Infections, inflammation and epilepsy
Abstract Epilepsy is the tendency to have unprovoked epileptic seizures. Anything causing structural or functional derangement of brain physiology may lead to seizures, and different conditions may express themselves solely by recurrent seizures and thus be labelled “epilepsy.” Worldwide, epilepsy is the most common serious neurological condition. The range of risk factors for the development of epilepsy varies with age and geographic location. Congenital, developmental and genetic conditions are mostly associated with the development of epilepsy in childhood, adolescence and early adulthood. Head trau...
Source: Acta Neuropathologica - September 30, 2015 Category: Neurology Source Type: research

Role of macrophages in Wallerian degeneration and axonal regeneration after peripheral nerve injury
Abstract The peripheral nervous system (PNS) has remarkable regenerative abilities after injury. Successful PNS regeneration relies on both injured axons and non-neuronal cells, including Schwann cells and immune cells. Macrophages are the most notable immune cells that play key roles in PNS injury and repair. Upon peripheral nerve injury, a large number of macrophages are accumulated at the injury sites, where they not only contribute to Wallerian degeneration, but also are educated by the local microenvironment and polarized to an anti-inflammatory phenotype (M2), thus contributing to axonal regeneration. Signif...
Source: Acta Neuropathologica - September 29, 2015 Category: Neurology Source Type: research

Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes
Abstract Diffuse intrinsic pontine glioma (DIPG) is the most severe paediatric solid tumour, with no significant therapeutic progress made in the past 50 years. Recent studies suggest that diffuse midline glioma, H3-K27M mutant, may comprise more than one biological entity. The aim of the study was to determine the clinical and biological variables that most impact their prognosis. Ninety-one patients with classically defined DIPG underwent a systematic stereotactic biopsy and were included in this observational retrospective study. Histone H3 genes mutations were assessed by immunochemistry and direct sequen...
Source: Acta Neuropathologica - September 23, 2015 Category: Neurology Source Type: research

PDCD10 (CCM3) regulates brain endothelial barrier integrity in cerebral cavernous malformation type 3: role of CCM3-ERK1/2-cortactin cross-talk
This study highlights the potential role of CCM3 in regulating TJ complex organization and brain endothelial barrier permeability. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - September 18, 2015 Category: Neurology Source Type: research

Quantitative analysis and clinico-pathological correlations of different dipeptide repeat protein pathologies in C9ORF72 mutation carriers
Abstract Hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of frontotemporal dementia and motor neuron disease. One consequence of the mutation is the formation of different potentially toxic polypeptides composed of dipeptide repeats (DPR) (poly-GA, -GP, -GR, -PA, -PR) generated by repeat-associated non-ATG (RAN) translation. While previous studies focusing on poly-GA pathology have failed to detect any clinico-pathological correlations in C9ORF72 mutation cases, recent data from animal and cell culture models suggested that it may be only specific DPR species that are toxic and only whe...
Source: Acta Neuropathologica - September 15, 2015 Category: Neurology Source Type: research

Physiological amyloid-beta clearance in the periphery and its therapeutic potential for Alzheimer’s disease
Abstract Amyloid-beta (Aβ) plays a pivotal role in the pathogenesis of Alzheimer’s disease (AD). The physiological capacity of peripheral tissues and organs in clearing brain-derived Aβ and its therapeutic potential for AD remains largely unknown. Here, we measured blood Aβ levels in different locations of the circulation in humans and mice, and used a parabiosis model to investigate the effect of peripheral Aβ catabolism on AD pathogenesis. We found that blood Aβ levels in the inferior/posterior vena cava were lower than that in the superior vena cava in both humans and mice. In add...
Source: Acta Neuropathologica - September 12, 2015 Category: Neurology Source Type: research

Frontotemporal dementia caused by CHMP2B mutation is characterised by neuronal lysosomal storage pathology
We report that mice which express FTD-causative mutant CHMP2B at physiological levels develop a novel lysosomal storage pathology characterised by large neuronal autofluorescent aggregates. The aggregates are an early and progressive pathology that occur at 3 months of age and increase in both size and number over time. These autofluorescent aggregates are not observed in mice expressing wild-type CHMP2B, or in non-transgenic controls, indicating that they are a specific pathology caused by mutant CHMP2B. Ultrastructural analysis and immuno- gold labelling confirmed that they are derived from the endolysosomal syst...
Source: Acta Neuropathologica - September 10, 2015 Category: Neurology Source Type: research

