C-reactive protein predicts hematoma growth in intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Early hematoma growth (EHG) occurs in about one third of patients with spontaneous intracerebral hemorrhage. The main aim of this study was to investigate the potential of plasma C-reactive protein (CRP) for predicting EHG after acute spontaneous intracerebral hemorrhage. METHODS: Plasma CRP was measured within 6 hours of onset (median, 120 minutes) in 399 patients with primary or vitamin K antagonist-associated spontaneous intracerebral hemorrhage and without recent infection. Computed tomography brain scans were performed at baseline and repeated within 24 hours (median, 22 hours). The primary outcome was EHG, defined as absolute growth>12.5 cm3 or relative growth>33%. Secondary outcomes included early neurological worsening (ENW) using the Glasgow Coma Scale and 30-day mortality. Multivariable regression analyses were used to evaluate associations of CRP concentration and outcomes. Kaplan-Meier analysis was used for survival. RESULTS: EHG occurred in 25.8%, ENW in 19.3%, and mortality was 31.8% at 30 days. Thirty-day mortality was significantly higher in patients with ENW (hazard ratio, 3.21; 95% confidence interval, 2.00-5.17; P<0.0001) and in patients with EHG (hazard ratio, 2.13; 95% confidence interval, 1.42-3.18; P<0.0001, log-rank test). Median CRP was 12 mg/L (interquartile range, 10-17) in the EHG group and 7 mg/L (interquartile range, 4-12.1) in those without EHG (P<0.0001). In multivariable analyses, plasma CRP>10 mg/L independently predicted EHG (odds ratio, 4.71; 95% confidence interval, 2.75-8.06; P<0.0001) and ENW (odds ratio, 2.70; 95% confidence interval, 1.50-4.84; P=0.0009). CONCLUSIONS: CRP>10 mg/L is independently predictive of EHG and ENW, both of which are associated with increased mortality. Inflammation may be important in contributing to EHG and warrants further investigation.

Matrix metalloproteinase-9 expression in the nuclear compartment of neurons and glial cells in aging and stroke.

Matrix metalloproteinases (MMPs) are well-recognized denominators for extracellular matrix remodeling in the pathology of both ischemic and hemorrhagic strokes. Recent data on non-nervous system tissue showed intracellular and even intranuclear localizations for different MMPs, and together with this, a plethora of new functions have been proposed for these intracellular active enzymes, but are mostly related to apoptosis induction and malign transformation. In neurons and glial cells, on human tissue, animal models and cell cultures, different active MMPs have been also proven to be located in the intra-cytoplasmic or intra-nuclear compartments, with no clear-cut function. In the present study we show for the first time on human tissue the nuclear expression of MMP-9, mainly in neurons and to a lesser extent in astrocytes. We have studied ischemic and hemorrhagic stroke patients, as well as aged control patients. Age and ischemic suffering seemed to be the best predictors for an elevated MMP-9 nuclear expression, and there was no evidence of a clear-cut extracellular proteolytic activity for this compartment, as revealed by intact vascular basement membranes and assessment of vascular densities. More, the majority of the cells expressing MMP-9 in the nuclear compartment also co-expressed activated-caspase 3, indicating a possible link between nuclear MMP-9 localization and apoptosis in neuronal and glial cells following an ischemic or hemorrhagic event. These results, besides showing for the first time the nuclear localization of MMP-9 on a large series of human stroke and aged brain tissues, raise new questions regarding the unknown spectrum of the functions MMPs in human CNS pathology.

Fractal analysis of astrocytes in stroke and dementia.

The varied morphological forms in which astrocytes occur in brain of ischemic/hemorrhagic stroke and Alzheimer's disease (AD) patients are complex and the mechanisms that drive their formation are not yet properly understood. Subjective differences can be described between these pathologies in what it concerns astrocyte implication, but these have not been yet subjected to a morphometrical quantification. Here we apply a fractal dimension (FD) analysis algorithm to differentiate both between fibrous, protoplasmatic and activated astroglia; but also between the three pathological conditions studied. Analyzing more than 1000 astroglia, we show here first that FD can clearly differentiate between the three morphological subtypes. Second, we describe resemblances of the FD values for ischemic and hemorrhagic lesions, and significant differences when these are compared to AD patients. These results are further discussed and integrated in what it regards the preferential regions proved to be affected in these conditions, and which parallels our results. This work illustrates that fractal dimension analysis of astroglia is a useful method for quantitatively describing gliosis in different pathologies, and that it may offer more insight into the pathogenesis of brain diseases.

