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1.
Stroke ; : STROKEAHA119025732, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31409268

RESUMO

Background and Purpose- In patients with symptomatic intracranial atherosclerotic stenosis, identifying the underlying stroke mechanisms may inform secondary prevention. We aimed to propose reproducible classification criteria for stroke mechanisms based on routine neuroimaging in symptomatic intracranial atherosclerotic stenosis and explore their clinical implications. Methods- We recruited patients with acute ischemic stroke attributed to 50% to 99% intracranial atherosclerotic stenosis in anterior circulation from 2 centers. Two investigators independently classified probable stroke mechanisms as parent artery atherosclerosis occluding penetrating artery, artery-to-artery embolism, hypoperfusion, and mixed mechanisms, with prespecified criteria based on infarct topography and magnetic resonance/computed tomography angiography. These stroke mechanisms were correlated with features of the patients at baseline and recurrent ischemic stroke in the same territory or relevant transient ischemic attack within 1 year. Results- Among 153 patients recruited, the most common stroke mechanisms were isolated hypoperfusion (35.3%) and mixed mechanism of artery-to-artery embolism and hypoperfusion (37.3%) that was associated with higher incidence of dyslipidemia (P=0.045) and hypertension (P=0.033) than patients with other stroke mechanisms. The proposed criteria showed substantial to excellent intrarater and interrater reproducibilities (κ, 0.791-0.908). Overall, 31 patients received interventional treatment of the diseased intracranial artery; 122 received medical treatment, among whom a mixed mechanism of artery-to-artery embolism and hypoperfusion at baseline was associated with higher risk of ischemic stroke in the same territory within 1 year (24.4% versus 7.8%; hazard ratio, 3.40; 95% CI, 1.25-9.20; log-rank P=0.010) than other mechanisms combined. Conclusions- Artery-to-artery embolism and hypoperfusion commonly coexist in ischemic stroke attributed to intracranial atherosclerotic stenosis, which may be associated with higher risk of stroke relapse.

2.
Ann Neurol ; 85(5): 752-764, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30840312

RESUMO

OBJECTIVE: To investigate whether hemodynamic features of symptomatic intracranial atherosclerotic stenosis (sICAS) might correlate with the risk of stroke relapse, using a computational fluid dynamics (CFD) model. METHODS: In a cohort study, we recruited patients with acute ischemic stroke attributed to 50 to 99% ICAS confirmed by computed tomographic angiography (CTA). With CTA-based CFD models, translesional pressure ratio (PR = pressurepoststenotic /pressureprestenotic ) and translesional wall shear stress ratio (WSSR = WSSstenotic - throat /WSSprestenotic ) were obtained in each sICAS lesion. Translesional PR ≤ median was defined as low PR and WSSR ≥4th quartile as high WSSR. All patients received standard medical treatment. The primary outcome was recurrent ischemic stroke in the same territory (SIT) within 1 year. RESULTS: Overall, 245 patients (median age = 61 years, 63.7% males) were analyzed. Median translesional PR was 0.94 (interquartile range [IQR] = 0.87-0.97); median translesional WSSR was 13.3 (IQR = 7.0-26.7). SIT occurred in 20 (8.2%) patients, mostly with multiple infarcts in the border zone and/or cortical regions. In multivariate Cox regression, low PR (adjusted hazard ratio [HR] = 3.16, p = 0.026) and high WSSR (adjusted HR = 3.05, p = 0.014) were independently associated with SIT. Patients with both low PR and high WSSR had significantly higher risk of SIT than those with normal PR and WSSR (risk = 17.5% vs 3.0%, adjusted HR = 7.52, p = 0.004). INTERPRETATION: This work represents a step forward in utilizing computational flow simulation techniques in studying intracranial atherosclerotic disease. It reveals a hemodynamic pattern of sICAS that is more prone to stroke relapse, and supports hypoperfusion and artery-to-artery embolism as common mechanisms of ischemic stroke in such patients. Ann Neurol 2019;85:752-764.

