Pathogenic implications of cerebrospinal fluid barrier pathology in neuromyelitis optica
AbstractPathogenic autoantibodies associated with neuromyelitis optica (NMO) induce disease by targeting aquaporin-4 (AQP4) water channels enriched on astrocytic endfeet at blood –brain interfaces. AQP4 is also expressed at cerebrospinal fluid (CSF)–brain interfaces, such as the pial glia limitans and the ependyma and at the choroid plexus blood–CSF barrier. However, little is known regarding pathology at these sites in NMO. Therefore, we evaluated AQP4 expression, mic roglial reactivity, and complement deposition at pial and ependymal surfaces and in the fourth ventricle choroid plexus in 23 autopsy case...
Source: Acta Neuropathologica - February 9, 2017 Category: Neurology Source Type: research

Dermal phospho-alpha-synuclein deposits confirm REM sleep behaviour disorder as prodromal Parkinson ’s disease
AbstractPhosphorylated alpha-synuclein (p-alpha-syn) deposits, one of the neuropathological hallmarks of Parkinson ’s disease (PD), have recently been detected in dermal nerve fibres in PD patients with good specificity and sensitivity. Here, we studied whether p-alpha-syn may serve as a biomarker in patients with a high risk of developing PD, such as those with REM sleep behaviour disorder (RBD). We compared the presence and distribution of p-alpha-syn deposits in dermal nerve fibres in 18 patients with RBD, 25 patients with early PD and 20 normal controls. Skin biopsy was taken at C7, Th10, and the upper and lower ...
Source: Acta Neuropathologica - February 8, 2017 Category: Neurology Source Type: research

Tau aggregation influences cognition and hippocampal atrophy in the absence of beta-amyloid: a clinico-imaging-pathological study of primary age-related tauopathy (PART)
AbstractWe investigate whether there is any association between the Braak neurofibrillary tangle (NFT) stage and clinical and MRI features in definite primary age-related tauopathy (PART). We analysed 52 cases with a Braak NFT tangle stage>0 and  ≤IV, and a Thal phase of 0 (no beta-amyloid present). Twenty-nine (56%) were female. Median age at death was 88 years (IQR 82–92 years). Fifteen (29%) were TDP-positive (75% TDP stage I), 16 (31%) had argyrophilic grain disease and three (6%) had alpha-synuclein-positive Lewy bodies. TDP-43 inclusion when present were rare and predominantly perivascular....
Source: Acta Neuropathologica - February 3, 2017 Category: Neurology Source Type: research

Marginal vitamin A deficiency facilitates Alzheimer ’s pathogenesis
AbstractDeposition of amyloid β protein (Aβ) to form neuritic plaques in the brain is the unique pathological hallmark of Alzheimer’s disease (AD). Aβ is derived from amyloid β precursor protein (APP) by β- and γ-secretase cleavages and turned over by glia in the central nervous system (CNS). Vitamin A deficiency (VAD) h as been shown to affect cognitive functions. Marginal vitamin A deficiency (MVAD) is a serious and widespread public health problem among pregnant women and children in developing countries. However, the role of MVAD in the pathogenesis of AD remains elusive. Our study ...
Source: Acta Neuropathologica - January 27, 2017 Category: Neurology Source Type: research

Global epigenetic profiling identifies methylation subgroups associated with recurrence-free survival in meningioma
AbstractMeningioma is the most common primary brain tumor and carries a substantial risk of local recurrence. Methylation profiles of meningioma and their clinical implications are not well understood. We hypothesized that aggressive meningiomas have unique DNA methylation patterns that could be used to better stratify patient management. Samples (n = 140) were profiled using the Illumina HumanMethylation450BeadChip. Unsupervised modeling on a training set (n = 89) identified 2 molecular methylation subgroups of meningioma (MM) with significantly different recurrence-free survival (RFS) times between th...
Source: Acta Neuropathologica - January 27, 2017 Category: Neurology Source Type: research

Expansion of the classification of FTLD-TDP: distinct pathology associated with rapidly progressive frontotemporal degeneration
AbstractFrontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) can typically be categorized into one of four distinct histopathologic patterns of TDP-43 pathology, types A to D. The strength of this histopathologic classification lies in the association between FTLD-TDP subtypes and various clinical and genetic features of disease. Seven cases of FTLD-TDP were identified here which were difficult to classify based on existing pathologic criteria. Distinct features common to these cases included TDP-43 aggregates over a wide neuroanatomic distribution comprised of granulofilamentous neuronal inclusions, abundan...
Source: Acta Neuropathologica - January 27, 2017 Category: Neurology Source Type: research

