Analysis of the Association Between Polymorphisms within PAI-1 and ACE genes and Ischemic Stroke Outcome After rt-PA Therapy.

PURPOSE: Treatment of Ischemic stroke (IS) in acute phase is based on the use of thrombolytic rt-PA therapy. We aimed to determine whether different alleles and genotypes of I/D ACE gene and 4G/5G PAI-1 gene polymorphisms may influence outcome of rt-PA therapy in patients with IS and the occurrence of haemorrhagic transformation (HT). METHODS: Our study included 94 consecutive patients with IS treated with rt-PA. Modified Rankin Scale (mRS) at 3rd month after IS was used to determine the stroke outcome, with scores 0-1 defining the favourable outcome, and scores 2-6 defining poor outcome. Genotypisation of the ACE-1 I/D polymorphism was performed by polymerase chain reaction and of the PAI-1 4G/5G polymorphism by polymerase chain reaction - restriction fragment length analysis. RESULTS: Regarding PAI-I 4G/5G polymorphism, 44 patients (46.8%) were heterozygotes, and the number of 4G/4G and 5G/5G homozygotes was the same - 25 each (26.6%). Number of heterozygotes for the ACE I/D polymorphism was 54 (57.4%), 9 patients (9.6%) had II, and 31 (33%) DD genotypes. A favourable outcome was recorded in 26 (28.0%) and the poor outcome in 67 (72.0%) patients. Favourable and poor outcome groups did not differ significantly in PAI-1 4G/5G and ACE I/D polymorphisms genotype or allele frequencies. There was a statistically significant difference in the occurrence of HT between patients with ACE II and patients with ACE ID or DD genotypes (p=0.035). CONCLUSION: Results of our study suggest that stroke patients with ACE II genotype, treated with rt-PA, may be at risk of HT.

Improvement of language functions in a chronic non-fluent post-stroke aphasic patient following bilateral sequential theta burst magnetic stimulation.

In chronic non-fluent aphasia patients, inhibition of the intact right hemisphere (RH), by transcranial magnetic stimulation (TMS) or similar methods, can induce improvement in language functions. The supposed mechanism behind this improvement is a release of preserved left hemisphere (LH) language networks from RH transcallosal inhibition. Direct stimulation of the damaged LH can sometimes bring similar results too. Therefore, we developed a novel treatment approach that combined direct LH (Broca's area (BA)) stimulation, by intermittent theta burst stimulation (TBS), with homologue RH area's inhibition, by continuous TBS. We present the results of application of 15 daily sessions of the described treatment approach in a right-handed patient with chronic post-stroke non-fluent aphasia. The intervention appeared to improve several language functions, but most notably propositional speech, semantic fluency, short-term verbal memory, and verbal learning. Bilateral TBS modulation of activation of the language-related areas of both hemispheres seems to be a feasible and promising way to induce recovery in chronic aphasic patients. Due to potentially cumulative physiological effects of bilateral stimulation, the improvements may be even greater than following unilateral interventions.

Association of IL-6 rs1800795, but not TNF-α rs1800629, and IL-1ß rs16944 polymorphisms' genotypes with recovery of ischemic stroke patients following thrombolysis.

OBJECTIVES: Inflammatory cytokines like tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, and IL-6 can cause brain injury, slow recovery, and adverse effects (ADEs) in ischemic stroke (IS) patients treated with recombinant tissue plasminogen activator (rtPA). We explored the relationship between selected polymorphisms within TNF-α, IL-1ß and IL-6 genes, and post-IS outcome and ADEs in patients treated with rtPA. METHODS: One hundred and sixty-six patients with IS treated with rtPA were included in this study. The modified Rankin Scale (mRS) was used to assess functional recovery 3 months after IS likewise thrombolytic therapy efficacy. Patients were classified into groups with favorable (0-1) or poor recovery based on their mRS score at the ninetieth day post-IS. During hospitalization, ADEs following rtPA were monitored. TNF-α-308 G/A (rs1800629), IL-1ß-511 G/A (rs16944), and IL-6-174 G/C (rs1800795) polymorphisms were genotyped using Real-Time PCR. SPSS software version 22.0 was used for statistical analyses. RESULTS: Patients with the TNF-α-308 G/A GG genotype had a higher mean NIHSS value at admission (12.75 ± 5.176) than those carrying A-allele (10.56 ± 3.979;p = 0.016). Individuals with the CC genotype of the IL-6-174 G/C polymorphism had significantly lower NIHSS scores (8.79 ± 5.053) than those with G-allele (12.06 ± 6.562) 24 hours after rtPA (p = 0.050). Patients with the GG genotype of the IL-6-174 G/C polymorphism had a significantly poorer outcome (p = 0.024; OR = 2.339; 95%CI 1.121-4.880), while patients who were G-allele carriers of the Il-6-174 G/C polymorphism and had the AA genotype of the IL-1ß-511 G/A polymorphism were statistically significantly more likely to experience hemorrhagic transformation (p = 0.046; OR = 2.7273; 95%CI 1.0414-7.1426). CONCLUSION: GG genotype of the IL-6-174 G/C polymorphism is associated with poor recovery after IS treated with rtPA therapy.