3.
J Cereb Blood Flow Metab ; : 271678X18805209, 2018 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-30351176

RESUMO

We aimed to investigate the roles of antegrade residual flow and leptomeningeal collateral flow in sustaining cerebral perfusion distal to an intracranial atherosclerotic stenosis (ICAS). Patients with apparently normal cerebral perfusion distal to a symptomatic middle cerebral artery (MCA)-M1 stenosis were enrolled. Computational fluid dynamics models were built based on CT angiography to obtain a translesional pressure ratio (PR) to gauge the residual antegrade flow. Leptomeningeal collaterals (LMCs) were scaled on CT angiography. Cerebral perfusion metrics were obtained in CT perfusion maps. Among 83 patients, linear regression analyses revealed that both translesional PR and LMC scale were independently associated with relative ipsilesional mean transit time (rMTT). Subgroup analyses showed that ipsilesional rMTT was significantly associated with translesional PR ( p < 0.001) rather than LMC scale in those with a moderate (50-69%) MCA stenosis, which, however, was only significantly associated with LMC scale ( p = 0.051) in those with a severe (70-99%) stenosis. Antegrade residual flow and leptomeningeal collateral flow have complementary effects in sustaining cerebral perfusion distal to an ICAS, while cerebral perfusion may rely more on the collateral circulation in those with a severe stenosis.

4.
J Stroke Cerebrovasc Dis ; 27(1): 44-52, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29107636

RESUMO

BACKGROUND: Computational fluid dynamics (CFD) allows noninvasive fractional flow (FF) computation in intracranial arterial stenosis. Removal of small artery branches is necessary in CFD simulation. The consequent effects on FF value needs to be judged. METHODS: An idealized vascular model was built with 70% focal luminal stenosis. A branch with one third or one half of the radius of the parent vessel was added at a distance of 5, 10, 15 and 20 mm to the lesion. With pressure and flow rate applied as inlet and outlet boundary conditions, CFD simulations were performed. Flow distribution at bifurcations followed Murray's law. By including or removing side branches, five patient-specific intracranial artery models were simulated. Transient simulation was performed on a patient-specific model, with a larger branch for validation. Branching effect was considered trivial if the FF difference between paired models (branches included or removed) was within 5%. RESULTS: Compared with the control model without a branch, in all idealized models the relative differences of FF was within 2%. In five pairs of cerebral arteries (branches included/removed), FFs were 0.876 and 0.877, 0.853 and 0.858, 0.874 and 0.869, 0.865 and 0.858, 0.952 and 0.948. The relative difference in each pair was less than 1%. In transient model, the relative difference of FF was 3.5%. CONCLUSION: The impact of removing side branches with radius less than 50% of the parent vessel on FF measurement accuracy is negligible in static CFD simulations, and minor in transient CFD simulation.


Assuntos
Artérias Cerebrais/fisiopatologia , Circulação Cerebrovascular , Doenças Arteriais Intracranianas/fisiopatologia , Modelos Cardiovasculares , Modelagem Computacional Específica para o Paciente , Velocidade do Fluxo Sanguíneo , Angiografia Cerebral/métodos , Artérias Cerebrais/diagnóstico por imagem , Angiografia por Tomografia Computadorizada , Constrição Patológica , Humanos , Hidrodinâmica , Doenças Arteriais Intracranianas/diagnóstico por imagem , Interpretação de Imagem Radiográfica Assistida por Computador , Fluxo Sanguíneo Regional
5.
Neuroscience ; 367: 72-84, 2017 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-29111361

