Pathogenic implications of distinct patterns of iron and zinc in chronic MS lesions
AbstractMultiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) in which oligodendrocytes, the CNS cells that stain most robustly for iron and myelin are the targets of injury. Metals are essential for normal CNS functioning, and metal imbalances have been linked to demyelination and neurodegeneration. Using a multidisciplinary approach involving synchrotron techniques, iron histochemistry and immunohistochemistry, we compared the distribution and quantification of iron and zinc in MS lesions to the surrounding normal appearing and periplaque white matter, and assessed th...
Source: Acta Neuropathologica - March 22, 2017 Category: Neurology Source Type: research

Axonal transport deficits in multiple sclerosis: spiraling into the abyss
AbstractThe transport of mitochondria and other cellular components along the axonal microtubule cytoskeleton plays an essential role in neuronal survival. Defects in this system have been linked to a large number of neurological disorders. In multiple sclerosis (MS) and associated models such as experimental autoimmune encephalomyelitis (EAE), alterations in axonal transport have been shown to exist before neurodegeneration occurs. Genome-wide association (GWA) studies have linked several motor proteins to MS susceptibility, while neuropathological studies have shown accumulations of proteins and organelles suggestive for...
Source: Acta Neuropathologica - March 17, 2017 Category: Neurology Source Type: research

Ultrasensitive and selective detection of 3-repeat tau seeding activity in Pick disease brain and cerebrospinal fluid
AbstractThe diagnosis and treatment of diseases involving tau-based pathology such as Alzheimer disease and certain frontotemporal dementias is hampered by the inability to detect pathological forms of tau with sufficient sensitivity, specificity and practicality. In these neurodegenerative diseases, tau accumulates in self-seeding filaments. For example, Pick disease (PiD) is associated with frontotemporal degeneration and accumulation of 3-repeat (3R) tau isoforms in filaments constituting Pick bodies. Exploiting the self-seeding activity of tau deposits, and using a 3R tau fragment as a substrate, we have developed an a...
Source: Acta Neuropathologica - March 13, 2017 Category: Neurology Source Type: research

Shared genetic risk between corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia
AbstractCorticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and a subset of frontotemporal dementia (FTD) are neurodegenerative disorders characterized by tau inclusions in neurons and glia (tauopathies). Although clinical, pathological and genetic evidence suggests overlapping pathobiology between CBD, PSP, and FTD, the relationship between these disorders is still not well understood. Using summary statistics (odds ratios andp values) from large genome-wide association studies (totaln = 14,286 cases and controls) and recently established genetic methods, we investigated the genetic overlap bet...
Source: Acta Neuropathologica - March 6, 2017 Category: Neurology Source Type: research

Proteomic differences in amyloid plaques in rapidly progressive and sporadic Alzheimer ’s disease
AbstractRapidly progressive Alzheimer ’s disease (rpAD) is a particularly aggressive form of Alzheimer’s disease, with a median survival time of 7–10 months after diagnosis. Why these patients have such a rapid progression of Alzheimer’s disease is currently unknown. To further understand pathological differences between rpAD a nd typical sporadic Alzheimer’s disease (sAD) we used localized proteomics to analyze the protein differences in amyloid plaques in rpAD and sAD. Label-free quantitative LC–MS/MS was performed on amyloid plaques microdissected from rpAD and sAD patients (n&nb...
Source: Acta Neuropathologica - March 3, 2017 Category: Neurology Source Type: research

Adult infiltrating gliomas with WHO 2016 integrated diagnosis: additional prognostic roles of ATRX and TERT
AbstractThe “integrated diagnosis” for infiltrating gliomas in the 2016 revised World Health Organization (WHO) classification of tumors of the central nervous system requires assessment of the tumor forIDH mutations and 1p/19q codeletion. SinceTERT promoter mutations and ATRX alterations have been shown to be associated with prognosis, we analyzed whether these tumor markers provide additional prognostic information within each of the five WHO 2016 categories. We used data for 1206 patients from the UCSF Adult Glioma Study, the Mayo Clinic and The Cancer Genome Atlas (TCGA) with infiltrative glioma, grades II-...
Source: Acta Neuropathologica - March 1, 2017 Category: Neurology Source Type: research

Misfolded SOD1 is not a primary component of sporadic ALS
AbstractA common feature of inherited and sporadic ALS is accumulation of abnormal proteinaceous inclusions in motor neurons and glia. SOD1 is the major protein component accumulating in patients with SOD1 mutations, as well as in mutant SOD1 mouse models. ALS-linked mutations of SOD1 have been shown to increase its propensity to misfold and/or aggregate. Antibodies specific for monomeric or misfolded SOD1 have detected misfolded SOD1 accumulating predominantly in spinal cord motor neurons of ALS patients with SOD1 mutations. We now use seven different conformationally sensitive antibodies to misfolded human SOD1 (includin...
Source: Acta Neuropathologica - February 27, 2017 Category: Neurology Source Type: research

Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS -associated amyotrophic lateral sclerosis
AbstractMotor neuron-extrinsic mechanisms have been shown to participate in the pathogenesis of ALS-SOD1, one familial form of amyotrophic lateral sclerosis (ALS). It remains unclear whether such mechanisms contribute to other familial forms, such as TDP-43 and FUS-associated ALS. Here, we characterize a single-copy mouse model of ALS-FUS that conditionally expresses a disease-relevant truncating FUS mutant from the endogenous murineFus gene. We show that these mice, but not mice heterozygous for aFus null allele, develop similar pathology as ALS-FUS patients and a mild motor neuron phenotype. Most importantly, CRE-mediate...
Source: Acta Neuropathologica - February 27, 2017 Category: Neurology Source Type: research

Genome-wide association study identifies four novel loci associated with Alzheimer ’s endophenotypes and disease modifiers
AbstractMore than 20 genetic loci have been associated with risk for Alzheimer ’s disease (AD), but reported genome-wide significant loci do not account for all the estimated heritability and provide little information about underlying biological mechanisms. Genetic studies using intermediate quantitative traits such as biomarkers, or endophenotypes, benefit from increased s tatistical power to identify variants that may not pass the stringent multiple test correction in case–control studies. Endophenotypes also contain additional information helpful for identifying variants and genes associated with other aspe...
Source: Acta Neuropathologica - February 27, 2017 Category: Neurology Source Type: research

Genetic confirmation that ependymoma can arise as part of multiple endocrine neoplasia type 1 (MEN1) syndrome
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - February 24, 2017 Category: Neurology Source Type: research

Axonal disruption in white matter underlying cortical sulcus tau pathology in chronic traumatic encephalopathy
AbstractChronic traumatic encephalopathy (CTE) is a progressive degenerative disorder associated with repetitive traumatic brain injury. One of the primary defining neuropathological lesions in CTE, based on the first consensus conference, is the accumulation of hyperphosphorylated tau in gray matter sulcal depths. Post-mortem CTE studies have also reported myelin loss, axonal injury and white matter degeneration. Currently, the diagnosis of CTE is restricted to post-mortem neuropathological analysis. We hypothesized that high spatial resolution advanced diffusion MRI might be useful for detecting white matter microstructu...
Source: Acta Neuropathologica - February 17, 2017 Category: Neurology Source Type: research

Prion-specific and surrogate CSF biomarkers in Creutzfeldt-Jakob disease: diagnostic accuracy in relation to molecular subtypes and analysis of neuropathological correlates of p-tau and A β42 levels
AbstractThe differential diagnosis of Creutzfeldt-Jakob disease (CJD) from other, sometimes treatable, neurological disorders is challenging, owing to the wide phenotypic heterogeneity of the disease. Real-time quaking-induced prion conversion (RT-QuIC) is a novel ultrasensitive in vitro assay, which, at variance with surrogate neurodegenerative biomarker assays, specifically targets the pathological prion protein (PrPSc). In the studies conducted to date in CJD, cerebrospinal fluid (CSF) RT-QuIC showed good diagnostic sensitivity (82 –96%) and virtually full specificity. In the present study, we investigated the dia...
Source: Acta Neuropathologica - February 14, 2017 Category: Neurology Source Type: research

Mixed pathologies including chronic traumatic encephalopathy account for dementia in retired association football (soccer) players
AbstractIn retired professional association football (soccer) players with a past history of repetitive head impacts, chronic traumatic encephalopathy (CTE) is a potential neurodegenerative cause of dementia and motor impairments. From 1980 to 2010, 14 retired footballers with dementia were followed up regularly until death. Their clinical data, playing career, and concussion history were prospectively collected. Next-of-kin provided consent for six to have post-mortem brain examination. Of the 14 male participants, 13 were professional and 1 was a committed amateur. All were skilled headers of the ball and had played foot...
Source: Acta Neuropathologica - February 14, 2017 Category: Neurology Source Type: research

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 8, 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 7, 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 2, 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 26, 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 26, 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 26, 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 24, 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 19, 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 16, 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 15, 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 12, 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 11, 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 10, 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 9, 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 9, 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 8, 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 6, 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 6, 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 4, 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 4, 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 27, 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 25, 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 22, 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 22, 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 20, 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 20, 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 19, 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 19, 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 16, 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 16, 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 7, 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 7, 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 - November 30, 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 28, 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 27, 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 24, 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 23, 2016 Category: Neurology Source Type: research