Cerebellar c9RAN proteins associate with clinical and neuropathological characteristics of C9ORF72 repeat expansion carriers
Abstract Clinical and neuropathological characteristics associated with G4C2 repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, are highly variable. To gain insight on the molecular basis for the heterogeneity among C9ORF72 mutation carriers, we evaluated associations between features of disease and levels of two abundantly expressed “c9RAN proteins” produced by repeat-associated non-ATG (RAN) translation of the expanded repeat. For these studies, we took a departure from traditional immuno...
Source: Acta Neuropathologica - September 8, 2015 Category: Neurology Source Type: research

A 30-unit hexanucleotide repeat expansion in C9orf72 induces pathological lesions with dipeptide-repeat proteins and RNA foci, but not TDP-43 inclusions and clinical disease
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - September 7, 2015 Category: Neurology Source Type: research

Erratum to: Vascular endothelial growth factor induces contralesional corticobulbar plasticity and functional neurological recovery in the ischemic brain
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - September 4, 2015 Category: Neurology Source Type: research

Progressive multifocal leukoencephalopathy and immune reconstitution inflammatory syndrome (IRIS)
Abstract Progressive multifocal leukoencephalopathy is a viral encephalitis induced by the John Cunningham (JC) virus, an ubiquitous neurotropic papovavirus of the genus polyomavirus that in healthy people in latency resides in kidney and bone marrow cells. Activation and entry into the CNS were first seen in patients with malignancies of the hematopoietic system and an impaired immune system. During the 1980 and the 1990s with the appearance of human immunodeficiency virus infection in humans, PML was found to be the most important opportunistic infection of the central nervous system. As a result of highly effic...
Source: Acta Neuropathologica - August 31, 2015 Category: Neurology Source Type: research

Genetic, epigenetic, and molecular landscapes of multifocal and multicentric glioblastoma
Abstract Ten to twenty percent of newly diagnosed glioblastoma (GBM) patients initially present with multiple lesions, termed multifocal or multicentric GBM (M-GBM). The prognosis of these patients is poorer than that of solitary GBM (S-GBM) patients. However, it is unknown whether multifocality has a genetic, epigenetic, or molecular basis. Here, we identified the genetic and epigenetic characteristics of M-GBM by performing a comprehensive analysis of multidimensional data, including imaging, genetic, epigenetic, and gene expression profiles, from 30 M-GBM cases in The Cancer Genome Atlas database and compa...
Source: Acta Neuropathologica - August 31, 2015 Category: Neurology Source Type: research

Rab1-dependent ER–Golgi transport dysfunction is a common pathogenic mechanism in SOD1, TDP-43 and FUS-associated ALS
Abstract Several diverse proteins are linked genetically/pathologically to neurodegeneration in amyotrophic lateral sclerosis (ALS) including SOD1, TDP-43 and FUS. Using a variety of cellular and biochemical techniques, we demonstrate that ALS-associated mutant TDP-43, FUS and SOD1 inhibit protein transport between the endoplasmic reticulum (ER) and Golgi apparatus in neuronal cells. ER–Golgi transport was also inhibited in embryonic cortical and motor neurons obtained from a widely used animal model (SOD1G93A mice), validating this mechanism as an early event in disease. Each protein inhibited transport by ...
Source: Acta Neuropathologica - August 23, 2015 Category: Neurology Source Type: research

Regional mosaic genomic heterogeneity in the elderly and in Alzheimer’s disease as a correlate of neuronal vulnerability
Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by fibrillary aggregates of Aβ peptide and tau protein. The distribution of these pathological hallmarks throughout the brain is not random; it follows a predictive pattern that is used for pathological staging. However, most etiopathogenetic concepts, irrespective of whether they focus on Aβ or tau pathology, leave a key question unanswered: what is the explanation for the different vulnerabilities of brain regions in AD? The pattern of regional progression of neurofibrillary degeneration in AD to some extent inversely...
Source: Acta Neuropathologica - August 23, 2015 Category: Neurology Source Type: research