RESUMO

To mimic the expected pathological changes of white matter lesions (WMLs) and increase the stability, we applied modified two-vessel occlusion (modified 2VO) (1-week interval bilateral carotid artery occlusion) in stroke-prone renovascular hypertensive rats (RHRSP) and established a modified WMLs model (RHRSP/modified 2VO) that compared their phenotypes with RHRSP and sham-operated rats. In addition, we tried to differentiate small veins from small arteries through the presence of smooth muscle to study the pathological changes of small veins detailed in the model. RHRSP/modified 2VO rats showed higher stability and more extensive white matter damage without an obvious increase in mortality rate at 12 weeks after the modified 2VO operation compared to RHRSP rats. RHRSP/modified 2VO rats showed more severe small venous collagen deposition than RHRSP rats, and the majority of the deposition was collagen I and IV rather than collagen III. In addition, RHRSP/modified 2VO rats possessed cognitive impairment, mild wall thickness and blood-brain barrier disruption. Our findings suggest that the modified WMLs model (RHRSP/modified 2VO) mimics cognitive impairment and small vessel pathological changes similar to WMLs in humans. Differentiating small veins from small arteries through smooth muscle is feasible, and marked small venous deposition may play an important role in the hypertensive white matter lesions.


Assuntos
Veias Cerebrais/metabolismo , Colágeno/metabolismo , Modelos Animais de Doenças , Leucoencefalopatias/patologia , Actinas/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/ultraestrutura , Artérias Carótidas/metabolismo , Artérias Carótidas/patologia , Artérias Carótidas/ultraestrutura , Estenose das Carótidas/complicações , Veias Cerebrais/ultraestrutura , Hipertensão Renovascular/complicações , Leucoencefalopatias/etiologia , Aprendizagem em Labirinto/fisiologia , Microscopia Eletrônica de Transmissão , Ratos , Ratos Endogâmicos SHR/fisiologia , Ratos Sprague-Dawley , Fatores de Tempo , Substância Branca/patologia , Substância Branca/ultraestrutura
7.
Curr Neurovasc Res ; 14(2): 149-157, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28412909

RESUMO

BACKGROUND: Intracranial arterial stenosis (ICAS) is the dominant cause for ischemic stroke worldwide, with hemodynamic compromise as a crucial contributor. Prolonged perfusion is commonly observed in ICAS patients on CT perfusion (CTP) maps, while the clinical significance of this perfusion pattern has not been elucidated. METHOD: Patients having symptomatic ICAS of 50-99% stenosis with sustained downstream cerebral blood flow (CBF) were enrolled in this study. Prolonged perfusion was defined as increased mean transit time (MTT) in vascular territories of the target ICAS on CTP maps. The primary clinical outcome was recurrence of ipsilateral ischemic stroke, and secondary outcome was any ipsilateral ischemic events at 2 years follow-up. RESULTS: Of the 95 patients (median age 61y; 70% males) with symptomatic ICAS, 29 patients (30.5%) had prolonged perfusion. Such delayed perfusion was persistent in a majority of patients according to the 1-year imaging follow-up. The prolongation of cerebral perfusion was associated with subsequent risk for ipsilateral ischemic stroke (HR 7.01; 95% CI 1.86-26.46; p = 0.004), but not for any ipsilateral ischemic events (HR 1.52; 95% CI 0.63-3.68; p = 0.348). Further comparison of perfusion measures showed lower CBF (p = 0.034) and higher MTT (p = 0.064) in patients with recurrent ischemic stroke, but not in those with recurrent transient ischemic attack (TIA). Among patients with recurrent stroke, a majority had multiple infarcts along the borderzone regions. CONCLUSION: In patients with symptomatic ICAS, persistent prolonged cerebral perfusion might contribute to the relapse of ischemic stroke, but not TIA.


