Cerebral Palsy

Background and purpose: Previous studies suggested that biochemical markers of brain damage could act as prognostic factors in ischaemic stroke. The aim of the present study was to assess predictive value of the selected biomarkers S100B protein, neuron-specific enolase (NSE), C-reactive protein (CRP) and D-dimers, as well as GABA and excitatory amino-acids (EAA) measured in blood for 3-month functional outcome in ischaemic stroke patients. Material and methods: We investigated 54 patients with ischaemic stroke (mean age: 73.3 +/-11.7). Serum con-centrations of S100B, NSE, CRP, EAA and GABA, as well as plasma concentrations of D-dimers, were assessed in blood samples taken at admission and at 12, 24, and 72 hours after stroke onset. Functional status was measured with modified Rankin Scale (mRS) 3 months after stroke onset. Results: Significant independent predictors of outcome in ischaemic stroke patients 3 months after stroke were: S100B level at 12 h (OR: 1.7; 95% CI: 0.5-7.0; p = 0.007), NSE at 12 h (OR: 2.4; 95% CI: 0.7-8.1; p = 0.037), 24 h (OR: 10.2; 95% CI: 2.4-43.2; p = 0.0007), and 72 h (OR: 10.2; 95% CI: 2.3-45.0; p = 0.0001), CRP at 72 h (OR: 8.3; 95% CI: 1.5-45.4; p = 0.009) and D-dimers at admission (OR: 4.8; 95% CI: 1.1-20.7; p = 0.02), 24 h (OR: 5.5; 95% CI: 1.4-20.9; p = 0.004), and 72 h after stroke onset (OR: 2.7; 95% CI: 0.6-11.8; p = 0.01). Conclusions: The results of the present study are consistent with previous evidence indicating that selected biomarkers could help in prediction of the outcome in ischaemic stroke early after symptoms onset.

PURPOSE: In this article, we investigate the role of tumor necrosis factor-alpha (TNF) in the initiation of acute damage to the blood-brain barrier (BBB) and brain tissue following radiotherapy (RT) for CNS tumors. METHODS AND MATERIALS: Intravital microscopy and a closed cranial window technique were used to measure quantitatively BBB permeability to FITC-dextran 4.4-kDa molecules, leukocyte adhesion (Rhodamine-6G) and vessel diameters before and after 20-Gy cranial radiation with and without treatment with anti-TNF. Immunohistochemistry was used to quantify astrogliosis post-RT and immunofluorescence was used to visualize protein expression of TNF and ICAM-1 post-RT. Recombinant TNF (rTNF) was used to elucidate the role of TNF in leukocyte adhesion and vessel diameter. RESULTS: Mice treated with anti-TNF showed significantly lower permeability and leukocyte adhesion at 24 and 48 h post-RT vs. RT-only animals. We observed a significant decrease in arteriole diameters at 48 h post-RT that was inhibited in TNF-treated animals. We also saw a significant increase in activated astrocytes following RT that was significantly lower in the anti-TNF-treated group. In addition, immunofluorescence showed protein expression of TNF and ICAM-1 in the cerebral cortex that was inhibited with anti-TNF treatment. Finally, administration of rTNF induced a decrease in arteriole diameter and a significant increase in leukocyte adhesion in venules and arterioles. CONCLUSIONS: TNF plays a significant role in acute changes in BBB permeability, leukocyte adhesion, arteriole diameter, and astrocyte activation following cranial radiation. Treatment with anti-TNF protects the brain’s microvascular network from the acute damage following RT.

Following severe traumatic brain injury (TBI), a complex interplay of pathomechanism, such as exitotoxicity, oxidative stress, inflammatory events, and mitochondrial dysfunction occur. This leads to a cascade of neuronal and axonal pathologies, which ultimately lead to axonal failure, neuronal energy metabolic failure, and neuronal death, which in turn determines patient outcome. For mild and moderate TBI, the pathomechanism are similar but much less frequent and ischemic cell death is unusual, except with mass lesions. Involvement of mitochondria in acute post-traumatic neurodegeneration has been extensively studied during the last decade, and there are a number of investigations implicating the activation of the mitochondrial permeability transition pore (mPTP) as a “critical switch” which determines cell survival after TBI. Opening of the mPTP is modulated by several factors occurring after a severe brain injury. Modern neuroprotective strategies for prevention of the neuropathological squeal of traumatic brain injury have now begun to address the issue of mitochondrial dysfunction, and drugs that protect mitochondrial viability and prevent apoptotic cascade induced by mPTP opening are about to begin phase II and III clinical trials. Cyclosporin A, which has been reported to block the opening of mPTP, showed a significant decrease in mitochondrial damage and intra-axonal cytoskeletal destruction thereby protecting the axonal shaft and blunting axotomy. This review addresses an important issue of MPT activation after severe head injury, its role in acute post-traumatic neurodegeneration, and the rationale for targeting the mPTP in experimental and clinical TBI studies.

