Extent Of Gliosis Research Articles

Spinal cord occupation ratio (SCOR) and its application in the diagnosis of cervical spinal cord compression in Mucopolysaccharidoses

Introduction Mucopolysaccharidoses (MPS) can lead to cervical spinal cord compression (SCC). Diagnostic scores for SCC in MPS use the obliteration of the passage of cerebrospinal fluid in the anterior and posterior spinal cord in the sagittal section of magnetic resonance imaging (MRI). The spinal cord occupation ratio (SCOR) published, by Nouri et al (2018), establishes the spinal cord filling index for the spinal cord, identifying disproportionate spinal cord occupation in the canal. When evaluating congenital canal stenosis, the risk of spinal cord injury has been considered increased when the SCOR is ≥70% in the median sagittal plane or ≥ 80% in the axial plane. Although these values ​​have not been validated for MPS populations, they could be useful. Objective To verify the SCOR in MPS patients with diagnosis of cervical SCC comparing the SCOR with other markers proposed in the existing MPS SCC scores, such as the extent of gliosis, clinical impact and the SCC assessment as represented by the obliteration of CSF flow. Methods We reviewed imaging tests of the cervical spine from MPS patients with previously confirmed SCC, using the SCOR measure in the median sagittal plane, evaluation of the presence and extent of spinal gliosis on MRI, evaluation of the clinical impact using a clinical score and evaluation of the images for the obliteration of cerebral spinal fluid (CSF) flow. Results Thirty-one MRI of 24 different patients were included. The average SCOR was 87.1%. This was lower (81.6%) in patients without gliosis, when compared to those with focal (90.5%) and extensive (97%) gliosis. The only patient with gliosis associated with a lacunar lesion, resulting from an acute compressive injury, had a 68% SCOR, due to the atrophic spinal cord injury. As expected, SCOR was higher in patients with total or partial CSF obliteration, but one among the 3 patients without CSF flow obliteration, with a 76% SCOR, had already developed focal gliosis and mild clinical abnormalities. Patients with more extensive gliosis had higher clinical scores. Four patients had more than one imaging scan evaluated. SCOR upward trend showed an annual average increase of 3.8%. Discussion & Conclusions The use of SCOR allows the diagnosis of cervical spinal canal stenosis in an objective way. It is possible that the cut-off values used by Nouri et al in patients with congenital stenosis could be useful to diagnose cervical stenosis in MPS patients, preceding the finding of CSF flow obstruction, presence of gliosis or clinical abnormalities. Furthermore, the use of SCOR may assist in the longitudinal evaluation of disease progression. Better follow-up and timely diagnosis allows for scheduling of surgery at the best clinical moment, minimizing complications.

Clinical spectrum of pediatric drug refractory epilepsy secondary to parieto-occipital gliosis

BackgroundParieto-occipital (PO) gliosis secondary to perinatal insult, is often associated with neurologic sequelae such as epilepsy, which can be drug resistant. ObjectiveTo evaluate the spectrum of epilepsy among patients presenting with seizures in association with PO gliosis and to determine factors that influence the development of epileptic encephalopathy (EE) in these patients. MethodsWe retrospectively evaluated patients aged < 16 years with drug refractory epilepsy and PO gliosis who underwent video electroencephalography (Video EEG). We evaluated the clinical, electrophysiological and radiological profile including treatment responsiveness of subjects with EE. ResultsOne hundred one patients (M: F=3:1) with mean age of onset of epilepsy at 28.9 ± 33.1 months were recruited into the study. Based on video EEG findings, Based on video EEG findings, the commonest type of focal onset ictus was tonic seizures with impaired awareness (n = 26, 29.9%). Myoclonic jerks (n = 20, 23%) were the commonest type of generalised onset seizures. Ictal onset from parieto occipital region were observed in 28 patients. Ictal onset from frontal, temporal and fronto temporal region were observed in 6 (6.8%), 7(7.9%) and 9 (8.9%) patients, respectively. Comparison of the seizure types and ictal onset among subgroups of patients with occipital gliosis, parieto-occipital gliosis and parieto-occipital with frontal gliosis revealed that the extent of gliosis did not significantly affect seizure semiology or ictal onset. EE was significantly associated with presence of neonatal seizures (p = 0.04), hypoglycaemia (p = 0.005), longer duration of ICU stay (Z score = −3.55, p < 0.001) and younger age of onset of seizures (Z score = - 2.97, p = 0.03). Eleven out of eighteen (64.7%) subjects with EE showed greater than 50% improvement in seizure frequency following three months of pulse intravenous methylprednisolone therapy. ConclusionsAmong subjects with PO gliosis on MRI, the seizure semiology is unaffected by laterality, radiologic extension beyond the occipital cortex or presence of ulegyria. Patients with PO gliosis can have florid interictal epileptiform discharges anteriorly and can have seizures with ictal onset from frontal and temporal region. Development of EE is strongly related to the age of onset of seizures, neonatal seizures, prolonged NICU admission, rather than the radiological findings. Subjects with EE and PO gliosis show good response to intravenous pulse methylprednisolone.