Intrinsic damage to the major white matter tracts in patients with different clinical phenotypes of multiple sclerosis: a voxelwise diffusion-tensor MR study.

PURPOSE: To apply voxelwise analysis of diffusion-tensor (DT) magnetic resonance (MR) tractography and T2-weighted MR lesion measurements to characterize intrinsic damage to the brain white matter (WM) tracts and the relation of this damage to the presence and location of focal lesions among the main clinical phenotypes of multiple sclerosis (MS). MATERIALS AND METHODS: The study was conducted with institutional review board approval. Written informed consent was obtained from each participant. Brain dual-echo and DT MR images were obtained in 172 patients with MS (22 [13%] with clinically isolated syndromes [CIS] suggestive of MS, 51 [30%] with relapsing-remitting [RR] MS, 44 [26%] with secondary progressive MS, 20 [12%] with benign MS, 35 [20%] with primary progressive MS) and 46 healthy control subjects. Probability maps of the major brain WM tracts were produced. Between-group comparisons were assessed by using analysis of covariance. RESULTS: Compared with the healthy control subjects, the patients with CIS had significantly increased (P < .001) mean diffusivity, axial diffusivity, and radial diffusivity in the majority of WM tracts. The primary progressive MS group showed diffuse increases in mean, axial, and radial diffusivity, with fractional anisotropy (FA) damage involving the majority of WM tracts. No relevant difference in diffusivity measures was found between the CIS and RR-MS groups. Compared with the benign MS group, the RR-MS group had reduced FA values in all WM tracts and decreased axial diffusivity in the majority of tracts. The secondary progressive MS group had pronounced damage to the majority of tracts and, compared with the benign MS group, pronounced FA alteration of the tracts relevant for motor impairment. CONCLUSION: Voxelwise assessment of DT MR index abnormalities is a rewarding strategy for understanding the heterogeneity of clinical MS phenotypes.

TT genotype of the MMP-9-1562C/T polymorphism may be a risk factor for thrombolytic therapy-induced hemorrhagic complications after acute ischemic stroke.

INTRODUCTION: Levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) influence recombinant tissue plasminogen activator (rtPA) therapy response in patients with acute ischemic stroke (AIS). Serum levels of MMPs and TIMPs along with the expression of genes coding these proteins are related to the recovery and appearance of adverse effects (AE) after AIS. Consequently, it is important to explore whether polymorphisms in regulatory sequences of MMPs and TIMPs are associated with rtPA response in AIS patients. OBJECTIVES: To determine whether selected polymorphic variants within MMP-2, MMP-9, and TIMP-2 genes may influence rtPA therapy response with regard to outcomes in patients with AIS and the occurrence of AE. METHODS: Our study included 166 patients suffering AIS, treated with rtPA. Patients' recovery was estimated using the Modified Rankin Scale (mRS) 3 months after the AIS occurred. Favorable outcome was defined with scores 0-1 and poor outcome with scores 2-6. Genotyping was performed using real-time PCR (rs243866, rs243865, rs243864, rs2277698, and rs8179090) and PCR-RFLP (rs2285053, rs3918242) methods. Additionally, rtPA AE were followed during the hospitalization. RESULTS: There was no significant association between genotypes and alleles of selected polymorphisms and rtPA therapy response measured through the decrease of the mRS score in patients with AIS. Intracranial hemorrhage, as well as parenchymal hematoma type 2, was significantly more frequent in patients with TT genotype of the MMP-9-1562C/T polymorphism (p = 0.047, p = 0.011, respectively). Patients with intracranial hemorrhages after rtPA were significantly more likely to have the TT genotype of TIMP-2-303C/T polymorphism and the TT genotype of MMP-9-1562C/T polymorphism (p < 0.001). CONCLUSION: TT genotype of the MMP-9-1562C/T polymorphism may be a risk factor for rtPA-induced hemorrhagic complications after AIS.

Migraine with Aura: Surface-Based Analysis of the Cerebral Cortex with Magnetic Resonance Imaging.