Brain-derived neurotrophic factor (BDNF) plays a regulatory role in neuronal differentiation and synaptic plasticity and has been linked to glucose regulation and cognition. Associations among plasma BDNF, cognition, and insulin function were explored. Forty-one participants with impaired insulin function (IIF), ranging from insulin resistance to type 2 diabetes mellitus (T2DM), were matched with 41 healthy controls on gender, age, education, and IQ. Participants received complete medical, neurological, psychiatric, and neuropsychological evaluations. IIF individuals had significantly lower plasma BDNF levels than controls, particularly females, and higher BDNF levels were associated with poorer explicit memory in IIF females, suggesting that higher levels within this group may reflect the body’s efforts to respond to damage. After accounting for age, education, and HbA1c, BDNF significantly predicted 13.1-23.5% of the variance in explicit memory in IIF women. These findings suggest that BDNF elevations within diseased groups may not always be a marker of health.

SMND-309, a novel compound named (2E)-2-{6-[(E)-2-carboxylvinyl]-2,3-dihydroxyphenyl}-3-(3,4-dihydroxyphenyl) propenoic acid, is a new derivate of salvianolic acid B. The present study was conducted to investigate whether SMND-309 has a protective effect on brain injury after focal cerebral ischemia, and if it did so, to investigate its effects on brain mitochondria. Adult male SD rats were subjected to middle cerebral artery occlusion (MCAO) by bipolar electro-coagulation. Behavioral tests and brain patho-physiological tests were used to evaluate the damage to central nervous system. Origin targets including mitochondria production of reactive oxygen species, antioxidant potentia, membrane potential, energy metabolism, mitochondrial respiratory enzymes activities and mitochondria swelling degree were evaluated. The results showed that SMND-309 decreased neurological deficit scores, reduced the number of dead hippocampal neuronal cells in accordance with its depression on mitochondria swelling degree, reactive oxygen species production, improvements on mitochondria swelling, energy metabolism, membrane potential level and mitochondrial respiratory chain complex activities. All of these findings indicate that SMND-309 exerted potent neuroprotective effects in the model of permanent cerebral ischemia, contributed to its protections on brain mitochondrial structure and function.

ABSTRACT: BACKGROUND: S100B protein and Neuron Specific Enolase (NSE) can increase due to brain cell damage and/or increased permeability of the blood-brain-barrier. Elevation of these proteins has been shown after various neurological diseases with cognitive dysfunction. Delirium is characterized by temporal cognitive deficits and is an important risk factor for dementia. The aim of this study was to compare the level of S100B and NSE of patients before, during and after delirium with patients without delirium and investigate the possible associations with different subtypes of delirium. METHODS: The study population were patients aged 65 years or more acutely admitted after hip fracture. Delirium was diagnosed by the Confusion Assessment Method and the subtype by Delirium Symptom interview. In maximal four serum samples per patient S100B and NSE levels were determined by electrochemiluminescence immunoassay. RESULTS: Of 120 included patients with mean age 83.9 years, 62 experienced delirium. Delirious patients had more frequently pre-existing cognitive impairment (67% vs. 18%, p<0.001). Comparing the first samples during delirium to samples of non-delirious patients, a difference was observed in S100B (median 0.16 versus 0.10 ug/L, p=<0.001), but not in NSE (median 11.7 versus 11.7 ng/L, p=0.97). Delirious state (before, during, after) (p<0.001), day of blood withdrawal (p<0.001), pre- or postoperative status (p=0.001) and type of fracture (p=0.036) were all associated with S100B level. The highest S100B levels were found 'during' delirium. S100B levels 'before' and 'after' delirium were still higher than those from 'non-delirious' patients. No significant difference in S100B (p=0.43) or NSE levels (p=0.41) was seen between the hyperactive, hypoactive and mixed subtype of delirium. CONCLUSIONS: Delirium was associated with increased level of S100B which could indicate cerebral damage either due to delirium or leading to delirium. The possible association between higher levels of S100B during delirium and the higher risk of developing dementia after delirium is an interesting field for future research. More studies are needed to elucidate the role of S100B proteins in the pathophysiological pathway leading to delirium and to investigate its possibility as biomarker for delirium.