CNS-accessible Inhibitor of Glucosylceramide Synthase for Substrate Reduction Therapy of Neuronopathic Gaucher Disease.

Gaucher disease (GD) is caused by a deficiency of glucocerebrosidase and the consequent lysosomal accumulation of unmetabolized glycolipid substrates. Enzyme-replacement therapy adequately manages the visceral manifestations of nonneuronopathic type-1 Gaucher patients, but not the brain disease in neuronopathic types 2 and 3 GD. Substrate reduction therapy through inhibition of glucosylceramide synthase (GCS) has also been shown to effectively treat the visceral disease. Here, we evaluated the efficacy of a novel small molecule inhibitor of GCS with central nervous system (CNS) access (Genz-682452) to treat the brain disease. Treatment of the conduritol β epoxide-induced mouse model of neuronopathic GD with Genz-682452 reduced the accumulation of liver and brain glycolipids (>70% and >20% respectively), extent of gliosis, and severity of ataxia. In the genetic 4L;C* mouse model, Genz-682452 reduced the levels of substrate in the brain by >40%, the extent of gliosis, and paresis. Importantly, Genz-682452-treated 4L;C* mice also exhibited an ~30% increase in lifespan. Together, these data indicate that an orally available antagonist of GCS that has CNS access is effective at attenuating several of the neuropathologic and behavioral manifestations associated with mouse models of neuronopathic GD. Therefore, Genz-682452 holds promise as a potential therapeutic approach for patients with type-3 GD.

The Severity of Gliosis in Hippocampal Sclerosis Correlates with Pre-Operative Seizure Burden and Outcome After Temporal Lobectomy.

Astrogliosis and microgliosis in hippocampal sclerosis (HS) are widespread and are postulated to contribute to the pro-excitatory neuropathological environment. This study aimed to establish if seizure burden at the time of surgery or post-surgical outcome were correlated with the extent of gliosis in HS. As a secondary aim, we wanted to determine if the degree of gliosis could be predicted by pre-operative neuroimaging.Children and adults who underwent epilepsy surgery for HS between 2002 and 2011 were recruited (n = 43), and age-matched autopsy controls obtained (n = 15). Temporal lobe specimens were examined by DAB immunohistochemistry for astrocytes (glial fibrillary acidic protein (GFAP)) and microglia (CD68). Cell counting for GFAP and CD68 was performed and quantitative densitometry undertaken for GFAP. Seizure variables and outcome (Engel) were determined through medical record and patient review. Seizure frequency in the 6months prior to surgery was measured to reflect the acute seizure burden. Duration of seizures, age at onset and age at operation were regarded to reflect chronic seizure burden. Focal, lobar and generalized atrophy on pre-operative MRI were independently correlated with the degree of cortical gliosis in the surgical specimen.In HS, both acute and chronic seizure burden were positively correlated with the degree of gliosis. An increase in reactive astrocyte number in CA3 was the strongest predictor of poor post-operative seizure outcome at 1 and 3years post-operatively in this cohort. Changes in lower cortical astrocyte and upper cortical microglial number also correlated with post-operative outcome at 1year. Post-surgical seizure outcome (1, 3 and 5years) did not otherwise correlate with GFAP immunoreactivity (GFAP-IR) or CD68 immunoreactivity (CD68-IR). Increased microglial activation was detected in patients with pre-operative bilateral convulsive seizures, compared to those without convulsive seizures. Furthermore, focal, lobar and generalized atrophy on pre-operative neuroimaging were independently correlated with the degree of cortical gliosis in the surgical specimen.