Pan-mutant IDH1 inhibitor BAY 1436032 for effective treatment of IDH1 mutant astrocytoma in vivo
In conclusion, we developed a pan-inhibitor targeting tumors with different IDH1R132 mutations. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - January 25, 2017 Category: Neurology Source Type: research

Dimethyl fumarate accelerates peripheral nerve regeneration via activation of the anti-inflammatory and cytoprotective Nrf2/HO-1 signaling pathway
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - January 20, 2017 Category: Neurology Source Type: research

Damaged reward areas in human alcoholics: neuronal proportion decline and astrocyte activation
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - January 17, 2017 Category: Neurology Source Type: research

Hyperphosphorylated tau causes reduced hippocampal CA1 excitability by relocating the axon initial segment
AbstractHyperphosphorylated tau has a critical role in tauopathies such as Alzheimer ’s disease and frontotemporal dementia, impairing neuronal function and eventually leading to neurodegeneration. A critical role for tau is supported by studies in transgenic mouse models that express the P301L tau mutation found in cases of familial frontotemporal dementia, with the accumulation of hyperphosphorylated tau in the hippocampus causing reductions in hippocampal long-term potentiation and impairments in spatial learning and memory. However, what has remained unexplored is the role of hyperphosphorylated tau in reducing n...
Source: Acta Neuropathologica - January 16, 2017 Category: Neurology Source Type: research

Prion disease: experimental models and reality
AbstractThe understanding of the pathogenesis and mechanisms of diseases requires a multidisciplinary approach, involving clinical observation, correlation to pathological processes, and modelling of disease mechanisms. It is an inherent challenge, and arguably impossible to generate model systems that can faithfully recapitulate all aspects of human disease. It is, therefore, important to be aware of the potentials and also the limitations of specific model systems. Model systems are usually designed to recapitulate only specific aspects of the disease, such as a pathological phenotype, a pathomechanism, or to test a hypo...
Source: Acta Neuropathologica - January 13, 2017 Category: Neurology Source Type: research

Tau interactome mapping  based identification of Otub1 as Tau deubiquitinase involved in accumulation of pathological Tau forms in vitro and in vivo
AbstractDysregulated proteostasis is a key feature of a variety of neurodegenerative disorders. In Alzheimer ’s disease (AD), progression of symptoms closely correlates with spatiotemporal progression of Tau aggregation, with “early” oligomeric Tau forms rather than mature neurofibrillary tangles (NFTs) considered to be pathogenetic culprits. The ubiquitin–proteasome system (UPS) controls degradati on of soluble normal and abnormally folded cytosolic proteins. The UPS is affected in AD and is identified by genomewide association study (GWAS) as a risk pathway for AD. The UPS is determined by balance...
Source: Acta Neuropathologica - January 12, 2017 Category: Neurology Source Type: research

Genome-wide methylation profiles in primary intracranial germ cell tumors indicate a primordial germ cell origin for germinomas
AbstractIntracranial germ cell tumors (iGCTs) are the second most common brain tumors among children under 14 in Japan. The World Health Organization classification recognizes several subtypes of iGCTs, which are conventionally subclassified into pure germinoma or non-germinomatous GCTs. Recent exhaustive genomic studies showed that mutations of the genes involved in the MAPK and/or PI3K pathways are common in iGCTs; however, the mechanisms of how different subtypes develop, often as a mixed-GCT, are unknown. To elucidate the pathogenesis of iGCTs, we investigated 61 GCTs of various subtypes by genome-wide DNA methylation ...
Source: Acta Neuropathologica - January 11, 2017 Category: Neurology Source Type: research

Glioma: experimental models and reality
AbstractIn theory, in vitro and in vivo models for human gliomas have great potential to not only enhance our understanding of glioma biology, but also to facilitate the development of novel treatment strategies for these tumors. For reliable prediction and validation of the effects of different therapeutic modalities, however, glioma models need to comply with specific and more strict demands than other models of cancer, and these demands are directly related to the combination of genetic aberrations and the specific brain micro-environment gliomas grow in. This review starts with a brief introduction on the pathological ...
Source: Acta Neuropathologica - January 10, 2017 Category: Neurology Source Type: research

