Glioblastoma Multiforme in the Posterior Cranial Fossa in a Patient with Neurofibromatosis Type I

Patients with Neurofibromatosis type 1 (NF1) have an increased risk of developing neoplasms. The most common brain tumors, found in 15%–20% of NF1 patients, are hypothalamic-optic gliomas, followed by brainstem and cerebellar pilocytic astrocytomas. These tumors generally have a benign nature. NF1 patients are predisposed to a 5-fold increased incidence of high-grade astrocytomas, which are usually located in supratentorial regions of the brain. We present an NF1 patient who developed a high-grade astrocytoma in the posterior fossa and discuss possible pathophysiological mechanisms

White Matter Lesions Are Not Related to β-Amyloid Deposition in an Autopsy-Based Study

Population-based studies have investigated the relation between β-amyloid levels in cerebrospinal fluid or plasma and white matter lesions (WMLs). However, these circulating levels of β-amyloid in cerebrospinal fluid or plasma may not reliably reflect the actual degree of amyloid present in the brain. Therefore, we investigated the relation between WMLs and β-amyloid plaques and amyloid angiopathy in brain tissue. WML on MRI or CT were rated in 28 nondemented patients whose neuroimaging was available prior to death. β-amyloid in plaques and arterioles were immunohistochemically stained and quantified in postmortem brain necropsies. WMLs were present in 43% of the total population. Both cortex and periventricular region showed no differences for β-amyloid deposition in either plaques or blood vessel walls in patients with WMLs compared to those without WMLs. Thus, our results indicate that there is no relation between the degree of WMLs and β-amyloid deposition in the brain

Sharon Macdonald – Memorylands: Heritage and Identity in Europe Today

Memorylands: Heritage and Identity in Europe Today é um livro de síntese que assinala o culminar de anos de trabalho da antropóloga britânica Sharon Macdonald sobre os temas relacionados do património, da memória e da identidade em contextos europeus. Em Reimagining Culture: Histories, Identities and the Gaelic Renaissance, de 1997, situava o eixo analítico entre o local e o global, focando o seu olhar na questão dos muitos “renascimentos identitários” de escala local e regional que à época –..

Distinct DNA Methylation Patterns of Subependymal Giant Cell Astrocytomas in Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) is a monogenic disorder caused by mutations in either the TSC1 or TSC2 gene, two key regulators of the mechanistic target of the rapamycin complex pathway. Phenotypically, this leads to growth and formation of hamartomas in several organs, including the brain. Subependymal giant cell astrocytomas (SEGAs) are low-grade brain tumors commonly associated with TSC. Recently, gene expression studies provided evidence that the immune system, the MAPK pathway and extracellular matrix organization play an important role in SEGA development. However, the precise mechanisms behind the gene expression changes in SEGA are still largely unknown, providing a potential role for DNA methylation. We investigated the methylation profile of SEGAs using the Illumina Infinium HumanMethylation450 BeadChip (SEGAs n = 42, periventricular control n = 8). The SEGA methylation profile was enriched for the adaptive immune system, T cell activation, leukocyte mediated immunity, extracellular structure organization and the ERK1 & ERK2 cascade. More interestingly, we identified two subgroups in the SEGA methylation data and show that the differentially expressed genes between the two subgroups are related to the MAPK cascade and adaptive immune response. Overall, this study shows that the immune system, the MAPK pathway and extracellular matrix organization are also affected on DNA methylation level, suggesting that therapeutic intervention on DNA level could be useful for these specific pathways in SEGA. Moreover, we identified two subgroups in SEGA that seem to be driven by changes in the adaptive immune response and MAPK pathway and could potentially hold predictive information on target treatment response

The coding and non-coding transcriptional landscape of subependymal giant cell astrocytomas

Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited neurocutaneous disorder caused by inactivating mutations in TSC1 or TSC2, key regulators of the mechanistic target of rapamycin complex 1 (mTORC1) pathway. In the CNS, TSC is characterized by cortical tubers, subependymal nodules and subependymal giant cell astrocytomas (SEGAs). SEGAs may lead to impaired circulation of CSF resulting in hydrocephalus and raised intracranial pressure in patients with TSC. Currently, surgical resection and mTORC1 inhibitors are the recommended treatment options for patients with SEGA. In the present study, high-throughput RNA-sequencing (SEGAs n = 19, periventricular control n = 8) was used in combination with computational approaches to unravel the complexity of SEGA development. We identified 9400 mRNAs and 94 microRNAs differentially expressed in SEGAs compared to control tissue. The SEGA transcriptome profile was enriched for the mitogen-activated protein kinase (MAPK) pathway, a major regulator of cell proliferation and survival. Analysis at the protein level confirmed that extracellular signal-regulated kinase (ERK) is activated in SEGAs. Subsequently, the inhibition of ERK independently of mTORC1 blockade decreased efficiently the proliferation of primary patient-derived SEGA cultures. Furthermore, we found that LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5 were overexpressed at both gene and protein levels in SEGA compared to control tissue. Taken together LAMTOR1-5 can form a complex, known as the 'Ragulator' complex, which is known to activate both mTORC1 and MAPK/ERK pathways. Overall, this study shows that the MAPK/ERK pathway could be used as a target for treatment independent of, or in combination with mTORC1 inhibitors for TSC patients. Moreover, our study provides initial evidence of a possible link between the constitutive activated mTORC1 pathway and a secondary driver pathway of tumour growth

Cellular distribution of vascular endothelial growth factor A (VEGFA) and B (VEGFB) and VEGF receptors 1 and 2 in focal cortical dysplasia type IIB