An ανβ3 Integrin-Binding Peptide Ameliorates Symptoms of Chronic Progressive Experimental Autoimmune Encephalomyelitis by Alleviating Neuroinflammatory Responses in Mice

MOG35-55 triggers chronic, progressive experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice, and the clinical course of EAE in this model is characterized by macrophage infiltration, axonal demyelination/damage, and progressive paralysis. These stages are usually associated with inflammatory responses in the central nervous system (CNS). This study was designed to investigate the effects of C16, an ανβ3 integrin-binding peptide that targets integrins involved in the transendothelial migration of extravasating inflammatory cells. C16 was applied for only 2weeks, but the benefits of this therapy lasted at least 8weeks. Multiple histological and immunohistochemical staining studies, western blotting, enzyme-linked immunosorbent assays, electron microscopy, and cortical somatosensory-evoked potential (c-SEP) electrophysiological tests were employed to assess the degree of inflammation, axonal loss, white matter demyelination, neuronal apoptosis, extent of gliosis, expression of pro-inflammatory cytokines, and functional recovery of differently treated EAE model mice. The results showed that C16 treatment inhibited extensive leukocyte and macrophage accumulation and infiltration, reduced the expression of pro-inflammatory cytokines (tumor necrosis factor-α and interferon-γ), and thereby attenuated and delayed the progression of EAE. Moreover, astrogliosis, demyelination, and axonal and neuronal loss were all alleviated in C16-treated EAE animals, contributing to the improvement of function. These data suggest that the C16 peptide may act as a protective agent by reducing neuroinflammatory responses and improving the microenvironment.

Contralaterally transplanted human embryonic stem cell-derived neural precursor cells (ENStem-A) migrate and improve brain functions in stroke-damaged rats

The transplantation of neural precursor cells (NPCs) is known to be a promising approach to ameliorating behavioral deficits after stroke in a rodent model of middle cerebral artery occlusion (MCAo). Previous studies have shown that transplanted NPCs migrate toward the infarct region, survive and differentiate into mature neurons to some extent. However, the spatiotemporal dynamics of NPC migration following transplantation into stroke animals have yet to be elucidated. In this study, we investigated the fates of human embryonic stem cell (hESC)-derived NPCs (ENStem-A) for 8 weeks following transplantation into the side contralateral to the infarct region using 7.0T animal magnetic resonance imaging (MRI). T2- and T2*-weighted MRI analyses indicated that the migrating cells were clearly detectable at the infarct boundary zone by 1 week, and the intensity of the MRI signals robustly increased within 4 weeks after transplantation. Afterwards, the signals were slightly increased or unchanged. At 8 weeks, we performed Prussian blue staining and immunohistochemical staining using human-specific markers, and found that high percentages of transplanted cells migrated to the infarct boundary. Most of these cells were CXCR4-positive. We also observed that the migrating cells expressed markers for various stages of neural differentiation, including Nestin, Tuj1, NeuN, TH, DARPP-32 and SV38, indicating that the transplanted cells may partially contribute to the reconstruction of the damaged neural tissues after stroke. Interestingly, we found that the extent of gliosis (glial fibrillary acidic protein-positive cells) and apoptosis (TUNEL-positive cells) were significantly decreased in the cell-transplanted group, suggesting that hESC-NPCs have a positive role in reducing glia scar formation and cell death after stroke. No tumors formed in our study. We also performed various behavioral tests, including rotarod, stepping and modified neurological severity score tests, and found that the transplanted animals exhibited significant improvements in sensorimotor functions during the 8 weeks after transplantation. Taken together, these results strongly suggest that hESC-NPCs have the capacity to migrate to the infarct region, form neural tissues efficiently and contribute to behavioral recovery in a rodent model of ischemic stroke.