Objective: Previous migraine studies have reported gray matter alterations in various cortical regions with conflicting results. This study aimed to explore a cortical morphometric difference in migraineurs with aura (MA) compared to healthy subjects (HS) and to delineate a possible difference between the cortical morphological features and different aura phenotypes. Materials and Methods: Forty-eight MA and 30 HS that were balanced by sex, age, and educational level were selected for this study. T2-weighted and three-dimensional T1-weighted magnetic resonance imaging (MRI) of the brain were acquired using a 1.5T MRI scanner. Surface-based morphometry from the MRI data was used to identify differences between the MA and HS group, and then between MA subgroups. The MA group was subdivided into migraineurs who experienced only visual aura (MVA) and migraineurs who had visual, somatosensory and dysphasic symptoms (MVA+). Results: The MVA+ group had significantly reduced cortical surface area of the left rostral middle frontal cortex compared with the MVA group (p < 0.001). Migraine patients had significantly reduced volume of the left fusiform gyrus relative to HS (p < 0.001). Also, the sulcal depth increased at the level of the left temporal pole in the MVA+ group relative to the MVA group (p < 0.001). The vertex-by-vertex analysis did not exhibit any significant difference in cortical thickness between MA and HS, and between MVA+ and MVA, when corrected for multiple comparisons. Conclusion: Migraineurs with aura demonstrates different morphometric features from HS in multiple cortical regions. MVA+ have different morphometric features in the left frontal and temporal lobe relative to MVA, which could be a source of distinct symptoms and serve as potential biomarkers of different MA subtypes.

Migraine with aura and white matter tract changes.

We aimed to explore whether a migraine with aura (MA) is associated with structural changes in tracts of a white matter and to compare parameters of diffusivity between subgroups in migraineurs. Forty-three MA and 20 healthy subjects (HS), balanced by sex and age, were selected for this study. Analysis of diffusion tensor parameters was used to identify differences between MA patients and HS, and then between MA subgroups. A diffusion tensor probabilistic tractography analysis showed that there is no difference between MA patients and HS. However, using more-liberal uncorrected statistical threshold, we noted a trend in MA patients toward lower diffusivity indices of selected white matter tracts located in the forceps minor and right anterior thalamic radiation (ATR), superior longitudinal fasciculus (temporal part) (SLFT), cingulum-cingulate tract, and left uncinate fasciculus. Migraineurs who experienced somatosensory and dysphasic aura, besides visual symptoms, had tendency toward lower diffusivity indices, relative to migraineurs who experienced only visual symptoms, in the right inferior longitudinal fasciculus, forceps minor, and right superior longitudinal fasciculus (parietal part), SLFT, and cingulum-angular bundle. Aura frequency were negatively correlated with axial diffusivity and mean diffusivity of the right ATR (partial correlation = - 0.474; p = 0.002; partial correlation = - 0.460; p = 0.002), respectively. There were no significant differences between MA patients and HS, neither between MA subgroups. Migraineurs with abundant symptoms during the aura possibly have more myelinated fibers relative to those who experience only visual symptoms. Lower diffusivity indices of the right ATR are linked to more frequent migraine with aura attacks.

[The use of magnetic resonance and MR angiography in the detection of cerebral infarction--a complication of pediatric bacterial meningitis].

BACKGROUND: Association of both cerebral infarction and acute bacterial meningitis is more common in younger patients than in the elderly. The rate of mortality and the frequency of sequela are very high inspite of the use of modern antibiotic therapy. In more than 30% of the cases of childhood bacterial meningitis, both arterial and venous infarctions can occur. The aim of this study was to present the role of the use of magnetic resonance (MRI), and MR angiography (MRA) in the detection of bacterial meningitis in children complicated with cerebral infarctions. METHOD: In the Centre for MR, the Clinical Centre of Serbia, 25 patients with the diagnosis of bacterial meningitis, of which 9 children with cerebral infarction whose clinical condition deteriorated acutely, despite the antibiotic therapy, underwent MRI and MR angiography examination on a 1T scanner. Examination included the conventional spin-echo techniques with T1-weighted saggital and coronal, and T2- weighted axial and coronal images. Coronal fluid attenuated inversion recovery (FLAIR) and the postcontrast T1-weighted images in three orthogonal planes were also used. The use MR angiography was accomplished by the three-dimensional time-of-flight (3D TOF) technique. RESULTS: The findings included: multiple hemorrhagic infarction in 4 patients, multiple infarctions in 3 patients, focal infarction in 1 patient and diffuse infarction (1 patient). Common sites of involvement were: the frontal lobes, temporal lobes and basal ganglia. The majority of infarctions were bilateral. In 3 of the patients empyema was found, and in 1 patient bitemporal abscess was detected. In 8 of the patients MR angiography confirmed inflammatory vasculitis. CONCLUSION: Infarction is the most common sequela of severe meningitis in children. Since the complication of cerebral infarction influences the prognosis of meningitis, repetitive MRI examinations are very significant for the evaluation of the time course of vascular involvement. The use of MRI, especially FLAIR imaging, confirmed its value in the detection and determination of the site and the extent of cerebral infarction. Non-invasive technique of examination, 3D TOF MR angiography clearly shoud show the presence of inflammatory vasculitis.