Experimental models of neurological disease: neuropathology determines what is virtual reality, science or fiction
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - January 10, 2017 Category: Neurology Source Type: research

Opposing effects of progranulin deficiency on amyloid and tau pathologies via microglial TYROBP network
AbstractProgranulin (PGRN) is implicated in Alzheimer ’s disease (AD) as well as frontotemporal lobar degeneration. Genetic studies demonstrate an association of the commonGRN rs5848 variant that results in reduced PGRN levels with increased risk for AD. However, the mechanisms by which PGRN reduction from theGRN AD risk variant or mutation exacerbates AD pathophysiology remain ill defined. Here, we show that theGRN AD risk variant has no significant effects on florbetapir positron emission tomographic amyloid imaging and cerebrospinal fluid (CSF) A β levels, whereas it is associated with increased CSF tau level...
Source: Acta Neuropathologica - January 9, 2017 Category: Neurology Source Type: research

Incipient progressive supranuclear palsy is more common than expected and may comprise clinicopathological subtypes: a forensic autopsy series
AbstractWe investigated 998 serial Japanese forensic autopsy cases (0 –101 years old, mean age 61.7 ± 21.9), with no case selection, using immunohistochemistry to detect cases with progressive supranuclear palsy (PSP). Twenty-nine cases (mean age 82.3 ± 7.2 years, 11 males, 18 females) fulfilled the National Institute of Neuronal Disorders and Stroke (NINDS) -PSP pathological criteria (2.9% of all cases, 4.6% of cases over 60). All had neuronal and glial inclusions in the basal ganglia and brainstem. However, 13 cases had low tau pathology and were categorized as atypical P...
Source: Acta Neuropathologica - January 7, 2017 Category: Neurology Source Type: research

Ischemic stroke: experimental models and reality
AbstractThe vast majority of cerebral stroke cases are caused by transient or permanent occlusion of a cerebral blood vessel ( “ischemic stroke”) eventually leading to brain infarction. The final infarct size and the neurological outcome depend on a multitude of factors such as the duration and severity of ischemia, the existence of collateral systems and an adequate systemic blood pressure, etiology and localization of the infarct, but also on age, sex, comorbidities with the respective multimedication and genetic background. Thus, ischemic stroke is a highly complex and heterogeneous disorder. It is immediate...
Source: Acta Neuropathologica - January 7, 2017 Category: Neurology Source Type: research

ALS/FTLD: experimental models and reality
AbstractAmyotrophic lateral sclerosis is characterised by a loss of upper and lower motor neurons and characteristic muscle weakness and wasting, the most common form being sporadic disease with neuronal inclusions containing the tar DNA-binding protein 43 (TDP-43). Frontotemporal lobar degeneration is characterised by atrophy of the frontal and/or temporal lobes, the most common clinical form being the behavioural variant, in which neuronal inclusions containing either TDP-43 or 3-repeat tau are most prevalent. Although the genetic mutations associated with these diseases have allowed various experimental models to be dev...
Source: Acta Neuropathologica - January 5, 2017 Category: Neurology Source Type: research

Genome-wide DNA methylation profiling identifies primary central nervous system lymphoma as a distinct entity different from systemic diffuse large B-cell lymphoma
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - January 5, 2017 Category: Neurology Source Type: research

A driver role for GABA metabolism in controlling stem and proliferative cell state through GHB production in glioma
AbstractCell populations with differing proliferative, stem-like and tumorigenic states co-exist in most tumors and especially malignant gliomas. Whether metabolic variations can drive this heterogeneity by controlling dynamic changes in cell states is unknown. Metabolite profiling of human adult glioblastoma stem-like cells upon loss of their tumorigenicity revealed a switch in the catabolism of the GABA neurotransmitter toward enhanced production and secretion of its by-product GHB (4-hydroxybutyrate). This switch was driven by succinic semialdehyde dehydrogenase (SSADH) downregulation. Enhancing GHB levels via SSADH dow...
Source: Acta Neuropathologica - December 28, 2016 Category: Neurology Source Type: research