Dose-Dependent Anti-Inflammatory and Neuroprotective Effects of anανβ3 Integrin-Binding Peptide

Previous studies have shown that prevention of leukocyte infiltration by targeting integrins involved in transendothelial migration may suppress the clinical and pathological features of neuroinflammatory disease. This study was designed to investigate the effects of C16, an α ν β3 integrin-binding peptide, in an acute experimental allergic encephalomyelitis (EAE) rat model. Multiple histological and immunohistochemical staining, electron microscopy observation, ELISA assay, Western blot, and magnetic resonance imaging (MRI) were employed to assess the degree of inflammation, axonal loss, neuronal apoptosis, white matter demyelination, and extent of gliosis in the brain and spinal cord of differently treated EAE models. The results showed that C16 treatment could inhibit extensive leukocyte and macrophage accumulation and infiltration and reduce cytokine tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) expression levels. A significantly lower clinical score at the peak time of disease was also demonstrated in the C16 treated group. Moreover, astrogliosis, demyelination, neuronal death, and axonal loss were all alleviated in C16 treated EAE animals, which may be attributed to the improvement of microenvironment. The data suggests that C16 peptide may act as a protective agent by attenuating inflammatory progression and thus affecting the expression of some proinflammatory cytokines during neuroinflammatory disease.

A proteomic study identifies different levels of light chain ferritin in corticobasal degeneration and progressive supranuclear palsy

Clinical and pathological evidence supports the notion that corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) are distinct, but overlapping neurodegenerative tauopathies. Although both disorders are characterized by abnormal accumulation of 4-repeat tau, they display distinct proteolytic profiles of tau species and they have distinct astrocytic lesions, astrocytic plaques in CBD and tufted astrocytes in PSP. To investigate other differences between these two disorders at the molecular level, we compared the profiles of proteins from caudate nucleus of CBD and PSP by quantitative two-dimensional difference gel electrophoresis. Twenty-one protein spots differentially expressed in CBD and PSP were dissected for mass spectrometry (MS). One of the spots was identified by MS to contain light chain (LC) ferritin. Western blot analysis verified the presence of LC ferritin in this spot and showed that this protein was two-fold higher in caudate of CBD than that of PSP samples. These results were confirmed by LC ferritin immunohistochemistry. Co-labeling of caudate nucleus with tau and LC ferritin antibodies showed the presence of LC ferritin immunoreactivity in astrocytic plaques of CBD, but minimal labeling of tufted astrocytes in PSP. This difference did not reflect the extent of gliosis. Analysis of other brain regions in CBD and PSP showed no difference in LC ferritin levels. Together the data suggest that LC ferritin is a unique marker of astrocytic lesions in CBD, adding further support to the notion that CBD and PSP are distinct clinicopathologic entities.

A comment on impaired peri-nidal cerebrovascular reserve in seizure patients with brain arteriovenous malformations

Sir, We read with great interest the article by Fierstra et al . (2011), recently published in your journal. This article reopens the debate regarding the unsolved problem of the origin of seizures in patients with brain arteriovenous malformations, the pathophysiology of which remains poorly understood. Although angiographic studies have shown some associations between different brain arteriovenous malformation angioarchitectural features and epilepsy, they have not elucidated the underlying pathophysiology (Turjman et al ., 1995 a , b ; Hoh et al ., 2002). Similarly, MRI studies have often shown gliosis and chronic ischaemic changes in peri-nidal tissue as well as in remote regions, but any significant correlation has been demonstrated between extent of gliosis and clinical symptoms (Essig et al ., 2000). The main pathophysiological hypotheses to date include: (i) focal cerebral ischaemia attributable to a steal phenomenon as described by Spetzler et al . (1992) and Taylor et al . (2002); (ii) gliosis, demyelination and haemosiderin deposits in peri-nidal tissue; and (iii) secondary epileptogenesis in ipsilateral temporomesial cortex (Yeh et al ., 1990), or at a distant site, attributable to a ‘kindling’ phenomenon, in which epileptic discharges are enhanced by excitatory synaptic connections from brain arteriovenous malformations (Hoh et al ., 2002). Bleeding was deemed responsible for triggering seizure activity by Turjman et al . (1995 a ) and Stein and Wolpert (1980); in contrast, in the study by Hoh et al . (2002), intracranial haemorrhage was not a statistically significant factor associated with epilepsy. Fierstra et al . (2011) studied in vivo the possible haemodynamic effect …

