Cerebral Palsy

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.

Brain damage may induce a dysfunction of upright body position termed “pusher syndrome”. Patients with such disorder suffer from an alteration of their sense of body verticality. They experience their body as oriented upright when actually tilted nearly 20 degrees to the ipsilesional side. Pusher syndrome typically is associated with posterior thalamic stroke; less frequently with extra-thalamic lesions. This argued for a fundamental role of these structures in our control of upright body posture. Here we investigated whether such patients may show additional functional or metabolic abnormalities outside the areas of brain lesion. We investigated 19 stroke patients with thalamic or with extra-thalamic lesions showing versus not showing misperception of body orientation. We measured fluid-attenuated inversion-recovery (FLAIR) imaging, diffusion-weighted imaging (DWI), and perfusion-weighted imaging (PWI). This allowed us to determine the structural damage as well as to identify the malperfused but structural intact tissue. Pusher patients with thalamic lesions did not show dysfunctional brain areas in addition to the ones found to be structurally damaged. In the pusher patients with extra-thalamic lesions, the thalamus was neither structurally damaged nor malperfused. Rather, these patients showed small regions of abnormal perfusion in the structurally intact inferior frontal gyrus, middle temporal gyrus, inferior parietal lobule, and parietal white matter. The results indicate that these extra-thalamic brain areas contribute to the network controlling upright body posture. The data also suggest that damage of the neural tissue in the posterior thalamus itself rather than additional malperfusion in distant cortical areas is associated with pusher syndrome. Hence, it seems as if the normal functioning of both extra-thalamic as well as posterior thalamic structures is integral to perceiving gravity and controlling upright body orientation in humans.

During acute bacterial infections such as meningitis, neutrophils enter the tissue where they combat the infection before they undergo apoptosis and are taken up by macrophages. Neutrophils show pro-inflammatory activity and may contribute to tissue damage. In pneumococcal meningitis, neuronal damage despite adequate chemotherapy is a frequent clinical finding. This damage may be due to excessive neutrophil activity. We here show that transgenic expression of Bcl-2 in haematopoietic cells blocks the resolution of inflammation following antibiotic therapy in a mouse model of pneumococcal meningitis. The persistence of neutrophil brain infiltrates was accompanied by high levels of IL-1beta and G-CSF as well as reduced levels of anti-inflammatory TGF-beta. Significantly, Bcl-2-transgenic mice developed more severe disease that was dependent on neutrophils, characterized by pronounced vasogenic edema, vasculitis, brain haemorrhages and higher clinical scores. In vitro analysis of neutrophils demonstrated that apoptosis inhibition completely preserves neutrophil effector function and prevents internalization by macrophages. The inhibitor of cyclin-dependent kinases, roscovitine induced apoptosis in neutrophils in vitro and in vivo. In wild type mice treated with antibiotics, roscovitine significantly improved the resolution of the inflammation after pneumococcal infection and accelerated recovery. These results indicate that apoptosis is essential to turn off activated neutrophils and show that inflammatory activity and disease severity in a pyogenic infection can be modulated by targeting the apoptotic pathway in neutrophils.

Hepatocyte growth factor (HGF) is a member of the angiogenic growth factor family, which exerts a variety of effects on epithelial, endothelial, and neuronal cells by binding to the c-MET receptor tyrosine kinase. It was reported that HGF attenuates cerebral ischemia-induced increase in permeability of the blood-brain barrier (BBB) and decreases in expression of tight junction proteins in cerebral vessels of rats. Studies on the localization of the c-Met/HGF receptor in the rat brain and the interaction with HGF after brain injuries show that HGF plays an important role as a neurotrophic factor in the brain. To assess the role of HGF in patients with eosinophilic meningitis, a retrospective, cohort study was conducted to measure the dynamic changes of HGF in the cerebrospinal fluid (CSF) and blood of nine patients with eosinophilic meningitis. The mean HGF(CSF) at presentation, 1 week, 2 weeks, and 3 weeks after admission was 539 pg/mL, 540 pg/mL, 376 pg/mL, and 279 pg/mL, respectively. The mean level of HGF(CSF) at presentation (539 +/- 242 pg/mL) and 1 week after admission (540 +/- 213 pg/mL) was significantly higher than in controls (162 +/- 207 pg/mL)(P = 0.02 and P = 0.01, respectively). The CSF/blood ratio of HGF at presentation (0.61) was higher when compared with physiologic situations in uninfected individuals (0.51). The levels of HGF in CSF were not correlated with the amount of CSF cells or proteins. All patients recovered without neurologic sequelae. These results indicate that high concentrations of HGF in the CSF occur in eosinophilic meningitis, and may have a role in protecting against endothelial injury and reducing BBB dysfunction.