Alzheimer ’s disease: experimental models and reality
AbstractExperimental models of Alzheimer ’s disease (AD) are critical to gaining a better understanding of pathogenesis and to assess the potential of novel therapeutic approaches. The most commonly used experimental animal models are transgenic mice that overexpress human genes associated with familial AD (FAD) that result in the format ion of amyloid plaques. However, AD is defined by the presence and interplay of both amyloid plaques and neurofibrillary tangle pathology. The track record of success in AD clinical trials thus far has been very poor. In part, this high failure rate has been related to the premature ...
Source: Acta Neuropathologica - December 26, 2016 Category: Neurology Source Type: research

Brain-to-stomach transfer of α-synuclein via vagal preganglionic projections
AbstractDetection of α-synuclein lesions in peripheral tissues is a feature of human synucleinopathies of likely pathogenetic relevance and bearing important clinical implications. Experiments were carried out to elucidate the relationship between α-synuclein accumulation in the brain and in peripheral organs, and to identify potential pathways involved in long-distance protein transfer. Results of this in vivo study revealed a route-specific transmission of α-synuclein from the rat brain to the stomach. Following targeted midbrain overexpression of human α-synuclein, the exogenous protein was capab...
Source: Acta Neuropathologica - December 23, 2016 Category: Neurology Source Type: research

Dihydropyridine receptor (DHPR, CACNA1S ) congenital myopathy
We describe a cohort of 11 patients from 7 families presenting with perinatal hypotonia, severe axial and generalized weakness. Ophthalmoplegia is present in four patients. The analysis of muscle biopsies demonstrated a characteristic intermyofibrillar network due to SR dilatation, internal nuclei, and areas of myofibrillar disorganization in some samples. Exome sequencing revealed ten recessive or dominant mutations inCACNA1S (Cav1.1), the pore-forming subunit of DHPR in skeletal muscle. Both recessive and dominant mutations correlated with a consistent phenotype, a decrease in protein level, and with a major impairment o...
Source: Acta Neuropathologica - December 23, 2016 Category: Neurology Source Type: research

Tauroursodeoxycholic bile acid arrests axonal degeneration by inhibiting the unfolded protein response in X-linked adrenoleukodystrophy
AbstractThe activation of the highly conserved unfolded protein response (UPR) is prominent in the pathogenesis of the most prevalent neurodegenerative disorders, such as Alzheimer ’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), which are classically characterized by an accumulation of aggregated or misfolded proteins. This activation is orchestrated by three endoplasmic reticulum (ER) stress sensors: PERK, ATF6 and IRE1. These sensors tr ansduce signals that induce the expression of the UPR gene programme. Here, we first identified an early activator of the UPR and investigat...
Source: Acta Neuropathologica - December 21, 2016 Category: Neurology Source Type: research

Histones facilitate α-synuclein aggregation during neuronal apoptosis
This study provides new clues to the mechanism underlying initial pathological aggregation of αS in PD and related disorders, and could lead to novel diagnostic and therapeutic approaches. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - December 21, 2016 Category: Neurology Source Type: research

Paradoxical antidepressant effects of alcohol are related to acid sphingomyelinase and its control of sphingolipid homeostasis
AbstractAlcohol is a widely consumed drug that can lead to addiction and severe brain damage. However, alcohol is also used as self-medication for psychiatric problems, such as depression, frequently resulting in depression-alcoholism comorbidity. Here, we identify the first molecular mechanism for alcohol use with the goal to self-medicate and ameliorate the behavioral symptoms of a genetically induced innate depression. An induced over-expression of acid sphingomyelinase (ASM), as was observed in depressed patients, enhanced the consumption of alcohol in a mouse model of depression. ASM hyperactivity facilitates the esta...
Source: Acta Neuropathologica - December 20, 2016 Category: Neurology Source Type: research

Gain of 12p encompassing CCND2 is associated with gemistocytic histology in IDH mutant astrocytomas
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - December 20, 2016 Category: Neurology Source Type: research

An updated histological classification system for multiple sclerosis lesions
AbstractMultiple sclerosis is a complex and heterogeneous, most likely autoimmune, demyelinating disease of the central nervous system (CNS). Although a number of histological classification systems for CNS lesions have been used by different groups in recent years, no uniform classification exists. In this paper, we propose a simple and unifying classification of MS lesions incorporating many elements of earlier histological systems that aims to provide guidelines for neuropathologists and researchers studying MS lesions to allow for better comparison of different studies performed with MS tissue, and to aid in understand...
Source: Acta Neuropathologica - December 17, 2016 Category: Neurology Source Type: research