Soluble factor effects on glial cell reactivity at the surface of gel-coated microwires

A basal lamina gel preparation was incorporated into a modified neuroinflammation cell culture model to test the system as a characterization tool for surface-modified microwires. The extent of gliosis at the surface of gel-coated microwires was quantified in response to titrating the cell culture with a number of soluble factors reported to be involved in reactive gliosis. Positive control conditions (1% FBS, 10ng/ml bFGF, Neural Basal medium with B27 supplement) induced a layer of GFAP-expressing astrocytes to accumulate on all gel-coated microwires. Serum, inflammatory cytokines IL-1α and IL-1β and the neural progenitor cell (NPC) proliferating growth factors bFGF and PDGF all increased the number of reactive cells on the gel, in agreement with their reported roles in cell activation, migration and proliferation at the site of injury. Technically, this study shows that a fetal neuron-glia culture system is well suited for characterizing the impact of electrode coatings designed to mitigate implant-associated gliosis, and for screening the effect of multiple soluble factors that promote and/or inhibit implant-associated gliosis. Scientifically, this study points to essential roles of serum and inflammatory factors to induce NPC activation and migration to the site of injury, where growth factors like bFGF and PDGF induce proliferation of cells that will eventually form the glial scar.

DJ-1 deficient mice demonstrate similar vulnerability to pathogenic Ala53Thr human -syn toxicity

Parkinson's disease (PD) is the most common neurodegenerative movement disorder. A pathological hallmark of PD is the presence of intraneuronal inclusions composed of fibrillized alpha-synuclein (alpha-syn) in affected brain regions. Mutations in the gene, PARK7, which encodes DJ-1, can cause autosomal recessive early-onset PD. Although DJ-1 has been shown to be involved in diverse biological processes, several in vitro studies suggest that it can inhibit the formation and protect against the effects of alpha-syn aggregation. We previously established and characterized transgenic mice expressing pathogenic Ala53Thr human alpha-syn (M83 mice) that develop extensive alpha-syn pathologies in the neuroaxis resulting in severe motor impairments and eventual fatality. In the current study, we have crossbred M83 mice on a DJ-1 null background (M83-DJnull mice) in efforts to determine the effects of the lack of DJ-1 in these mice. Animals were assessed and compared for survival rate, distribution of alpha-syn inclusions, biochemical properties of alpha-syn protein, demise and function of nigral dopaminergic neurons, and extent of gliosis in the neuroaxis. M83 and M83-DJnull mice displayed a similar onset of disease and pathological changes, and none of the analyses to assess for changes in pathogenesis revealed any significant differences between M83 and M83-DJnull mice. These findings suggest that DJ-1 may not function to directly modulate alpha-syn nor does DJ-1 appear to play a role in protecting against the deleterious effects of expressing pathogenic Ala53Thr alpha-syn in vivo. It is possible that alpha-syn and DJ-1 mutations may lead to PD via independent mechanisms.

Fabrication and biocompatibility of polypyrrole implants suitable for neural prosthetics

Finding a conductive substrate that promotes neural interactions is an essential step for advancing neural interfaces. The biocompatibility and conductive properties of polypyrrole (PPy) make it an attractive substrate for neural scaffolds, electrodes, and devices. Stand-alone polymer implants also provide the additional advantages of flexibility and biodegradability. To examine PPy biocompatibility, dissociated primary cerebral cortical cells were cultured on PPy samples that had been doped with polystyrene-sulfonate (PSS) or sodium dodecylbenzenesulfonate (NaDBS). Various conditions were used for electrodeposition to produce different surface properties. Neural networks grew on all of the PPy surfaces. PPy implants, consisting of the same dopants and conditions, were surgically implanted in the cerebral cortex of the rat. The results were compared to stab wounds and Teflon implants of the same size. Quantification of the intensity and extent of gliosis at 3- and 6-week time points demonstrated that all versions of PPy were at least as biocompatible as Teflon and in fact performed better in most cases. In all of the PPy implant cases, neurons and glial cells enveloped the implant. In several cases, neural tissue was present in the lumen of the implants, allowing contact of the brain parenchyma through the implants.