Assuntos
Transtornos Cerebrovasculares/complicações , Ataque Isquêmico Transitório/complicações , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/etiologia , Idoso , Volume Sanguíneo Cerebral/fisiologia , Infarto Cerebral/diagnóstico por imagem , Infarto Cerebral/etiologia , Circulação Cerebrovascular/fisiologia , Transtornos Cerebrovasculares/diagnóstico por imagem , Estudos de Coortes , Constrição Patológica/diagnóstico por imagem , Constrição Patológica/etiologia , Feminino , Lateralidade Funcional , Humanos , Ataque Isquêmico Transitório/diagnóstico por imagem , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Perfusão , Imagem de Perfusão , Fatores de Risco , Fatores de Tempo
8.
Biomed Res Int ; 2017: 9372050, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28316994

RESUMO

White matter lesions (WMLs), also known as leukoaraiosis (LA) or white matter hyperintensities (WMHs), are characterized mainly by hyperintensities on T2-weighted or fluid-attenuated inversion recovery (FLAIR) images. With the aging of the population and the development of imaging technology, the morbidity and diagnostic rates of WMLs are increasing annually. WMLs are not a benign process. They clinically manifest as cognitive decline and the subsequent development of dementia. Although WMLs are important, their pathogenesis is still unclear. This review elaborates on the advances in the understanding of the pathogenesis of WMLs, focusing on anatomy, cerebral blood flow autoregulation, venous collagenosis, blood brain barrier disruption, and genetic factors. In particular, the attribution of WMLs to chronic ischemia secondary to venous collagenosis and cerebral blood flow autoregulation disruption seems reasonable. With the development of gene technology, the effect of genetic factors on the pathogenesis of WMLs is gaining gradual attention.


Assuntos
Leucoencefalopatias/diagnóstico por imagem , Imagem por Ressonância Magnética , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Idoso , Envelhecimento , Barreira Hematoencefálica , Encéfalo/patologia , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/patologia , Circulação Cerebrovascular , Transtornos Cognitivos/patologia , Colágeno/química , Ligação Genética , Predisposição Genética para Doença , Humanos , Inflamação , Leucoencefalopatias/patologia , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/patologia , Permeabilidade , Doenças Vasculares/patologia
9.
Int J Stroke ; 12(3): 236-245, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28067615

RESUMO

Background Intracranial atherosclerotic stenosis is an important etiology subtype of ischemic stroke. Stenosis severity was thought to be the main reference index for clinical treatment and research. However, stenosis could not reflect the ischemia risk completely, instead the hemodynamic state across the lesion, the extent of collateral circulation, and perfusion impairment downstream the stenosis are more important. Aims We write this review aimed to summarize novel angiographic methods applied in the evaluation of functional severity of ICAS, and commented on their limitations and prospects in future research. Summary of review The main methods to estimate cerebral blood flow including fractional flow assessed by signal intensity ratio, computational fluid dynamics analysis or pressure wire, quantitative magnetic resonance angiography. Fractional flow as a series cerebral hemodynamic parameters may reflect the status of collateral circulation and cerebral blood flow. But the accuracy of the methods was not validated. The method to calculate fractional flow reserve in cardiovascular disease cannot duplicate in cerebrovascular disease. Fractional flow measurement by floating a pressure guidewire across the intracranial stenosis was technically feasible and safe. In the future researches, a non-invasive method should be established to identify high-risk intracranial lesions and may help in decision-making. Conclusions The relationship between stenosis and cerebral blood flow was individualized. Cerebral hemodynamic criteria should be used to screen patients to endovascular treatment, which will optimize the diagnosis and treatment strategies for patients with symptomatic intracranial artery stenosis.


Assuntos
Arteriosclerose Intracraniana/diagnóstico por imagem , Arteriosclerose Intracraniana/fisiopatologia , Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/fisiopatologia , Hemodinâmica , Humanos , Arteriosclerose Intracraniana/patologia
11.
Cerebrovasc Dis ; 42(3-4): 232-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27173386