Copy number variations as potential diagnostic and prognostic markers for CNS melanocytic neoplasms in neurocutaneous melanosis
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - December 17, 2016 Category: Neurology Source Type: research

Genome-wide, high-content siRNA screening identifies the Alzheimer ’s genetic risk factor FERMT2 as a major modulator of APP metabolism
AbstractGenome-wide association studies (GWASs) have identified 19 susceptibility loci for Alzheimer ’s disease (AD). However, understanding how these genes are involved in the pathophysiology of AD is one of the main challenges of the “post-GWAS” era. At least 123 genes are located within the 19 susceptibility loci; hence, a conventional approach (studying the genes one by one) would not be time- and cost-effective. We therefore developed a genome-wide, high-content siRNA screening approach and used it to assess the functional impact of gene under-expression on APP metabolism. We found that 832 genes mod...
Source: Acta Neuropathologica - December 8, 2016 Category: Neurology Source Type: research

Copy number abnormalities in new or progressive ‘neurocutaneous melanosis’ confirm it to be primary CNS melanoma
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - December 8, 2016 Category: Neurology Source Type: research

Announcing cIMPACT-NOW: the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - December 1, 2016 Category: Neurology Source Type: research

Tau neuropathology correlates with FDG-PET, but not AV-1451-PET, in progressive supranuclear palsy
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - November 29, 2016 Category: Neurology Source Type: research

Towards a functional pathology of hereditary neuropathies
AbstractA growing number of hereditary neuropathies have been assigned to causative gene defects in recent years. The study of human nerve biopsy samples has contributed substantially to the discovery of many of these neuropathy genes. Genotype –phenotype correlations based on peripheral nerve pathology have provided a comprehensive picture of the consequences of these mutations. Intriguingly, several gene defects lead to distinguishable lesion patterns that can be studied in nerve biopsies. These characteristic features include the loss of certain nerve fiber populations and a large spectrum of distinct structural c...
Source: Acta Neuropathologica - November 28, 2016 Category: Neurology Source Type: research

Toll-like receptor 2 is increased in neurons in Parkinson ’s disease brain and may contribute to alpha-synuclein pathology
AbstractInflammation is likely a key contributor to the pathogenesis of Parkinson ’s disease (PD), a progressively debilitating neurodegenerative disease that is accompanied by a pathological accumulation of the α-synuclein protein in a staged manner through the brain. What leads to the accumulation of α-synuclein in PD and how this relates to inflammatory pathways, however, is not entirely clear. Toll-like receptor (TLR) signaling is a major pathway mediating inflammation and, in particular, TLR2 is increasingly being implicated in PD. We have, therefore, examined the expression of TLR2 in postmortem bra...
Source: Acta Neuropathologica - November 25, 2016 Category: Neurology Source Type: research

Localized cortical chronic traumatic encephalopathy pathology after single, severe axonal injury in human brain
In this study, we analyzed postmortem brain tissues from five institutionalized patients with schizophrenia and history of surgical leucotomy with subsequent survival of at least another 40 years. Because leucotomy involves severing axons bilaterally in prefrontal cortex, this s urgical procedure represents a human model of single traumatic brain injury with severe axonal damage and no external impact. We examined cortical tissues at the leucotomy site and at both prefrontal cortex rostral and frontal cortex caudal to the leucotomy site. For comparison, we analyzed brain ti ssues at equivalent neuroanatomical sites fr...
Source: Acta Neuropathologica - November 24, 2016 Category: Neurology Source Type: research

Widespread tau seeding activity at early Braak stages
AbstractTranscellular propagation of tau aggregates may underlie the progression of pathology in Alzheimer ’s disease (AD) and other tauopathies. Braak staging (B1, B2, B3) is based on phospho-tau accumulation within connected brain regions: entorhinal cortex (B1); hippocampus/limbic system (B2); and frontal and parietal lobes (B3). We previously developed a specific and sensitive assay that uses flow cytometry to quantify tissue seeding activity based on fluorescence resonance energy transfer (FRET) in cells that stably express tau reporter proteins. In a tauopathy mouse model, we have detected seeding activity far ...
Source: Acta Neuropathologica - November 22, 2016 Category: Neurology Source Type: research

