.5; CI: 1.9-7.8) after adjusting by confounding factors. Patients with lower Treg at 48 h showed higher frequency of END and risk of infections. In addition, a negative correlation was found between circulating Treg at 48 h (r = - 0.414) and 72 h (r = - 0.418) and infarct volume. CONCLUSIONS: These findings suggest that Treg may participate in the recovery of IS patients. Therefore, Treg may be considered a potential therapeutic target in acute ischemic stroke.
Assuntos
Isquemia Encefálica/imunologia , Recuperação de Função Fisiológica , Acidente Vascular Cerebral/imunologia , Linfócitos T Reguladores/imunologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Neuroprotective treatments in ischemic stroke are focused to reduce the pernicious effect of excitotoxicity, oxidative stress and inflammation. However, those cellular and molecular mechanisms may also have beneficial effects, especially during the late stages of the ischemic stroke. The objective of this study was to investigate the relationship between the clinical improvement of ischemic stroke patients and the time-dependent excitotoxicity and inflammation. We included 4295 ischemic stroke patients in a retrospective study. The main outcomes were intra and extra-hospital improvement. High glutamate and IL-6 levels at 24 hours were associated with a worse intra-hospital improvement (OR:0.993, 95%CI: 0.990-0.996 and OR:0.990, 95%CI: 0.985-0.995). High glutamate and IL-6 levels at 24 hours were associated with better extra-hospital improvement (OR:1.13 95%CI, 1.07-1.12 and OR:1.14, 95%CI, 1.09-1.18). Effective reperfusion after recanalization showed the best clinical outcome. However, the long term recovery is less marked in patients with an effective reperfusion. The variations of glutamate and IL6 levels in the first 24 hours clearly showed a relationship between the molecular components of the ischemic cascade and the clinical outcome of patients. Our findings suggest that the rapid reperfusion after recanalization treatment blocks the molecular response to ischemia that is associated with restorative processes.