Astrocyte pathology in Alexander disease causes a marked inflammatory environment
Abstract Astrocytes and microglia are commonly involved in a wide variety of CNS pathologies. However, they are typically involved in a secondary response in which many cell types are affected simultaneously and therefore it is difficult to know their contributions to the pathology. Here, we show that pathological astrocytes in a mouse model of Alexander disease (AxD; GFAP Tg;Gfap +/R236H) cause a pronounced immune response. We have studied the inflammatory response in the hippocampus and spinal cord of these mice and have found marked microglial activation, which follows that of astroc...
Source: Acta Neuropathologica - August 22, 2015 Category: Neurology Source Type: research

Erratum to: Distribution of dipeptide repeat proteins in cellular models and C9orf72 mutation cases suggests link to transcriptional silencing
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - August 20, 2015 Category: Neurology Source Type: research

A clinicopathologic study of diencephalic pediatric low-grade gliomas with BRAF V600 mutation
Abstract Among brain tumors, the BRAF V600E mutation is frequently associated with pleomorphic xanthoastrocytomas (PXAs) and gangliogliomas (GGs). This oncogenic mutation is also detected in ~5 % of other pediatric low-grade gliomas (LGGs) including pilocytic astrocytomas (PAs) and diffuse astrocytomas. In the current multi-institutional study of 56 non-PXA/non-GG diencephalic pediatric LGGs, the BRAF V600 mutation rate is 36 %. V600-mutant tumors demonstrate a predilection for infants and young children (
Source: Acta Neuropathologica - August 12, 2015 Category: Neurology Source Type: research

Inflammatory neuropathies: pathology, molecular markers and targets for specific therapeutic intervention
Abstract Inflammatory neuropathies encompass groups of heterogeneous disorders characterized by pathogenic immune-mediated hematogenous leukocyte infiltration of peripheral nerves, nerve roots or both, with resultant demyelination or axonal degeneration or both. Inflammatory neuropathies may be divided into three major disease categories: Guillain–Barré syndrome (particularly the acute inflammatory demyelinating polyradiculoneuropathy variant), chronic inflammatory demyelinating polyradiculoneuropathy and nonsystemic vasculitic neuropathy (or peripheral nerve vasculitis). Despite major advances in mol...
Source: Acta Neuropathologica - August 12, 2015 Category: Neurology Source Type: research

High frequency of H3F3A K27M mutations characterizes pediatric and adult high-grade gliomas of the spinal cord
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - August 1, 2015 Category: Neurology Source Type: research

The unfolded protein response in neurodegenerative diseases: a neuropathological perspective
Abstract The unfolded protein response (UPR) is a stress response of the endoplasmic reticulum (ER) to a disturbance in protein folding. The so-called ER stress sensors PERK, IRE1 and ATF6 play a central role in the initiation and regulation of the UPR. The accumulation of misfolded and aggregated proteins is a common characteristic of neurodegenerative diseases. With the discovery of the basic machinery of the UPR, the idea was born that the UPR or part of its machinery could be involved in neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and prio...
Source: Acta Neuropathologica - July 25, 2015 Category: Neurology Source Type: research

Functional recovery in new mouse models of ALS/FTLD after clearance of pathological cytoplasmic TDP-43
Abstract Accumulation of phosphorylated cytoplasmic TDP-43 inclusions accompanied by loss of normal nuclear TDP-43 in neurons and glia of the brain and spinal cord are the molecular hallmarks of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). However, the role of cytoplasmic TDP-43 in the pathogenesis of these neurodegenerative TDP-43 proteinopathies remains unclear, due in part to a lack of valid mouse models. We therefore generated new mice with doxycycline (Dox)-suppressible expression of human TDP-43 (hTDP-43) harboring a defective nuclear localization signal (∆NLS) unde...
Source: Acta Neuropathologica - July 21, 2015 Category: Neurology Source Type: research