RESUMO

BACKGROUND: Intracranial arterial stenosis (ICAS) is a predominant cause of ischemic stroke in Asia. Changes in the signal intensities (SIs) across ICAS lesions on time-of-flight magnetic resonance angiography (TOF-MRA) have been indicated to partially reflect the hemodynamic significance of the lesions, which we aimed to verify by correlating it with cerebral perfusion features provided by CT perfusion (CTP) imaging. METHODS: Ischemic stroke or transient ischemic attack patients with unilateral symptomatic stenosis (≥50%) of intracranial internal carotid artery or middle cerebral artery (MCA) were included in this study. Change of SIs across an ICAS lesion on TOF-MRA was calculated by the distal and proximal SI ratio (SIR). Cerebral blood volume (CBV), cerebral blood flow (CBF), and mean transit time (MTT) within the MCA territory of ipsilateral and contralateral hemispheres were evaluated on the CTP images at the basal ganglia level. Relative CBV, CBF and MTT were defined as ratios of the values obtained from ipsilateral and contralateral hemispheres. The relationships between SIR and CTP parameters were analyzed. RESULTS: Fifty subjects (74% male, mean age 62) were recruited. Overall, the mean SIR was 0.77 ± 0.17. SIR of ICAS was significantly, linearly and negatively correlated with ipsilateral CBV (r = -0.335, p = 0.017), ipsilateral MTT (r = -0.301, p = 0.034), and ipsilateral/contralateral MTT ratio (r = -0.443, p = 0.001). CONCLUSIONS: Diminished SIs distal to ICAS on TOF-MRA might be associated with delayed ipsilateral cerebral perfusion. Changes of the SIs across ICAS lesions on TOF-MRA may be a simple marker to reflect cerebral perfusion changes in patients with symptomatic ICAS.


Assuntos
Artéria Carótida Interna/diagnóstico por imagem , Estenose das Carótidas/diagnóstico por imagem , Angiografia Cerebral/métodos , Circulação Cerebrovascular , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Ataque Isquêmico Transitório/diagnóstico por imagem , Angiografia por Ressonância Magnética , Artéria Cerebral Média/diagnóstico por imagem , Imagem de Perfusão/métodos , Artéria Carótida Interna/fisiopatologia , Estenose das Carótidas/fisiopatologia , Constrição Patológica , Feminino , Humanos , Infarto da Artéria Cerebral Média/fisiopatologia , Ataque Isquêmico Transitório/fisiopatologia , Masculino , Pessoa de Meia-Idade , Artéria Cerebral Média/fisiopatologia , Valor Preditivo dos Testes , Estudos Prospectivos , Estudos Retrospectivos
12.
Neuroreport ; 26(17): 1039-43, 2015 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-26426859

RESUMO

Tight junctions (TJs) are the most important structure of the blood-brain barrier (BBB). Studies have shown that triggering of white matter lesions (WMLs) may be related to a BBB dysfunction, but rarely have studies observed the progressive changes in TJs longitudinally. In our present study, the ultrastructure of TJs was observed using a transmission electron microscope in Stroke-prone Renalvascular Hypertensive Rats. Western blotting was used to detect TJ-related proteins zonula occludens-1 and occludin. The results showed that in Stroke-prone Renalvascular Hypertensive Rats, the severity of WMLs increased gradually. TJs was destroyed gradually 8 weeks after hypertension. The levels of zonula occludens-1 and occludin also decreased gradually. These data suggested that long-term hypertension may contribute toward the gradual disruption of TJs of BBB and induce WMLs in chronic hypertensive rats.


Assuntos
Barreira Hematoencefálica/ultraestrutura , Hipertensão/patologia , Junções Íntimas/ultraestrutura , Substância Branca/patologia , Animais , Pressão Sanguínea , Doença Crônica , Hipertensão/metabolismo , Masculino , Ocludina/metabolismo , Ratos , Ratos Sprague-Dawley , Proteína da Zônula de Oclusão-1/metabolismo
13.
Metab Brain Dis ; 30(6): 1479-86, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26387009