Presynaptic proteins complexin-I and complexin-II differentially influence cognitive function in early and late stages of Alzheimer ’s disease
AbstractProgressive accumulation of Alzheimer ’s disease-related pathology is associated with cognitive dysfunction. Differences in cognitive reserve may contribute to individual differences in cognitive function in the presence of comparable neuropathology. The protective effects of cognitive reserve could contribute differentially in early versus late stages of the disease. We investigated presynaptic proteins as measures of brain reserve (a subset of total cognitive reserve), and used Braak staging to estimate the progression of Alzheimer’s disease. Antemortem evaluations of cognitive function, postmortem as...
Source: Acta Neuropathologica - November 19, 2016 Category: Neurology Source Type: research

The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants
Discussion at the meeting generated a series of consensus statements and recommendations from the attendees, which comment on the prognostic evaluation and treatment decisions of patients with intracranial ependymoma (WHO Grade II/III) based on the knowledge of its molecular subgroups. The major consensus among attendees was reached that treatment decisions for ependymoma (outside of clinical trials) should not be based on grading (II vs III). Supratentorial and posterior fossa ependymomas are distinct diseases, although the impact on therapy is still evolving. Molecular subgrouping should be part of all clinical trials he...
Source: Acta Neuropathologica - November 17, 2016 Category: Neurology Source Type: research

Differences in T cell cytotoxicity and cell death mechanisms between progressive multifocal leukoencephalopathy, herpes simplex virus encephalitis and cytomegalovirus encephalitis
AbstractDuring the appearance of human immunodeficiency virus infection in the 1980 and the 1990s, progressive multifocal leukoencephalopathy (PML), a viral encephalitis induced by the JC virus, was the leading opportunistic brain infection. As a result of the use of modern immunomodulatory compounds such as Natalizumab and Rituximab, the number of patients with PML is once again increasing. Despite the presence of PML over decades, little is known regarding the mechanisms leading to death of infected cells and the role the immune system plays in this process. Here we compared the presence of inflammatory T cells and the t...
Source: Acta Neuropathologica - November 5, 2016 Category: Neurology Source Type: research

Genomics and CSF analyses implicate thyroid hormone in hippocampal sclerosis of aging
We report evidence of a novel pathogenetic mechanism in which thyroid hormone dysregulation contributes to dementia in elderly persons. Two single nucleotide polymorphisms (SNPs) on chromosome 12p12 were the initial foci of our study: rs704180 and rs73069071. These SNPs were identified by separate research groups as risk alleles for non-Alzheimer ’s neurodegeneration. We found that the rs73069071 risk genotype was associated with hippocampal sclerosis (HS) pathology among people with the rs704180 risk genotype (National Alzheimer’s Coordinating Center/Alzheimer’s Disease Genetic Consortium data;n =&n...
Source: Acta Neuropathologica - November 4, 2016 Category: Neurology Source Type: research

Multimodal evaluation demonstrates in vivo 18 F-AV-1451 uptake in autopsy-confirmed corticobasal degeneration
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - November 4, 2016 Category: Neurology Source Type: research

UK Iatrogenic Creutzfeldt –Jakob disease: investigating human prion transmission across genotypic barriers using human tissue-based and molecular approaches
We report a comprehensive, tissue-based and molecular genetic analysis of the largest series of UK hGH-iCJD cases reported to date, including in vitr o kinetic molecular modelling of genotypic factors influencing prion transmission. The results show the interplay of prion strain and host genotype in governing the molecular, pathological and temporal characteristics of the UK hGH-iCJD epidemic and provide insights into the adaptive mechanisms invo lved when prions cross genotypic barriers. We conclude that all of the available evidence is consistent with the hypothesis that the UK hGH-iCJD epidemic resulted from transmissio...
Source: Acta Neuropathologica - November 3, 2016 Category: Neurology Source Type: research