TERT promoter mutations in primary central nervous system lymphoma are associated with spatial distribution in the splenium
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - July 20, 2015 Category: Neurology Source Type: research

Somatostatin receptor 2a is a more sensitive diagnostic marker of meningioma than epithelial membrane antigen
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - July 20, 2015 Category: Neurology Source Type: research

Tau pathology spread in PS19 tau transgenic mice following locus coeruleus (LC) injections of synthetic tau fibrils is determined by the LC’s afferent and efferent connections
Abstract Filamentous tau inclusions are hallmarks of Alzheimer’s disease (AD) and other neurodegenerative tauopathies. An increasing number of studies implicate the cell-to-cell propagation of tau pathology in the progression of tauopathies. We recently showed (Iba et al., J Neurosci 33:1024–1037, 2013) that inoculation of preformed synthetic tau fibrils (tau PFFs) into the hippocampus of young transgenic (Tg) mice (PS19) overexpressing human P301S mutant tau induced robust tau pathology in anatomically connected brain regions including the locus coeruleus (LC). Since Braak and colleagues hypothesized ...
Source: Acta Neuropathologica - July 7, 2015 Category: Neurology Source Type: research

Nrf2 and beyond: deciphering the mode of action of fumarates in the inflamed central nervous system
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - June 30, 2015 Category: Neurology Source Type: research

A clinicopathologic study of 11 rosette-forming meningiomas: a rare and potentially confusing pattern
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - June 24, 2015 Category: Neurology Source Type: research

Screening for α-synuclein immunoreactive neuronal inclusions in the hippocampus allows identification of atypical MSA (FTLD-synuclein)
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - June 21, 2015 Category: Neurology Source Type: research

Localization of SHH medulloblastoma in mice depends on the age at its initiation
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - June 20, 2015 Category: Neurology Source Type: research

Cell type-specific Nrf2 expression in multiple sclerosis lesions
In this study, we show that Nrf2 is already strongly up-regulated in active MS lesions. Nuclear Nrf2 expression was particularly observed in oligodendrocytes and its functional activity is indicated by the expression of one of its downstream targets (heme oxygenase 1) in the same cells. In contrast, only a minor number of Nrf2-positive neurons were detected, even in highly inflammatory cortical lesions presenting with extensive oxidative injury. Overall, the most pronounced Nrf2 expression was found in degenerating cells, which showed signs of apoptotic or necrotic cell death. Via whole-genome microarray analyses of MS les...
Source: Acta Neuropathologica - June 19, 2015 Category: Neurology Source Type: research

Adult IDH wild type astrocytomas biologically and clinically resolve into other tumor entities
Abstract IDH wild type (IDHwt) anaplastic astrocytomas WHO grade III (AA III) are associated with poor outcome. To address the possibilities of molecular subsets among astrocytoma or of diagnostic reclassification, we analyzed a series of 160 adult IDHwt tumors comprising 120 AA III and 40 diffuse astrocytomas WHO grade II (A II) for molecular hallmark alterations and established methylation and copy number profiles. Based on molecular profiles and hallmark alterations the tumors could be grouped into four major sets. 124/160 (78 %) tumors were diagnosed as the molecular equivalent of conventional ...
Source: Acta Neuropathologica - June 19, 2015 Category: Neurology Source Type: research

Distribution of dipeptide repeat proteins in cellular models and C9orf72 mutation cases suggests link to transcriptional silencing
Abstract A massive expansion of a GGGGCC repeat upstream of the C9orf72 coding region is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. Despite its intronic localization and lack of a canonical start codon, both strands are translated into aggregating dipeptide repeat (DPR) proteins: poly-GA, poly-GP, poly-GR, poly-PR and poly-PA. To address conflicting findings on the predominant toxicity of the different DPR species in model systems, we compared the expression pattern of the DPR proteins in rat primary neurons and postmortem brain and spinal cord of C9orf72 mutation pat...
Source: Acta Neuropathologica - June 18, 2015 Category: Neurology Source Type: research