Members of the vascular endothelial growth factor (VEGF) family are key signaling proteins in the induction and regulation of angiogenesis, both during development and in pathological conditions. However, signaling mediated through VEGF family proteins and their receptors has recently been shown to have direct effects on neurons and glial cells. In the present study, we immunocytochemically investigated the expression and cellular distribution of VEGFA, VEGFB, and their associated receptors (VEGFR-1 and VEGFR-2) in focal cortical dysplasia (FCD) type IIB from patients with medically intractable epilepsy. Histologically normal temporal cortex and perilesional regions displayed neuronal immunoreactivity (IR) for VEGFA, VEGFB, and VEGF receptors (VEGFR-1 and VEGFR-2), mainly in pyramidal neurons. Weak IR was observed in blood vessels and there was no notable glial IR within the grey and white matter. In all FCD specimens, VEGFA, VEGFB, and both VEGF receptors were highly expressed in dysplastic neurons. IR in astroglial and balloon cells was observed for VEGFA and its receptors. VEGFR-1 displayed strong endothelial staining in FCD. Double-labeling also showed expression of VEGFA, VEGFB and VEGFR-1 in cells of the microglia/macrophage lineage. The neuronal expression of both VEGFA and VEGFB, together with their specific receptors in FCD, suggests autocrine/paracrine effects on dysplastic neurons. These autocrine/paracrine effects could play a role in the development of FCD, preventing the death of abnormal neuronal cells. In addition, the expression of VEGFA and its receptors in glial cells within the dysplastic cortex indicates that VEGF-mediated signaling could contribute to astroglial activation and associated inflammatory reactions

Histology of the Pharyngeal Constrictor Muscle in 22q11.2 Deletion Syndrome and Non-Syndromic Children with Velopharyngeal Insufficiency

Plastic surgeons aim to correct velopharyngeal insufficiency manifest by hypernasal speech with a velopharyngoplasty. The functional outcome has been reported to be worse in patients with 22q11.2 deletion syndrome than in patients without the syndrome. A possible explanation is the hypotonia that is often present as part of the syndrome. To confirm a myogenic component of the etiology of velopharyngeal insufficiency in children with 22q11.2 deletion syndrome, specimens of the pharyngeal constrictor muscle were taken from children with and without the syndrome. Histologic properties were compared between the groups. Specimens from the two groups did not differ regarding the presence of increased perimysial or endomysial space, fiber grouping by size or type, internalized nuclei, the percentage type I fibers, or the diameters of type I and type II fibers. In conclusion, a myogenic component of the etiology of velopharyngeal insufficiency in children with 22q11.2 deletion syndrome could not be confirmed

Human Prion Diseases in The Netherlands (1998–2009): Clinical, Genetic and Molecular Aspects

Prion diseases are rare and fatal neurodegenerative disorders that can be sporadic, inherited or acquired by infection. Based on a national surveillance program in the Netherlands we describe here the clinical, neuropathological, genetic and molecular characteristics of 162 patients with neuropathologically confirmed prion disease over a 12-year period (1998–2009). Since 1998, there has been a relatively stable mortality of Creutzfeldt-Jakob disease (CJD) in the Netherlands, ranging from 0.63 to 1.53 per million inhabitants per annum. Genetic analysis of the codon 129 methionine/valine (M/V) polymorphism in all patients with sporadic CJD (sCJD) showed a trend for under-representation of VV cases (7.0%), compared with sCJD cohorts in other Western countries, whereas the MV genotype was relatively over-represented (22,4%). Combined PrPSc and histopathological typing identified all sCJD subtypes known to date, except for the VV1 subtype. In particular, a “pure" phenotype was demonstrated in 60.1% of patients, whereas a mixed phenotype was detected in 39.9% of all sCJD cases. The relative excess of MV cases was largely accounted for by a relatively high incidence of the MV 2K subtype. Genetic analysis of the prion protein gene (PRNP) was performed in 161 patients and showed a mutation in 9 of them (5.6%), including one FFI and four GSS cases. Iatrogenic CJD was a rare phenomenon (3.1%), mainly associated with dura mater grafts. Three patients were diagnosed with new variant CJD (1.9%) and one with variably protease-sensitive prionopathy (VPSPr). Post-mortem examination revealed an alternative diagnosis in 156 patients, most commonly Alzheimer's disease (21.2%) or vascular causes of dementia (19.9%). The mortality rates of sCJD in the Netherlands are similar to those in other European countries, whereas iatrogenic and genetic cases are relatively rare. The unusual incidence of the VV2 sCJD subtype compared to that reported to date in other Western countries deserves further investigation

Increased expression of connective tissue growth factor in amyotrophic lateral sclerosis human spinal cord

Connective tissue growth factor (CTGF) is a secreted protein involved in a variety of cellular events such as survival, proliferation, and extracellular matrix production. Recent studies suggest a role for this protein also in the repair processes of the central nervous system. The distribution and significance of CTGF in human brain is, however, poorly understood, particularly under pathological conditions. In the present study the expression of CTGF protein was investigated in the spinal cord of control and both sporadic and familial amyotrophic lateral sclerosis (sALS and fALS) patients. Western blot analysis showed a consistent increase in CTGF expression in six sALS patients compared with controls. Immunoreactivity signal for CTGF was equally present in blood vessels of control and ALS spinal cord, but was dramatically increased in reactive astrocytes of the ventral horn and white matter in both sALS and fALS. Increased expression was also observed in the cytoplasm of motor neurons of sALS and fALS patients with long duration of the disease. Our data indicate a role for CTGF in the complex reactive process that is associated with the progression of ALS spinal cord damage. The up-regulation in reactive astrocytes supports a role for CTGF in the molecular mechanisms underlying astrogliosis. However, the altered CTGF expression observed in neurons might represent an additional mechanism involved in motor neuron dysfunction and changes in glial-neuronal communication in the course of the neurodegenerative proces