The (pro)renin receptor [(P)RR] plays pivotal role in the renin angiotensin system and although experimental models emphasize the role of (P)RR in fibrosis , in organ damage associated with hypertension and diabetes, a mutation of the (P)RR gene resulting in a truncated Delta4-(P)RR is associated with X-linked mental retardation (XLMR) and epilepsy pointing to a novel role of (P)RR in brain development and cognitive function. Our aims were to study (P)RR expression in mouse brain and the effect of transfection of Delta4-(P)RR on neuronal differentiation of PC-12 cells induced by nerve growth factor (NGF). In situ hybridization showed the expression of (P)RR in cortical neurons, pyramidal cells and thalamic relay nuclei. In mouse neurons the receptor is found on plasma membrane and in synaptic vesicles and stimulation by renin provoked ERK1/2 phosphorylation. In PC-12 cells, (P)RR localized mainly in the endoplasmic reticulum and redistributed to neurite projections when cells were induced to differentiate by NGF. In contrast, Delta4-(P)RR remained cytosolic and inhibited NGF-induced neuronal differentiation and ERK1/2 activation. Co-transfection of PC-12 with (P)RR and Delta4-(P)RR cDNA resulted in altered localization of (P)RR and inhibited (P)RR redistribution to neurite projections upon NGF stimulation. Furthermore, (P)RR dimerized with itself and with Delta4-(P)RR suggesting that the XLMR and epilepsy phenotype resulted from a dominant negative effect of Delta4-(P)RR. In conclusion, our results show that (P)RR is expressed in mouse brain where it may have a role in neuronal cell differentiation and suggest that the XLMR and epilepsy phenotype resulted from a dominant negative effect of the Delta4-(P)RR protein. Key words: (pro)renin receptor, neuronal cell differentiation.

OBJECTIVE: Similar to patients with systemic lupus erythematosus, autoimmune MRL/lpr mice spontaneously develop behavioral deficits and pathologic changes in the brain. Given that the disease-associated brain atrophy in this model is not well understood, the present study was undertaken to determine the time course of morphometric changes in major brain structures of autoimmune MRL/lpr mice. METHODS: Computerized planimetry and high-resolution magnetic resonance imaging (MRI) were used to compare the areas and volumes of brain structures in cohorts of mice that differ in severity of lupus-like disease. RESULTS: A thinner cerebral cortex and smaller cerebellum were observed in the MRL/lpr substrain, even before severe autoimmunity developed. With progression of the disease, the brain area of coronal sections became smaller and the growth of the hippocampus was retarded, which likely contributed to the increase in the ventricle area:brain area ratio. MRI revealed reduced volume across different brain regions, with the structures in the vicinity of the ventricular system particularly affected. The superior colliculus, periaqueductal gray matter, pons, and midbrain were among the regions most affected, whereas the volumes of the parietal-temporal lobe, parts of the cerebellum, and lateral ventricles in autoimmune MRL/lpr mice were comparable with values in congenic controls. CONCLUSION: These results suggest that morphologic alterations in the brains of MRL/lpr mice are a consequence of several factors, including spontaneous development of lupus-like disease. A periventricular pattern of parenchymal damage is consistent with the cerebrospinal fluid neurotoxicity, limbic system pathologic features, and deficits in emotional reactivity previously documented in this model.

In this article the authors deal with the intricate relationship between acute brain injuries and stress cardiomyopathies. The complexity of heart-brain relationship raises some questions about the occurrence of Takotsubo cardiomyopathy in young patients with acute brain ischemia and vice versa.

Experimental traumatic brain injury (TBI) leads to a rapid and extensive necrosis at the primary site of injury that appears to be driven in part by significant mitochondrial dysfunction. The present study is based on the hypothesis that TBI-induced, aberrant glutamate release increases mitochondrial Ca(2+) cycling/overload ultimately leading to mitochondrial damage. Previous work from our laboratory demonstrates that mitochondrial uncoupling during the acute phases of TBI-induced excitotoxicity can reduce mitochondrial Ca(2+) uptake (cycling), ROS production and mitochondrial damage resulting in neuroprotection and improved behavioral outcome. The current study was designed to determine the optimal dosage and therapeutic window of opportunity for the potent mitochondrial uncoupler FCCP following moderate TBI. For this study, we used young adult male Sprague-Dawley rats (300-350 g); either sham operated or moderately (1.5 mm) injured using the controlled cortical impactor (CCI) model of TBI. In the first set of studies animals were injected with either vehicle (100% DMSO) or different concentrations of FCCP (0.5, 1, 2.5 and 5 mg/kg in 100% DMSO) intraperitoneally at 5 min post-injury; tested behaviorally at 10 days and cortical sparing assessed at 18 days post-injury. The results demonstrate that of all the dosages tested, 2.5 mg/kg rendered the maximum improvement in behavioral outcomes and tissue spared. Using this optimal dose (2.5 mg/kg) and time point for intervention (5 min post-injury), we assessed mitochondrial bioenergetics and mitochondrial structural integrity 24 hrs post-injury. Furthermore, using this dosage we assessed mitochondrial bioenergetics and Ca(2+) loading at 3 and 6 hrs post-injury to further verify our target mechanism and establish these assessments as a valid endpoint to use as a means to determine the therapeutic window of FCCP. To begin to address the window of opportunity for maintaining mitochondrial homeostasis, the optimal dose of FCCP was then administered at 5 min, 3, 6, or 24 hrs post-injury and several parameters of mitochondrial function were used as outcome measures. The results demonstrate that a prolonged window of opportunity exists for targeting mitochondrial dysfunction using uncouplers following TBI and give insight into the cellular pathology associated with TBI.