A new dopaminergic nigro-olfactory projection
Abstract Parkinson disease (PD) is a neurodegenerative disorder characterized by massive loss of midbrain dopaminergic neurons. Whereas onset of motor impairments reflects a rather advanced stage of the disorder, hyposmia often marks the beginning of the disease. Little is known about the role of the nigro-striatal system in olfaction under physiological conditions and the anatomical basis of hyposmia in PD. Yet, the early occurrence of olfactory dysfunction implies that pathogens such as environmental toxins could incite the disease via the olfactory system. In the present study, we demonstrate a dopaminergic inn...
Source: Acta Neuropathologica - June 14, 2015 Category: Neurology Source Type: research

Analyzing dendritic spine pathology in Alzheimer’s disease: problems and opportunities
Abstract Synaptic failure is an immediate cause of cognitive decline and memory dysfunction in Alzheimer’s disease. Dendritic spines are specialized structures on neuronal processes, on which excitatory synaptic contacts take place and the loss of dendritic spines directly correlates with the loss of synaptic function. Dendritic spines are readily accessible for both in vitro and in vivo experiments and have, therefore, been studied in great detail in Alzheimer’s disease mouse models. To date, a large number of different mechanisms have been proposed to cause dendritic spine dysfunction and loss in Alz...
Source: Acta Neuropathologica - June 11, 2015 Category: Neurology Source Type: research

FTD/ALS-associated poly(GR) protein impairs the Notch pathway and is recruited by poly(GA) into cytoplasmic inclusions
Abstract C9ORF72 repeat expansion is the most common genetic mutation in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Abnormal dipeptide repeat proteins (DPRs) generated from repeat-associated non-AUG (RAN) translation of repeat-containing RNAs are thought to be pathogenic; however, the mechanisms are unknown. Here we report that (GR)80 and (PR)80 are toxic in neuronal and non-neuronal cells in Drosophila. In contrast to reported shorter poly(GR) forms, (GR)80 is mostly localized throughout the cytosol without detectable accumulation in the nucleolus, accompanied by suppression...
Source: Acta Neuropathologica - June 1, 2015 Category: Neurology Source Type: research

Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy
Abstract Diabetic neuropathy (DNP), afflicting sensory and motor nerve fibers, is a major complication in diabetes. The underlying cellular mechanisms of axon degeneration are poorly understood. IGFBP5, an inhibitory binding protein for insulin-like growth factor 1 (IGF1) is highly up-regulated in nerve biopsies of patients with DNP. We investigated the pathogenic relevance of this finding in transgenic mice overexpressing IGFBP5 in motor axons and sensory nerve fibers. These mice develop motor axonopathy and sensory deficits similar to those seen in DNP. Motor axon degeneration was also observed in mice in which ...
Source: Acta Neuropathologica - May 30, 2015 Category: Neurology Source Type: research

Semi-automated quantification of C9orf72 expansion size reveals inverse correlation between hexanucleotide repeat number and disease duration in frontotemporal degeneration
Abstract We investigated whether chromosome 9 open reading frame 72 hexanucleotide repeat expansion (C9orf72 expansion) size in peripheral DNA was associated with clinical differences in frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) linked to C9orf72 repeat expansion mutations. A novel quantification workflow was developed to measure C9orf72 expansion size by Southern blot densitometry in a cross-sectional cohort of C9orf72 expansion carriers with FTD (n = 39), ALS (n = 33), both (n = 35), or who are unaffected (n = 21). Multivariate linear regres...
Source: Acta Neuropathologica - May 29, 2015 Category: Neurology Source Type: research

The influence of PRNP polymorphisms on human prion disease susceptibility: an update
Abstract Two normally occurring polymorphisms of the human PRNP gene, methionine (M)/valine (V) at codon 129 and glutamic acid (E)/lysine (K) at codon 219, can affect the susceptibility to prion diseases. It has long been recognized that 129M/M homozygotes are overrepresented in sporadic Creutzfeldt–Jakob disease (CJD) patients and variant CJD patients, whereas 219E/K heterozygotes are absent in sporadic CJD patients. In addition to these pioneering findings, recent progress in experimental transmission studies and worldwide surveillance of prion diseases have identified novel relationships between the PRNP ...
Source: Acta Neuropathologica - May 29, 2015 Category: Neurology Source Type: research