BACKGROUND AND PURPOSE: Stroke is a major cause of death and disability, and it is imperative to develop therapeutics to mitigate stroke-related injury. Despite many promising prospects, attempts at translating neuroprotective agents that show success in animal models of stroke have resulted in very limited clinical success. Summary of Review-This review discusses reasons for the lack of translational success based on the therapeutic targets tested and the pathophysiology of stroke. New recanalization therapies and alternative therapeutic strategies are discussed concerning mitochondria-mediated cell death. Mitochondrial death-regulation pathways are divided into 3 categories: Upstream signaling pathways, agents that target mitochondria directly, and downstream death-execution effectors. The apoptosis signal-related kinase/c-Jun-terminal kinase pathway is used as an example to provide rationale as to why inhibiting signaling pathway upstream of mitochondrial dysfunction is a promising therapeutic approach. Finally, the mechanisms of autophagy and mitochondrial biogenesis are discussed in relation to stroke. CONCLUSIONS: Increasing evidence suggests that reperfusion is necessary for improved neurological outcomes after stroke. Development of improved recanalization methods with increased therapeutic windows will aid in improving clinical outcome. Adjunct neuroprotective interventions must also be developed to ensure maximal brain tissue salvage. Targeting prodeath signaling pathways upstream of mitochondrial damage is promising for potential clinically effective treatment. Further understanding of the roles of equilibrium of autophagy and mitochondrial biogenesis in the pathogenesis of stroke could also lead to novel therapeutics.

Sound localization relies on the analysis of interaural time and intensity differences, as well as attenuation patterns by the outer ear. We investigated the relative contributions of interaural time and intensity difference cues to sound localization by testing 60 healthy subjects: 25 with focal left and 25 with focal right hemispheric brain damage. Group and single-case behavioural analyses, as well as anatomo-clinical correlations, confirmed that deficits were more frequent and much more severe after right than left hemispheric lesions and for the processing of interaural time than intensity difference cues. For spatial processing based on interaural time difference cues, different error types were evident in the individual data. Deficits in discriminating between neighbouring positions occurred in both hemispaces after focal right hemispheric brain damage, but were restricted to the contralesional hemispace after focal left hemispheric brain damage. Alloacusis (perceptual shifts across the midline) occurred only after focal right hemispheric brain damage and was associated with minor or severe deficits in position discrimination. During spatial processing based on interaural intensity cues, deficits were less severe in the right hemispheric brain damage than left hemispheric brain damage group and no alloacusis occurred. These results, matched to anatomical data, suggest the existence of a binaural sound localization system predominantly based on interaural time difference cues and primarily supported by the right hemisphere. More generally, our data suggest that two distinct mechanisms contribute to: (i) the precise computation of spatial coordinates allowing spatial comparison within the contralateral hemispace for the left hemisphere and the whole space for the right hemisphere; and (ii) the building up of global auditory spatial representations in right temporo-parietal cortices.

Recent studies demonstrate that progesterone (PROG) significantly reduces cerebral edema and enhances functional recovery from traumatic brain injury (TBI) and stroke in several animal models, but its concrete mechanism is still unknown. This study was designed to investigate the inhibitory effects of PROG on inflammatory response after stroke and its influence on the structure of blood-brain barrier (BBB). In the treatment group, PROG was dissolved in 22.5% 2-hydroxypropyl-bcyclodextrin and given in a dose of 8mg/kg by intraperitoneal injection 1h and 6h after permanent occlusion of middle cerebral artery (pMCAO). Additional injections of 8mg/kg were administered subcutaneously once a day after pMCAO. The expression of tumor necrosis factor-alpha (TNF-alpha), matrix metalloproteinase-9 (MMP-9) and claudin5 was measured by western blot technique. Evan’s blue extravasation and brain water content in the ipsilateral hemisphere was also detected to evaluate the permeability of BBB. Western blot analysis revealed that the expression of TNF-alpha and MMP-9 were reduced while claudin5 was up-regulated in brain tissues of PROG-treated rats. In addition, examination of BBB permeability also showed that administration of PROG significantly reduced Evan’s blue extravasation and brain water content in the ipsilateral hemisphere compared to vehicle-treated rats. Our findings reveal that PROG inhibited the inflammatory response after experimental stroke and mitigated the severity of brain damage, suggesting a role for PROG in the integrity of the BBB and subsequent edema formation following cerebral ischemia.

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.

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.

Abstract Freshwater turtles survive prolonged anoxia and reoxygenation without overt brain damage by well-described physiological processes, but little work has been done to investigate the molecular changes associated with anoxic survival. We examined stress proteins and apoptotic regulators in the turtle during early (1 h) and long-term anoxia (4, 24 h) and reoxygenation. Western blot analyses showed changes within the first hour of anoxia; multiple stress proteins (Hsp72, Grp94, Hsp60, Hsp27, and HO-1) increased while apoptotic regulators (Bcl-2 and Bax) decreased. Levels of the ER stress protein Grp78 were unchanged. Stress proteins remained elevated in long-term anoxia while the Bcl-2/Bax ratio was unaltered. No changes in cleaved caspase 3 levels were observed during anoxia while apoptosis inducing factor increased significantly. Furthermore, we found no evidence for the anoxic translocation of Bax from the cytosol to mitochondria, nor movement of apoptosis inducing factor between the mitochondria and nucleus. Reoxygenation did not lead to further increases in stress proteins or apoptotic regulators except for HO-1. The apparent protection against cell damage was corroborated with immunohistochemistry, which indicated no overt damage in the turtle brain subjected to anoxia and reoxygenation. The results suggest that molecular adaptations enhance pro-survival mechanisms and suppress apoptotic pathways to confer anoxia tolerance in freshwater turtles.