Expression patterns of aquaporins 1 and 4 in stroke.

Ischemic stroke occurs through embolic or thrombotic obliteration of an artery from cerebral circulation and represents over 80% of all stroke cases. One of the fiercest complications after stroke is edema, which results from imbalanced water diffusion around the blood vessels walls. Water diffusion around blood vessel walls occurs physiologically mainly through two protein-formed pores, namely aquaporins (AQPs) 1 and 4. Here, we compare for the first time the expression patterns and colocalization degrees of the two AQPs in control brain tissue and in peri-ischemic regions, on tissue obtained from eight patients with confirmed ischemic pathology and from five control cases. Our analysis showed that AQP4 is more abundant that AQP1, especially in the cortex and in the organized scar areas. The colocalization of the two markers was high, both located on the astrocytes membranes, but the colocalization degree decreased in the scar peri-ischemic regions. Colocalization with basement membranes was also lower for AQP1 compared to AQP4, in all regions analyzed.

Cerebrolysin and Aquaporin 4 Inhibition Improve Pathological and Motor Recovery after Ischemic Stroke.

BACKGROUND: Edema represents one of the earliest negative markers of survival and consecutive neurological deficit following stroke. The mixture of cellular and vasogenic edema makes treating this condition complicated, and to date, there is no pathogenically oriented drug treatment for edema, which leaves parenteral administration of a hypertonic solution as the only non-surgical alternative. OBJECTIVE: New insights into water metabolism in the brain have opened the way for molecular targeted treatment, with aquaporin 4 channels (AQP4) taking center stage. We aimed here to assess the effect of inhibiting AQP4 together with the administration of a neurotropic factor (Cerebrolysin) in ischemic stroke. METHODS: Using a permanent medial cerebral artery occlusion rat model, we administrated a single dose of the AQP4 inhibitor TGN-020 (100 mg/kg) at 15 minutes after ischemia followed by daily Cerebrolysin dosing (5ml/kg) for seven days. Rotarod motor testing and neuropathology examinations were next performed. RESULTS: We showed first that the combination treatment animals have a better motor function preservation at seven days after permanent ischemia. We have also identified distinct cellular contributions that represent the bases of behavior testing, such as less astrocyte scarring and a larger neuronalsurvival phenotype rate in animals treated with both compounds than in animals treated with Cerebrolysin alone or untreated animals. CONCLUSION: Our data show that water diffusion inhibition and Cerebrolysin administration after focal ischemic stroke reduces infarct size, leading to a higher neuronal survival in the peri-core glial scar region.

Study on cognitive decline in patients diagnosed with brain tumors.

AIM: The purpose of our study was to assess the cognitive performance in patients with primitive brain tumors and to analyze the cognitive status of these patients, correlated with histological type of brain tumors. PATIENTS, MATERIALS AND METHODS: The study enrolled 52 patients diagnosed with primitive brain tumors, hospitalized in Neuropsychiatry Hospital of Craiova, Romania, from December 2013 to December 2015. According to the histological type of tumors, the patients were classified into three groups: Group A included 22 patients with meningioma, Group B composed of 16 patients diagnosed with glioblastoma, and Group C including 14 patients diagnosed with diffuse astrocytoma. Neurological examination, neuroimaging assessment [computed tomography (CT) or magnetic resonance imaging (MRI) for skulls] to diagnose primitive brain tumors, then the confirmation of clinical and histopathological diagnoses were performed for these patients. For cognitive assessment performed before surgery, Montreal Cognitive Assessment (MoCA) and Cambridge Cognitive Examination (CAMCOG) scales were used. The results were statistically analyzed using the Student's t-test; p-values less than 0.05 were considered statistically significant. RESULTS: In terms of age, we did not observe statistically significant differences between the three groups of patients. The group of patients with diffuse astrocytoma presented a higher educational level compared to patients with glioblastoma or meningioma. MoCA score obtained in glioblastoma group was 21.7 points, while in the group of patients with diffuse astrocytoma was 23.5 points, and in the group of patients with meningioma 24.2 points. The cognitive assessment using CAMCOG scale led to the following results: group of patients diagnosed with glioblastoma showed an average score of 83.5 points, the diffuse astrocytoma group had an average score of 88.9 points and the group with meningioma an average score of 90.1 points. CONCLUSIONS: Patients diagnosed with glioblastoma showed a statistically significant cognitive decline in comparison to patients diagnosed with diffuse astrocytoma (p<0.05). We did not notice statistically significant differences in the cognitive decline of patients with meningioma compared to those diagnosed with diffuse astrocytoma (p>0.05).