Inefficient induction and spread of seeded tau pathology in P301L mouse model of tauopathy suggests inherent physiological barriers to transmission
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 15, 2015 Category: Neurology Source Type: research

Diffusely infiltrating astrocytomas: pathology, molecular mechanisms and markers
Abstract Diffusely infiltrating astrocytomas include diffuse astrocytomas WHO grade II and anaplastic astrocytomas WHO grade III and are classified under astrocytic tumours according to the current WHO Classification. Although the patients generally have longer survival as compared to those with glioblastoma, the timing of inevitable malignant progression ultimately determines the prognosis. Recent advances in molecular genetics have uncovered that histopathologically diagnosed astrocytomas may consist of two genetically different groups of tumours. The majority of diffusely infiltrating astrocytomas regardless of...
Source: Acta Neuropathologica - May 15, 2015 Category: Neurology Source Type: research

Dysregulation of locus coeruleus development in congenital central hypoventilation syndrome
Abstract Human congenital central hypoventilation syndrome (CCHS), resulting from mutations in transcription factor PHOX2B, manifests with impaired responses to hypoxemia and hypercapnia especially during sleep. To identify brainstem structures developmentally affected in CCHS, we analyzed two postmortem neonatal-lethal cases with confirmed polyalanine repeat expansion (PARM) or Non-PARM (PHOX2B∆8) mutation of PHOX2B. Both human cases showed neuronal losses within the locus coeruleus (LC), which is important for central noradrenergic signaling. Using a conditionally active transgenic mouse model of the PHOX2B∆...
Source: Acta Neuropathologica - May 15, 2015 Category: Neurology Source Type: research

Atypical multiple system atrophy is a new subtype of frontotemporal lobar degeneration: frontotemporal lobar degeneration associated with α-synuclein
In this study, we describe four patients with atypical MSA with clinical features consistent with frontotemporal dementia (FTD), including two with corticobasal syndrome, one with progressive non-fluent aphasia, and one with behavioral variant FTD. None had autonomic dysfunction. All had frontotemporal atrophy and severe limbic α-synuclein neuronal pathology. The neuronal inclusions were heterogeneous, but included Pick body-like inclusions. The latter were strongly associated with neuronal loss in the hippocampus and amygdala. Unlike typical Pick bodies, the neuronal inclusions were positive on Gallyas silver stain ...
Source: Acta Neuropathologica - May 12, 2015 Category: Neurology Source Type: research

IDH mutant diffuse and anaplastic astrocytomas have similar age at presentation and little difference in survival: a grading problem for WHO
Abstract The WHO 2007 classification of tumors of the CNS distinguishes between diffuse astrocytoma WHO grade II (A IIWHO2007) and anaplastic astrocytoma WHO grade III (AA III WHO2007). Patients with A II WHO2007 are significantly younger and survive significantly longer than those with AA III WHO2007. So far, classification and grading relies on morphological grounds only and does not yet take into account IDH status, a molecular marker of prognostic relevance. We here demonstrate that WHO 2007 grading performs poorly in predicting prognosis when applied to astrocytoma carrying IDH mutations. Three independent se...
Source: Acta Neuropathologica - May 12, 2015 Category: Neurology Source Type: research

Pathology, molecular mechanisms and markers of gliomas: new insight and new challenges
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 12, 2015 Category: Neurology Source Type: research

Microglia inflict delayed brain injury after subarachnoid hemorrhage
Abstract Inflammatory changes have been postulated to contribute to secondary brain injury after aneurysmal subarachnoid hemorrhage (SAH). In human specimens after SAH as well as in experimental SAH using mice, we show an intracerebral accumulation of inflammatory cells between days 4 and 28 after the bleeding. Using bone marrow chimeric mice allowing tracing of all peripherally derived immune cells, we confirm a truly CNS-intrinsic, microglial origin of these immune cells, exhibiting an inflammatory state, and rule out invasion of myeloid cells from the periphery into the brain. Furthermore, we detect secondary n...
Source: Acta Neuropathologica - May 8, 2015 Category: Neurology Source Type: research