Polymorphous low-grade neuroepithelial tumor of the young (PLNTY): an epileptogenic neoplasm with oligodendroglioma-like components, aberrant CD34 expression, and genetic alterations involving the MAP kinase pathway
In this report, we describe a morphologically and molecularly distinct epileptogenic neoplasm, the polymorphous low-grade neuroepithelial tumor of the young (PLNTY), which likely accounts for a sizable portion of oligodendroglioma-like tumors affecting the pediatric population. Characteristic microscopic findings most notably include infiltrative growth, the invariable presence of oligodendroglioma-like cellular components, and intense immunolabeling for cluster of differentiation 34 (CD34). Moreover, integrative molecular profiling reveals a distinct DNA methylation signature for PLNTYs, along with frequent genetic abnorm...
Source: Acta Neuropathologica - November 3, 2016 Category: Neurology Source Type: research

Slow expansion of multiple sclerosis iron rim lesions: pathology and 7  T magnetic resonance imaging
AbstractIn multiple sclerosis (MS), iron accumulates inside activated microglia/macrophages at edges of some chronic demyelinated lesions, forming rims. In susceptibility-based magnetic resonance imaging at 7  T, iron-laden microglia/macrophages induce a rim of decreased signal at lesion edges and have been associated with slowly expanding lesions. We aimed to determine (1) what lesion types and stages are associated with iron accumulation at their edges, (2) what cells at the lesion edges accumulate ir on and what is their activation status, (3) how reliably can iron accumulation at the lesion edge be detected by 7&n...
Source: Acta Neuropathologica - October 27, 2016 Category: Neurology Source Type: research

Depletion of TDP-43 decreases fibril and plaque β-amyloid and exacerbates neurodegeneration in an Alzheimer’s mouse model
AbstractTDP-43 proteinopathy, initially associated with ALS and FTD, is also found in 30 –60% of Alzheimer’s disease (AD) cases and correlates with worsened cognition and neurodegeneration. A major component of this proteinopathy is depletion of this RNA-binding protein from the nucleus, which compromises repression of non-conserved cryptic exons in neurodegenerative diseases. To te st whether nuclear depletion of TDP-43 may contribute to the pathogenesis of AD cases with TDP-43 proteinopathy, we examined the impact of depletion of TDP-43 in populations of neurons vulnerable in AD, and on neurodegeneration in a...
Source: Acta Neuropathologica - October 26, 2016 Category: Neurology Source Type: research

Reduced vascular amyloid burden at microhemorrhage sites in cerebral amyloid angiopathy
AbstractMicrohemorrhages are strongly associated with advanced cerebral amyloid angiopathy (CAA). Although it has been frequently proposed that the deposition of A β in the walls of cortical vessels directly causes microhemorrhages, this has not been studied in great detail, mainly because the ruptured vessels are often missed on routine histopathologic examination. Here, we examined histopathological data from studies targeting microhemorrhages with high-res olution ex vivo 7 T MRI in nine cases with moderate-to-severe CAA, and assessed the presence of Aβ in the walls of involved vessels. We also assessed the de...
Source: Acta Neuropathologica - October 22, 2016 Category: Neurology Source Type: research

Soluble pre-fibrillar tau and β-amyloid species emerge in early human Alzheimer’s disease and track disease progression and cognitive decline
AbstractPost-mortem investigations of human Alzheimer ’s disease (AD) have largely failed to provide unequivocal evidence in support of the original amyloid cascade hypothesis, which postulated deposition of β-amyloid (Aβ) aggregates to be the cause of a demented state as well as inductive to tau neurofibrillary tangles (NFTs). Conflicting evidence suggests, however, that Aβ plaques and NFTs, albeit to a lesser extent, are present in a substantial subset of non-demented individuals. Hence, a range of soluble tau and Aβ species has more recently been implicated as the disease-relevant toxic entitie...
Source: Acta Neuropathologica - October 21, 2016 Category: Neurology Source Type: research

Deep sequencing reveals persistence of cell-associated mumps vaccine virus in chronic encephalitis
AbstractRoutine childhood vaccination against measles, mumps and rubella has virtually abolished virus-related morbidity and mortality. Notwithstanding this, we describe here devastating neurological complications associated with the detection of live-attenuated mumps virus Jeryl Lynn (MuVJL5) in the brain of a child who had undergone successful allogeneic transplantation for severe combined immunodeficiency (SCID). This is the first confirmed report of MuVJL5 associated with chronic encephalitis and highlights the need to exclude immunodeficient individuals from immunisation with live-attenuated vaccines. The diagnosis wa...
Source: Acta Neuropathologica - October 21, 2016 Category: Neurology Source Type: research