Arteriovenous malformations: assessment of gliotic and ischemic changes with fluid-attenuated inversion-recovery MRI.

To evaluate the diagnostic potential of fluid-attenuated inversion-recovery (FLAIR) MRI in the assessment of patients with cerebral arteriovenous malformations (AVMs) and to correlate the MR findings with clinical symptoms, in particular, perilesional gliosis and ischemic changes. Forty-five patients with cerebral AVMs were examined with FLAIR and conventional T1- and T2-weighted MRI by using identical slice parameters. Images were assessed in a two-reader study for detection and delineation of gliotic and ischemic tissue. Also, the extent of the flow void phenomenon and image artifacts were evaluated. FLAIR MRI was rated superior to the conventional T2-weighted fast spin-echo imaging in the assessment of intralesional and perilesional gliosis. The superior delineation was a result of the suppression of cerebrospinal fluid, mild T1 weighting, and the more pronounced flow void phenomenon. There was no significant correlation between the extent of gliosis and the clinical symptoms. However, larger AVMs had more extensive signal changes. FLAIR is a valuable MRI technique to assess gliotic and ischemic changes in or close to cerebral AVMs. Because gliotic and ischemic changes are common findings and are known to be associated with epilepsy, in the assessment of these patients FLAIR is clinically useful and may guide decisions about treatment-for instance, the extent of surgical resection of the potential epileptogenic focus.

On the significance of brain extracellular uric acid detected with in-vivo monitoring techniques: a review

The concentration of uric acid [UA] in the extracellular fluid (ECF) estimated with in-vivo voltammetry and microdialysis data is compared for probes of different diameters from the day of implantation (acute) to several days (chronic) or even months after surgery. For small probes (diameter < 160 μm) the acute [UA] of ca. 5 μM decreased significantly to ca. 1 μM under chronic conditions. For larger probes (e.g., 320-μm diameter) the acute [UA] was also ca. 5 μM, but this value significantly increased to ca. 50 μM under chronic conditions. Associated with this difference in [UA], there were parallel differences in the extent of gliosis around the probes. These findings are discussed in terms of possible sources of extracellular UA and their implications for in-vivo monitoring techniques in behaving animals.

Tenascin knockout mice: barrels, boundary molecules, and glial scars

In light of a previous report suggesting that the brains of tenascin-deficient animals are grossly normal, we have studied the somatosensory cortical barrel field and injured cerebral cortex in postnatal homozygous tenascin knockout, heterozygote, and normal wild-type mice. Nissl staining, cytochrome oxidase, and Dil axonal tracing of thalamocortical axonal projections to the somatosensory cortex, all reveal the formation of normal barrels in the first postnatal week in homozygous knockout mice that cannot be distinguished from heterozygote or normal wild-type barrels. In addition to confirming the absence of tenascin in knockout animals, and reporting apparently reduced levels of the glycoprotein in barrel boundaries of heterozygote animals using well-characterized antibodies and immunocytochemistry, we also studied the DSD-1-PG proteoglycan, another developmentally regulated molecule known to be associated with transient glial/glycoconjugate boundaries that surround developing barrels; DSD-1-PG was also found to be expressed in barrel boundaries in apparently normal time frames in tenascin knockout mice. Peanut agglutinin (PNA) binding of galactosyl-containing glycoconjugates also revealed barrel boundaries in all three genotypes. We also examined the expression of tenascin-R, a paralog of tenascin-C (referred to here simply as tenascin). As previously reported, tenascin-R is prominently expressed in subcortical white matter, and we found it was not expressed in the barrel boundaries in any of the genotypes. Thus, the absence of tenascin does not result in a compensatory expression of tenascin-R in the barrel boundaries. Finally, we studied wounds of the cerebral cortex in the late postnatal mouse. The astroglial scar formed, for the most part, in the same time course and spatial distribution in the wild-type and tenascin knockout mice. However, there may be some differences in the extent of gliosis between the knockout and the wild type that warrant further study. Roles for boundary molecules like tenascin during brain pattern formation and injury are reconsidered in light of these findings on barrel development and cortical lesions in tenascin-deficient mice.