Capillaries in the olfactory bulb but not the cortex are highly susceptible to virus-induced vascular leak and promote viral neuroinvasion
In this study, we examined neuroinvasion of the mosquito-borne bunyavirus La Crosse (LACV), the leading cause of pediatric viral encephalitis in the USA. We found that the olfactory bulb (OB) and tract were the initial areas of CNS virus infection in mice. Removal of the OB reduced the incidence of LACV-induced disease demonstrating the importance of this area to neuroinvasion. However, we determined that infection of the OB was not due to axonal transport of virus from olfactory sensory neurons as ablation of these cells did not affect viral pathogenesis. Instead, we found that OB capillaries were compromised allowin...
Source: Acta Neuropathologica - May 8, 2015 Category: Neurology Source Type: research

Decreased orexin (hypocretin) immunoreactivity in the hypothalamus and pontine nuclei in sudden infant death syndrome
This study examined the immunoreactivity of orexin (OxA and OxB) in the tuberal hypothalamus (n = 27) and the pons (n = 15) of infants (1–10 months) who died from SIDS compared to age-matched non-SIDS infants. The percentage of orexin immunoreactive neurons and the total number of neurons were quantified in the dorsomedial, perifornical and lateral hypothalamus at three levels of the tuberal hypothalamus. In the pons, the area of orexin immunoreactive fibres were quantified in the locus coeruleus (LC), dorsal raphe (DR), laterodorsal tegmental (LDT), medial parabrachial, dorsal tegmental (DTg...
Source: Acta Neuropathologica - May 8, 2015 Category: Neurology Source Type: research

Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease
In conclusion, we highlight TBK1 as an important cause of pure FTLD-TDP, identify the first OPTN mutations in FTLD-TDP, and suggest a potential oligogenic basis for at least a subset of FTLD-TDP patients. Our data further add to the growing body of evidence linking ALS and FTD and suggest a key role for the OPTN/TBK1 pathway in these diseases. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 6, 2015 Category: Neurology Source Type: research

Oligodendroglioma: pathology, molecular mechanisms and markers
Abstract For nearly a century, the diagnosis and grading of oligodendrogliomas and oligoastrocytomas has been based on histopathology alone. Roughly 20 years ago, the first glioma-associated molecular signature was found with complete chromosome 1p and 19q codeletion being particularly common in histologically classic oligodendrogliomas. Subsequently, this codeletion appeared to not only carry diagnostic, but also prognostic and predictive information, the latter aspect only recently resolved after carefully constructed clinical trials with very long follow-up times. More recently described biomarkers, includ...
Source: Acta Neuropathologica - May 6, 2015 Category: Neurology Source Type: research

Non-steroidal anti-inflammatory drug indometacin enhances endogenous remyelination
Abstract Multiple sclerosis is the most frequent demyelinating disease in the CNS that is characterized by inflammatory demyelinating lesions and axonal loss, the morphological correlate of permanent clinical disability. Remyelination does occur, but is limited especially in chronic disease stages. Despite effective immunomodulatory therapies that reduce the number of relapses the progressive disease phase cannot be prevented. Therefore, promotion of neuroprotective and repair mechanisms, such as remyelination, represents an attractive additional treatment strategy. A number of pathways have been identified that m...
Source: Acta Neuropathologica - May 6, 2015 Category: Neurology Source Type: research

Beta-amyloid deposition in chronic traumatic encephalopathy
Abstract Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive mild traumatic brain injury. It is defined pathologically by the abnormal accumulation of tau in a unique pattern that is distinct from other tauopathies, including Alzheimer’s disease (AD). Although trauma has been suggested to increase amyloid β peptide (Aβ) levels, the extent of Aβ deposition in CTE has not been thoroughly characterized. We studied a heterogeneous cohort of deceased athletes and military veterans with neuropathologically diagnosed CTE (n = 114, mean age at dea...
Source: Acta Neuropathologica - May 6, 2015 Category: Neurology Source Type: research