Tau protein in neurodegenerative diseases - a review.

The study of rare, inherited forms of different diseases resulted in the discovery of gene defects that cause inherited variants of the respective diseases. The defective genes were found to encode major molecular players leading to the neuropathological lesions or factors that characterize these diseases. The exact role of the tau protein in the neurodegenerative process is still under debate. It is very important to understand the normal biological roles of tau and the specific events that induce tau to become neurotoxic. Tau is the major microtubule-associated protein (MAP) of a mature neuron. The other neuronal MAPs are MAP1 and MAP2. These three MAPs perform similar function, promoting assembly and stability of microtubules. Tau protein was isolated as a microtubule-associated factor in the porcine brain. It was isolated as a protein that co-purified with tubulin and had the ability to promote microtubule assembly in vitro. Normal adult human brain tau contains 2-3 moles phosphate÷mole of tau protein. Hyperphosphorylation of tau depress this biological activity of tau. Almost 80 diseases caused by missense mutations and intronic mutations in the tau gene have been found in familial cases of frontotemporal dementia (FTD). In Alzheimer's disease (AD), there are intraneuronal neurofibrillary tangles composed of the microtubule-associated protein tau (MAPT). In other neurodegenerative diseases, there are similar deposits of tau, in the absence of extracellular deposits (progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, etc.). Tau pathology is also often seen in some forms of Parkinson's disease (PD) and prion diseases. In genetic forms of FTD, mutations in tau implicate abnormal tau as the initiation of neurodegeneration. In FTD, there are deposits especially in temporal and frontal lobes, regions that are very important for behavior and executive function. It is critical to understand how tau becomes pathogenic, in order to consider developing any strategies for treatment.

Plasma levels of glucose and insulin in patients with brain tumors.

In the last years there were many authors that suggest the existence of an association between different components of metabolic syndrome and various cancers. Two important components of metabolic syndrome are hyperglycemia and hyperinsulinemia. Both of them had already been linked with the increased risk of pancreatic, breast, endometrial or prostate cancer. However the correlation of the level of the glucose and insulin with various types and grades of brain tumors remains unclear. In this article we have analysed the values of plasma glucose and insulin in 267 patients, consecutively diagnosed with various types of brain tumors. Our results showed no correlation between the glycemia and brain tumor types or grades. High plasma levels of insulin were found in brain metastasis and astrocytomas while the other types of brain tumors (meningiomas and glioblastomas) had lower levels of the peptide. The levels of insulin were also higher in brain metastasis and grade 3 brain tumors when compared with grade 1, grade 2 and grade 4 brain tumors.

Massive cortico-subcortical ischemic stroke with a consecutive hemorrhagic event: a case report.

BACKGROUND: We report a case of a 78-year-old woman with a large cerebral infarction probably due to athermanous embolism following atrial fibrillation. CASE DESCRIPTION: The patient, known with atrial fibrillation, high blood pressure and heart failure, complained of headache and motor impairment on the left side of the body. CT imaging revealed a subacute ischemic lesion in the right fronto-occipital lobes, and an old ischemic lesion in the right fronto-parietal lobes. Anticoagulant treatment was conducted with careful monitoring of the coagulability status. After almost three weeks, suddenly the patient became comatose and died shortly after. Macroscopic and microscopic examination confirmed the cortico-subcortical ischemic lesions, but also identified a fresh hemorrhagic site in pons, distant from the initial lesion sites. An immunohistochemical study identified blood vessels in the ischemic sites completely isolated from any glial support. CONCLUSIONS: This is a rare case of a large cerebral infarction with a pontine hemorrhagic event.