RESUMO

Hypertension is considered one of the most important controllable risk factors for white matter lesion (WML). Our previous work found that stroke-prone renovascular hypertensive rats (RHRSP) displayed a high rate of WML. This study aimed to investigate the WML in RHRSP from MRI, pathology and behavior. RHRSP model was established by two-kidney, two-clipmethod and kept for 20 weeks. WML was decteted by magnetic resonance imaging (MRI) and loyez staining. Cognition was tested by morris water maze (MWM). Vascular changes were observed by HE staining on brain and carotid sections. Ultrastucture of blood brain barrier (BBB) were observed by transmission electron microscope. Immunofluorescence was used to detect albumin leakage and cell proliferation. T(2)-weighted MRI scans of RHRSP displayed diffuse, confluent white-matter hyperintensities. Pathological examination of the same rat showed marked vacuoles, disappearence of myelin and nerve fibers in white matter, supporting the neuroimaging findings. Spatial learning and memory impairment were observed in RHRSP. The small arteries in brain exhibited fibrinoid necrosis, hyalinosis and vascular remodeling. BBB disruption and plasma albumin leakage into vascular wall was observed in RHRSP. Increased cell proliferation in subventricular zone was seen in RHRSP. RHRSP demonstrated spontaneous WML and cognitive impairment. Hypertensive small vessel lesions and BBB disruption might paly causative factors for the onset and development of WML. The characteristic features of WML in RHRSP suggested it a valid animal model for WML.


Assuntos
Hipertensão Renovascular/genética , Hipertensão Renovascular/patologia , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologia , Substância Branca/patologia , Animais , Comportamento Animal/efeitos dos fármacos , Pressão Sanguínea , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/ultraestrutura , Proliferação de Células , Doenças de Pequenos Vasos Cerebrais/genética , Doenças de Pequenos Vasos Cerebrais/patologia , Circulação Cerebrovascular/genética , Cognição/efeitos dos fármacos , Hipertensão Renovascular/psicologia , Imagem por Ressonância Magnética , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Bainha de Mielina/patologia , Fibras Nervosas/patologia , Ratos , Ratos Sprague-Dawley
14.
CNS Neurosci Ther ; 21(5): 410-6, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25611692

RESUMO

AIMS: Cerebrovascular white matter lesion (WML) is a major subtype of cerebral small vessel disease. Clinical drugs are not available for WML. We investigated whether peroxisome proliferator-activated receptor-γ agonist pioglitazone, with properties of vascular protection and antiinflammation, exerts beneficial effect in hypertensive WML rats. METHODS: Stroke-prone renovascular hypertensive rats (RHRSP) were treated with pioglitazone for 12 weeks. Morris water maze experiment was conducted to assess cognition. WML was observed by Luxol fast blue staining. Smooth muscle actin-alpha, collagen I, collagen IV, glial fibrillary acidic protein, and ionized calcium-binding adaptor molecule-1 were evaluated by immunohistochemistry. Interleukin-1 beta (IL-1ß) and tumor necrosis factor alpha (TNF-α) in brain and soluble intercellular adhesion molecule-1 (sICAM-1) in serum were detected. RESULTS: Pioglitazone significantly attenuated WML in corpus callosum, caudate putamen, external capsule, and internal capsule. Cognitive impairment in RHRSP was ameliorated by pioglitazone. Pioglitazone attenuated arteriolar remodeling and reduced sICAM-1 level in serum. Pioglitazone decreased the proliferation of microglia and astrocyte and lowered the expression of proinflammatory cytokines IL-1ß and TNF-α in the white matter. CONCLUSIONS: Long-term treatment of pioglitazone has beneficial effect on hypertension-induced WML and cognition decline, which may partly through its effect on attenuation of arteriolar remodeling, endothelial activation, and brain inflammation.


Assuntos
Encéfalo/efeitos dos fármacos , Transtornos Cognitivos/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Nootrópicos/farmacologia , Tiazolidinedionas/farmacologia , Substância Branca/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/patologia , Modelos Animais de Doenças , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Neuroimunomodulação/efeitos dos fármacos , Neuroimunomodulação/fisiologia , PPAR gama/agonistas , PPAR gama/metabolismo , Pioglitazona , Distribuição Aleatória , Ratos Sprague-Dawley , Substância Branca/metabolismo , Substância Branca/patologia
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